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WO2024263637A1 - Combination therapy with peptide receptor radionuclide and dna repair inhibitor - Google Patents

Combination therapy with peptide receptor radionuclide and dna repair inhibitor Download PDF

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Publication number
WO2024263637A1
WO2024263637A1 PCT/US2024/034612 US2024034612W WO2024263637A1 WO 2024263637 A1 WO2024263637 A1 WO 2024263637A1 US 2024034612 W US2024034612 W US 2024034612W WO 2024263637 A1 WO2024263637 A1 WO 2024263637A1
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Prior art keywords
integrin
peptide
amino acid
peg
cancer
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French (fr)
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Julie L. SUTCLIFFE
Tanushree GANGULY
Rebecca Harris
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University of California Berkeley
University of California San Diego UCSD
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University of California Berkeley
University of California San Diego UCSD
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • pancreatic ductal adenocarcinoma (PDAC) remains the fourth leading cause of cancer-related deaths, with a 5-y survival below 10% (R.L. Siegel, K.D. Miller KD & A. Jemal, CA Cancer J Clin 68 (2016): 7; J.K. Thomas, et al., Cancer Biol. Ther.15, (2014):963). Therefore, there clearly remains an urgent unmet clinical need for more effective molecularly targeted diagnostics and therapeutics.
  • the heterodimeric transmembrane receptor integrin ⁇ v ⁇ 6 has been identified as a potential molecular target; it is an epithelium-specific cell surface receptor that is undetectable in healthy adult epithelium but is significantly upregulated in a wide range of epithelium-derived cancers, including PDAC (A.S. Berghoff et al., Clin. Exp. Metastasis 31, (2014): 841; M.D. Allen, J.F. Marshall & J.L. Jones, Cancer Res. 74, (2014): 5942–5947; G.Y. Yang et al., World J. Gastroenterol. 21, (2015): 7457; J. Niu J & Z. Li, Cancer Lett.
  • ⁇ v ⁇ 6 integrin was initially identified in PDAC with nearly uniform high expression among patient samples screened; moreover, metastatic lesions demonstrate further highly upregulated expression of ⁇ v ⁇ 6 integrin when compared with the primary tumor, and ⁇ v ⁇ 6 integrin is undetectable in normal pancreas (C.S. Reader et al., J. Pathol. 249, (2019): 332). These traits further underscore the potential of ⁇ v ⁇ 6 integrin as an attractive target for targeted delivery of a therapeutic payload in PDAC. [0003] The practice of radiotheranostics combines molecular imaging with targeted radionuclide therapy, often using the same targeting ligand, and has shown efficacy in several cancers (K.
  • the disclosure provides a system including a DNA repair enzyme inhibitor and a peptide conjugate.
  • the peptide conjugate includes an integrin-binding peptide and a radionuclide.
  • the disclosure provides a composition, e.g., a pharmaceutical composition, including any of the systems disclosed herein.
  • the disclosure provides a cell, e.g., a mammalian cell or a human cell, including any of the systems disclosed herein.
  • the disclosure provides a method of preventing or treating an integrin- related disease in a subject.
  • the method includes administering to the subject a therapeutically effective amount of a DNA repair enzyme inhibitor.
  • the method further includes administering to the subject a therapeutically effective dose of a peptide conjugate.
  • the peptide conjugate includes an integrin-binding peptide and a radionuclide.
  • FIG.3 presents a graph plotting tumor volume in mice bearing Capan-1 tumors measured up to 16 days after start of study, i.e., day 0 of Olaparib treatment. Mice in Groups 2 and 4 received 50 mg/kg Olaparib once/day on days 0-6. Mice in Groups 3 and 4 received a single dose of 1 mCi 177 Lu-1 on day 1. Mice in Group 1 received saline (vehicle) on day 1.
  • FIG. 4A-B presents graphs showing cell viability and cell cycle analysis.
  • B Cell cycle analysis of all groups at 72 h after start of treatment.
  • FIG. 5A-D presents graphs with cell cycle analysis data. Complete analysis of all groups at 24 h (A) and 48 h (B) after start of treatment; G2/M fraction for all groups at 72 h after start of treatment (C); and Sub-G 1 fraction over time for all groups (D). [0015] FIG.
  • the present disclosure describes products and methods that include a combination of an inhibitor of a DNA repair enzyme, and a conjugate of an integrin-binding peptide and a radionuclide.
  • the combination is demonstrated as providing significant advantages as a molecularly targeted therapy for integrin-related diseases and disorders.
  • the DNA repair enzyme inhibitor and peptide conjugate are surprisingly effective in treating or preventing integrin-related cancers.
  • Results presented in the examples herein show that the peptide conjugate of the combination can prime a patient to have a beneficially increased response to the DNA repair enzyme, such as a poly (ADP-ribose) polymerase (PARP) inhibitor.
  • PARP poly (ADP-ribose) polymerase
  • administering refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to the subject.
  • a slow-release device e.g., a mini-osmotic pump
  • amino acid includes naturally-occurring ⁇ -amino acids and their stereoisomers, as well as unnatural amino acids and their stereoisomers.
  • “Stereoisomers” of amino acids refers to mirror image isomers of the amino acids, such as L-amino acids or D-amino acids.
  • a stereoisomer of a naturally-occurring amino acid refers to the mirror image isomer of the naturally-occurring amino acid, i.e., the D-amino acid.
  • Naturally-occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., ⁇ -carboxyglutamate and O-phosphoserine.
  • Naturally- occurring ⁇ -amino acids include, without limitation, alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), arginine (Arg), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), and combinations thereof.
  • Stereoisomers of a naturally-occurring ⁇ -amino acids include, without limitation, D-alanine (D-Ala), D-cysteine (D-Cys), D-aspartic acid (D-Asp), D-glutamic acid (D- Glu), D-phenylalanine (D-Phe), D-histidine (D-His), D-isoleucine (D-Ile), D-arginine (D-Arg), D- lysine (D-Lys), D-leucine (D-Leu), D-methionine (D-Met), D-asparagine (D-Asn), D-proline (D- Pro), D-glutamine (D-Gln), D-serine (D-Ser), D-threonine (D-Thr), D-valine (D-Val), D- tryptophan (D-Trp), D-tyrosine (D-Tyr), and combinations thereof.
  • Unnatural amino acids include, without limitation, amino acid analogs, amino acid mimetics, synthetic amino acids, N-substituted glycines, and N-methyl amino acids in either the L- or D-configuration that function in a manner similar to the naturally-occurring amino acids.
  • amino acid analogs are unnatural amino acids that have the same basic chemical structure as naturally-occurring amino acids, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, but have modified R (i.e., side-chain) groups.
  • Non-limiting examples of unnatural amino acids include 1-aminocyclopentane-1- carboxylic acid (Acp), 1-aminocyclobutane-1-carboxylic acid (Acb), 1-aminocyclopropane-1- carboxylic acid (Acpc), citrulline (Cit), homocitrulline (HoCit), ⁇ -aminohexanedioic acid (Aad), 3-(4-pyridyl)alanine (4-Pal), 3-(3-pyridyl)alanine (3-Pal), propargylglycine (Pra), ⁇ - aminoisobutyric acid (Aib), ⁇ -aminobutyric acid (Abu), norvaline (Nva), ⁇ , ⁇ -diaminopropionic acid (Dpr), ⁇ , ⁇ -diaminobutyric acid (Dbu), ⁇ -tert-butylglycine (Bug), 3,5-dinitrot
  • amino acid mimetics are chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that function in a manner similar to a naturally-occurring amino acid. Suitable amino acid mimetics include, without limitation, ⁇ -amino acids and ⁇ -amino acids. In ⁇ -amino acids, the amino group is bonded to the ⁇ -carbon atom of the carboxyl group such that there are two carbon atoms between the amino and carboxyl groups.
  • ⁇ -amino acids the amino group is bonded to the ⁇ -carbon atom of the carboxyl group such that there are three carbon atoms between the amino and carboxyl groups.
  • Suitable R groups for ⁇ - or ⁇ -amino acids include, but are not limited to, side-chains present in naturally-occurring amino acids and unnatural amino acids.
  • N-substituted glycines are unnatural amino acids based on glycine, where an amino acid side-chain is attached to the glycine nitrogen atom.
  • Suitable amino acid side-chains include, but are not limited to, side chains present in naturally-occurring amino acids and side-chains present in unnatural amino acids such as amino acid analogs.
  • N-substituted glycines include N-(2-aminoethyl)glycine, N-(3-aminopropyl)glycine, N-(2- methoxyethyl)glycine, N-benzylglycine, (S)-N-(1-phenylethyl)glycine, N- cyclohexylmethylglycine, N-(2-phenylethyl)glycine, N-(3-phenylpropyl)glycine, N-(6- aminogalactosyl)glycine, N-(2-(3′-indolylethyl)glycine, N-(2-(p-methoxyphenylethyl))glycine, N
  • N-substituted glycine oligomers referred to herein as “peptoids,” have been shown to be protease resistant (see, e.g., Miller et al., Drug Dev. Res., 35:20-32 (1995)).
  • Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.
  • an L-amino acid may be represented herein by its commonly known three letter symbol (e.g., Arg for L-arginine) or by an upper-case one-letter amino acid symbol (e.g., R for L-arginine).
  • a D-amino acid may be represented herein by its commonly known three letter symbol (e.g., D-Arg for D-arginine) or by a lower-case one-letter amino acid symbol (e.g., r for D-arginine).
  • D-Arg for D-arginine
  • r for D-arginine
  • amino acid sequences one of skill in the art will recognize that individual substitutions, additions, or deletions to a peptide, polypeptide, or protein sequence which alters, adds, or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a “conservatively modified variant” where the alteration results in the substitution of an amino acid with a chemically similar amino acid.
  • the chemically similar amino acid includes, without limitation, a naturally-occurring amino acid such as an L-amino acid, a stereoisomer of a naturally occurring amino acid such as a D-amino acid, and an unnatural amino acid such as an amino acid analog, amino acid mimetic, synthetic amino acid, N-substituted glycine, and N-methyl amino acid.
  • a naturally-occurring amino acid such as an L-amino acid
  • a stereoisomer of a naturally occurring amino acid such as a D-amino acid
  • an unnatural amino acid such as an amino acid analog, amino acid mimetic, synthetic amino acid, N-substituted glycine, and N-methyl amino acid.
  • Conservative substitution tables providing functionally similar amino acids are well known in the art. For example, substitutions may be made wherein an aliphatic amino acid (e.g., G, A, I, L, or V) is substituted with another member of the group.
  • an aliphatic polar- uncharged group such as C, S, T, M, N, or Q
  • basic residues e.g., K, R, or H
  • an amino acid with an acidic side chain e.g., E or D
  • its uncharged counterpart e.g., Q or N, respectively; or vice versa.
  • Each of the following eight groups contains other exemplary amino acids that are conservative substitutions for one another (see, e.g., Creighton, Proteins, 1993): 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M).
  • composition refers to a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • a “pharmaceutical composition” or “pharmaceutically acceptable composition” is one in which each ingredient, e.g., a carrier, diluent, or excipient, is compatible with the other ingredients of a formulation composition and not deleterious to the recipient thereof.
  • conjugate refers to a chemical compound that has been formed by the joining or attachment of two or more compounds.
  • a conjugate can comprise a peptide as described herein (e.g., an integrin-binding peptide) and a radionuclide. Therefore, in the context of the present disclosure, a conjugate may be referred to as a “peptide conjugate.”
  • a conjugate may be referred to as a “peptide conjugate.”
  • the term “integrin” refers to a class of cell surface receptor proteins. Such class of proteins are heterodimers, which contain two different chains, called ⁇ subunit and ⁇ subunit respectively.
  • Non-limiting examples of integrins include ⁇ 1 ⁇ 1 , ⁇ 2 ⁇ 1 , ⁇ 3 ⁇ 1 , ⁇ 4 ⁇ 1 , ⁇ 5 ⁇ 1 , ⁇ 6 ⁇ 1 , ⁇ 7 ⁇ 1, ⁇ 8 ⁇ 1, ⁇ 9 ⁇ 1, ⁇ 10 ⁇ 1, ⁇ 11 ⁇ 1, ⁇ v ⁇ 1, ⁇ v ⁇ 3, ⁇ v ⁇ 5, ⁇ v ⁇ 6, ⁇ v ⁇ 8, ⁇ IIb ⁇ 3, ⁇ 4 ⁇ 7, ⁇ E ⁇ 7, ⁇ 6 ⁇ 4, ⁇ L ⁇ 2, ⁇ M ⁇ 2, ⁇ X ⁇ 2, ⁇ D ⁇ 2, etc.
  • peptide refers to a polymer made up of a single chain of D- or L-amino acids or a mixture of D- and L-amino acids joined by covalent peptide bonds.
  • integrin-binding peptide and “binds to an integrin,” and variations thereof, refer to the binding/interaction of a peptide which shows the capacity of specific interaction with a specific integrin or a specific group of integrins.
  • the terms refer to the ability of a peptide or a portion thereof to interact with and/or bind to a target integrin (e.g., ⁇ v ⁇ 6 integrin) without cross-reacting with molecules of similar sequences or structures.
  • a peptide specifically binds to a target integrin when it binds to the target integrin with a substantially lower dissociation constant (i.e., tighter binding) than a molecule of similar sequence or structure.
  • a specific binding occurs when the peptide binds to the target integrin with an about 2, 3, 4, 5, 6, 8, 10, 15, 20, 25, 30, 40, 50, 100, or 1000-fold or greater affinity than a related molecule.
  • the binding of the peptide to a site on the target integrin may occur via intermolecular forces such as ionic bonds, hydrogen bonds, hydrophobic interactions, dipole-dipole bonds, and/or Van der Waals forces.
  • Cross- reactivity may be tested, for example, by assessing binding of the peptide under conventional conditions to the target integrin as well as to a number of more or less (e.g., structurally and/or functionally) closely related molecules.
  • RGD peptide refers to the binding/interaction of a peptide motif in a conjugate described herein which shows the capacity of specific interaction with ⁇ v ⁇ 6 integrin.
  • the RGD peptide interacts with and/or binds to ⁇ v ⁇ 6 integrin without cross- reacting with molecules of similar sequences or structures. In some instances, the RGD peptide specifically binds to ⁇ v ⁇ 6 integrin when it binds with a substantially lower dissociation constant (i.e., tighter binding) than a molecule of similar sequence or structure.
  • pharmaceutically acceptable carrier and “pharmaceutically acceptable excipient” refer to a substance that aids the administration of an active agent to and absorption by a subject and may be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject.
  • Non-limiting examples of pharmaceutically acceptable excipients and carriers include water, NaCl, normal saline solutions, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, and the like.
  • pharmaceutically acceptable excipients and carriers include water, NaCl, normal saline solutions, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, and the like.
  • PEG polyethylene glycol
  • Suitable polyethylene glycols may have a free hydroxyl group at each end of the polymer molecule, or may have one or more hydroxyl groups etherified with a lower alkyl, e.g., a methyl group. Also suitable are derivatives of polyethylene glycols having carboxy groups or amide groups.
  • Polyethylene glycols useful in the present invention can be polymers of any chain length or molecular weight, and can include branching, the details of which are provided herein.
  • PEGylation refers to the process of covalently coupling a polyethylene glycol (PEG) molecule to another molecule, e.g., an RGD peptide, which is then referred to as “PEGylated.”
  • PEG polyethylene glycol
  • RGD peptide may be PEGylated at both the amino-terminus and the carboxyl terminus with monodisperse PEG molecules having a defined chain length to generate bi-terminal PEGylated peptide conjugates.
  • Monodisperse PEG molecules typically comprise discrete molecular weights with an exactly defined number of repeating ethylene glycol units.
  • PEG moieties suitable for use are commercially available from Polypure AS (Oslo, Norway), which supplies monodisperse PEG molecules and PEG derivatives thereof consisting of substantially one oligomer only (e.g., greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% oligomer purity).
  • the RGD peptide is PEGylated at both ends with a single type or mixtures of different types of monodisperse PEG moieties having a molecular weight of less than about 5,000 Daltons (Da) (e.g., less than about 5,000, 4,000, or 3,000 Da), such as, e.g., PEG11, PEG12 (PEG 800), PEG28 (PEG 1500), and/or (PEG 28 ) 2 (PEG 1500 ⁇ 2).
  • Da Daltons
  • a “nuclide” is a type of atom specified by its atomic number, atomic mass, and energy state, such as carbon 14 ( 14 C).
  • Radioactivity refers to the radiation, including alpha particles, beta particles, nucleons, electrons, positrons, neutrinos, and gamma rays, emitted by a radioactive substance.
  • radionuclides suitable for use in the conjugates described herein include, but are not limited to, tritium ( 3 H), fluorine 18 ( 18 F), phosphorus 32 ( 32 P), sulfur 35 ( 35 S), scandium 47 ( 47 Sc), cobalt 55 ( 55 Co), copper 60 ( 60 Cu), copper 61 ( 61 Cu), copper 62 ( 62 Cu), copper 64 ( 64 Cu), gallium 66 ( 66 Ga), copper 67 ( 67 Cu), gallium 67 ( 67 Ga), gallium 68 ( 68 Ga), rubidium 82 ( 82 Rb), yttrium 86 ( 86 Y), yttrium 87 ( 87 Y), strontium 89 ( 89 Sr), strontium 90 ( 90 Sr), yttrium 90 ( 90 Y), rhodium 105 ( 105 Rh), silver 111 ( 111 Ag), indium 111 ( 111 In), iodine 124 ( 124 I), iodine 125 ( 125 I), i
  • the “m” in 117m Sn and 99m Tc stands for the meta state.
  • radioactive elements such as uranium, radium, and thorium, which typically represent mixtures of radioisotopes, are suitable examples of radionuclides.
  • 67 Cu, 131 I, 177 Lu, and 186 Re are beta- and gamma-emitting radionuclides.
  • 212 Bi is an alpha- and beta- emitting radionuclide.
  • 3 H, 32 P, 35 S, 47 Sc, 89 Sr, 90 Sr, 90 Y, 105 Rh, 111 Ag, 117m Sn, 149 Pm, 153 Sm, 166 Ho, and 188 Re are examples of beta-emitting radionuclides.
  • 67 Ga, 111 In, 99m Tc, 137 Cs, and 201 Tl are examples of gamma-emitting radionuclides.
  • 55 Co, 60 Cu, 61 Cu, 62 Cu, 66 Ga, 68 Ga, 82 Rb, and 86 Y are examples of positron-emitting radionuclides.
  • 64 Cu is a beta- and positron- emitting radionuclide.
  • the term “subject” refers to a vertebrate, and preferably to a mammal.
  • Mammalian subjects for which the provided composition is suitable include, but are not limited to, mice, rats, simians, humans, farm animals, sport animals, and pets.
  • the subject is human.
  • the subject is male.
  • the subject is female.
  • the subject is an adult.
  • the subject is an adolescent.
  • the subject is a child.
  • the subject is above 10 years of age, e.g., above 20 years of age, above 30 years of age, above 40 years of age, above 50 years of age, above 60 years of age, above 70 years of age, or above 80 years of age. In some embodiments, the subject is less than 80 years of age, e.g., less than 70 years of age, less than 60 years of age, less than 50 years of age, less than 40 years of age, less than 30 years of age, less than 20 years of age, or less than 10 years of age.
  • the term “therapeutically effective amount” refers to an amount or dose of a compound, composition, or formulation that produces therapeutic effects for which it is administered.
  • the terms “treat,” “treating,” and “treatment” refer to a procedure resulting in any indicia of success in the elimination or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of one or more symptoms.
  • the treatment or amelioration of symptoms can be based on any objective or subjective parameter, including, e.g., the result of a physical examination or laboratory test.
  • the terms “including,” “comprising,” “having,” “containing,” and variations thereof, are inclusive and open-ended and do not exclude additional, unrecited elements or method steps beyond those explicitly recited.
  • the phrase “consisting of” is closed and excludes any element, step, or ingredient not explicitly specified.
  • the phrase “consisting essentially of” limits the scope of the described feature to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the disclosed feature.
  • a DNA repair ezyme inhibitor optionally includes a combination of two or more DNA repair enzyme inhibitors, and the like.
  • the term “about” denotes a range of value that is +/- 10% of a specified value. For instance, “about 10” denotes the value range of 9 to 11 (10 +/- 1). III. Systems and Pharmaceutical Compositions [0041] In one aspect, the present disclosure provides various systems that include a DNA repair enzyme inhibitor and a peptide conjugate.
  • the particular selections and relative amounts of these components provide the system with surprisingly improved characteristics, especially when the system is used as a therapy for the treatment or prevention of integrin-related disorders, such as integrin-related cancers.
  • the provided systems are demonstrated herein as exhibiting substantially greater therapeutic efficacy against integrin-related cancers than the efficacy of either the DNA repair enzyme inhibitor or the peptide conjugate alone.
  • the relative amounts of the DNA repair enzyme inhibitor and the peptide conjugate in the system can be selected to provide the system with its advantageous therapeutic properties.
  • the ratio of the amount of the DNA repair enzyme inhibitor to the amount of radioactivity of the peptide conjugate in the system can be between about 5 ⁇ g of the inhibitor per mCi of the conjugate, and about 150 mg of the inhibitor per mCi of the conjugate, e.g., between about 5 ⁇ g per mCi and about 2.4 mg per mCi, between about 14 ⁇ g per mCi and about 6.8 mg per mCi, between about 39 ⁇ g per mCi and about 19 mg per mCi, between about 110 ⁇ g per mCi and about 54 mg per mCi, or about 310 ⁇ g per mCi and about 150 mg per mCi.
  • the ratio of the DNA repair enzyme inhibitor to the peptide conjugate can be, for example, less than about 150 mg per mCi, e.g., less than about 54 mg per mCi, less than about 19 mg per mCi, less than about 6.8 mg per mCi, less than about 2.4 mg per mCi, less than about 870 ⁇ g per mCi, less than about 310 ⁇ g per mCi, less than about 110 ⁇ g per mCi, less than about 39 ⁇ g per mCi, or less than about 14 ⁇ g per mCi.
  • the ratio of the DNA repair enzyme inhibitor to the peptide conjugate can be, for example, greater than about 5 ⁇ g per mCi, e.g., greater than about 14 ⁇ g per mCi, greater than about 39 ⁇ g per mCi, greater than about 110 ⁇ g per mCi, greater than about 310 ⁇ g per mCi, greater than about 870 ⁇ g per mCi, greater than about 2.4 mg per mCi, greater than about 6.8 mg per mCi, greater than about 19 mg per mCi, or greater than about 54 mg per mCi.
  • the provided systems generally include a DNA repair enzyme inhibitor.
  • the system includes only one species of DNA repair enzyme inhibitor.
  • the system can include two or more structurally and/or functionally different species of DNA repair enzyme inhibitors.
  • a provided system can include, for example, two or more different species of DNA repair enzyme inhibitors, e.g., three or more, four or more, five or more, six or more, seven or more, seven or more, eight or more, nine or more, or ten or more.
  • DNA repair enzyme inhibitors are compounds that interfere with the activity of enzymes that are involved in repairing damaged DNA.
  • DNA damage can occur due to various factors, such as exposure to radiation, chemicals, oxidative stress, replication errors and spontaneous hydrolysis. DNA damage can lead to mutations, chromosomal aberrations and genomic instability, which can compromise cell functions and viability, and contribute to various diseases, especially cancer. Accordingly, DNA repair mechanisms can be important for maintaining genome integrity and preventing disease.
  • DNA repair mechanisms can also pose a challenge for cancer therapy, as they can protect tumor cells from the cytotoxic effects of DNA-damaging agents, such as radiation and chemotherapy. These therpaeutic agents can be used to induce DNA double-strand breaks (DSBs), which are the most lethal form of DNA damage.
  • DSBs DNA double-strand breaks
  • DSBs can be repaired by two major pathways: homologous recombination (HR) and non-homologous end joining (NHEJ).
  • HR homologous recombination
  • NHEJ non-homologous end joining
  • HR requires a sister chromatid as a template and is active during the S and G2 phases of the cell cycle.
  • NHEJ directly ligates the broken ends without a template and is active throughout the cell cycle.
  • DNA-PK DNA-dependent protein kinase
  • DNA-PKcs catalytic subunit
  • Ku70–Ku80 heterodimer Ku70–Ku80 heterodimer.
  • DNA-PKcs is a serine/threonine kinase that phosphorylates itself and other proteins involved in NHEJ, such as XRCC4, Ligase IV and Artemis. DNA-PKcs also regulates cell cycle checkpoints and apoptosis in response to DNA damage. DNA-PKcs is overexpressed in many tumor cells and is associated with resistance to radiation and chemotherapy. [0047] Another important enzyme involved in DNA repair is poly(ADP-ribose) polymerase (PARP), which is abundant and ubiquitous in the nucleus of cells. PARP detects and signals single- strand breaks (SSBs) in DNA, which can arise from various sources or be intermediates of other repair pathways.
  • PARP poly(ADP-ribose) polymerase
  • DNA repair enzyme inhibitors are agents designed or selected for their ability to block the activity of these enzymes and sensitize tumor cells to DNA-damaging agents. For example, by inhibiting DNA-PKcs, NHEJ is impaired and DSBs accumulate in tumor cells, leading to cell death or genomic instability.
  • PARP inhibitors can sensitize cells to DNA damage from treatments such as radiotherapy (N.J. Curtin et al., Mol. Asp. Med. 34, (2013): 1217) by inhibiting repair mechanisms and increasing the number of DNA double strand breaks.
  • DNA repair enzyme inhibitors can exploit the synthetic lethality between different repair pathways and selectively kill tumor cells while sparing normal cells.
  • DNA repair enzyme inhibitors suitable for use with the provided systems can include, for example, DNA-PKcs inhibitors, PARP inhibitors, alkylating agents, novobiocin, APE1 inhibitors, RAD51 inhibitors, ATM inhibitors, Ataxia Telangiectasia and Rad3-related protein (ATR) inhibitors, O6-methylguanine-DNA methyltransferase (MGMT) inhibitors, DNA ligase inhibitors, ERCC1-XPF endonuclease inhibitors, Werner syndrome RecQ helicase (WRN) inhibitors, DNA glycolase inhibitors, Fanconi anemia complementation group M protein (FANCM) inhibitors, and combinations thereof.
  • DNA-PKcs inhibitors for use with the provided systems
  • PARP inhibitors can include, for example, DNA-PKcs inhibitors, PARP inhibitors, alkylating agents, novobiocin, APE1 inhibitors, RAD51 inhibitors, ATM inhibitors, Ataxia Telangiectasia and Rad3-related
  • the DNA repair enzyme inhibitor of the provided system includes or consists of one or more PARP inhibitors.
  • PARP inhibitors suitable for use in the provided systems include those described by Rose et al, Front. Cell Dev. Biol. 8, (2020): 564601, which is incorporated herein by reference.
  • the PARP inhibitor of the provided system includes or consists of olaparib (3-aminobenzamide, 4-(3-(1-(cyclopropanecarbonyl)piperazine-4-carbonyl)-4- fluorobenzyl)phthalazin-1(2H)-one; AZD-2281; AstraZeneca).
  • the PARP inhibitor of the provided system includes or consists of rucaparib (6-fluoro-2-[4- (methylaminomethyl)phenyl]-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraen-9-one; Clovis Oncology, Inc.).
  • the PARP inhibitor of the provided system includes or consists of niraparib tosylate ((S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide hydrochloride; MK-4827; GSK).
  • the PARP inhibitor of the provided system includes or consists of talazoparib (11S,12R)-7-fluoro-11-(4-fluorophenyl)-12-(2-methyl- 1,2,4-triazol-3-yl)-2,3,10-triazatricyclo[7.3.1.05,13]trideca-1,5(13),6,8-tetraen-4-one; BMN-673; Pfizer).
  • the PARP inhibitor of the provided system includes or consists of fluzoparib (4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7- carbonyl]phenyl]methyl]-2H-phthalazin-1-one; Jiangsu Hengrui Pharmaceuticals).
  • the PARP inhibitor of the provided system includes or consists of veliparib (2- [(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide dihydrochloride benzimidazole carboxamide; ABT-888; Abbvie).
  • the PARP inhibitor of the provided system includes or consists of pamiparib (2R)-14-fluoro-2-methyl-6,9,10,19- tetrazapentacyclo[14.2.1.02,6.08,18.012,17]nonadeca-1(18),8,12(17),13,15-pentaen-11-one; BGB-290; BeiGene).
  • the PARP inhibitor of the provided system includes or consists of CEP-8983 and/or CEP 9722, a small-molecule prodrug of CEP-8983, a 4-methoxy- carbazole inhibitor (CheckPoint Therapeutics).
  • the PARP inhibitor of the provided system includes or consists of E7016 (Eisai), In some embodiments, the PARP inhibitor of the provided system includes or consists of PJ34 (2-(dimethylamino)-N-(6-oxo-5H- phenanthridin-2-yl)acetamide;hydrochloride). In some embodiments, the PARP inhibitor of the provided system includes or consists of 3-aminobenzamide. In some embodiments, the PARP inhibitor of the provided system includes or consists of any combination of the PARP inhibitors described herein. 2. Peptide conjugates [0051] The provided systems further generally include a peptide conjugate. In some embodiments, the system includes only one species of peptide conjugate.
  • the system can include two or more structurally and/or functionally different species of peptide conjugates.
  • a provided system can include, for example, two or more different species of peptide conjugates, e.g., three or more, four or more, five or more, six or more, seven or more, seven or more, eight or more, nine or more, or ten or more.
  • a) Integrin-binding peptides [0052]
  • the peptide conjugates of the provided systems generally include an integrin-binding peptide.
  • the integrins are a superfamily of cell adhesion receptors that bind to extracellular matrix ligands, cell-surface ligands, and soluble ligands.
  • Integrins are transmembrane ⁇ heterodimers and at least 18 ⁇ and eight ⁇ subunits are known in humans, generating 24 heterodimers.
  • the ⁇ and ⁇ subunits have distinct domain structures, with extracellular domains from each subunit contributing to the ligand-binding site of the heterodimer.
  • Non-limiting examples of integrins include ⁇ 1 ⁇ 1 , ⁇ 2 ⁇ 1 , ⁇ 3 ⁇ 1 , ⁇ 4 ⁇ 1 , ⁇ 5 ⁇ 1 , ⁇ 6 ⁇ 1 , ⁇ 7 ⁇ 1 , ⁇ 8 ⁇ 1 , ⁇ 9 ⁇ 1 , ⁇ 10 ⁇ 1 , ⁇ 11 ⁇ 1 , ⁇ v ⁇ 1 , ⁇ v ⁇ 3 , ⁇ v ⁇ 5 , ⁇ v ⁇ 6 , ⁇ v ⁇ 8 , ⁇ IIb ⁇ 3, ⁇ 4 ⁇ 7, ⁇ E ⁇ 7, ⁇ 6 ⁇ 4, ⁇ L ⁇ 2, ⁇ M ⁇ 2, ⁇ X ⁇ 2, ⁇ D ⁇ 2, and combinations thereof.
  • the integrin bound by the integrin-binding peptide is ⁇ v ⁇ 3 integrin, ⁇ IIb ⁇ 3 integrin, or ⁇ v ⁇ 6 integrin.
  • the integrin-binding peptide binds to (e.g., targets) ⁇ v ⁇ 6 integrin.
  • ⁇ v ⁇ 6 integrin which is a receptor for fibronectin, tenascin, vitronectin, the latency associated peptide (LAP) of TGF- ⁇ , and viral capsid protein (VP1) of foot-and-mouth disease virus (FMDV), is expressed at very low or undetectable levels in only a subset of epithelial cells in normal adult tissues (Breuss et al., J. Cell Sci. 108, (1995): 2241). However, ⁇ v ⁇ 6 integrin expression is increased dramatically during development, following injury or inflammation, or in a variety of epithelial neoplasms.
  • keratinocytes show de novo expression of ⁇ v ⁇ 6 integrin in both oral and skin wounds (Breuss et al., J. Cell Sci. 108, (1995): 2241; Clark et al., Am. J. Path. 148, (1996): 1407).
  • ⁇ v ⁇ 6 integrin plays an active role in tumor invasion because its expression is often higher at the invasive margins of oral squamous cell carcinomas.
  • ⁇ v ⁇ 6 integrin is an attractive target for therapy of diseases or disorders such as pancreatic cancer, oral cancer, ovarian cancer, breast cancer, and colon cancer.
  • the integrin-binding peptide of the peptide conjugate is an RGD peptide that is selective for binding ⁇ v ⁇ 6 integrin.
  • the peptide comprises the RGD motif, RGDLX 1 X 2 X 3 (SEQ ID NO:50), where X 1 and X 2 are independently selected amino acids, and X3 is L or I.
  • the peptide comprises the RGD motif, RGDLX1X2X3 (SEQ ID NO:51), where X1 and X2 are independently selected from the group consisting of Glu, Ala, Leu, Met, Gln, Lys, Arg, Val, Ile, His, Thr, Trp, Phe, and Asp.
  • X 1 is Q
  • X 2 is V
  • X 3 is L.
  • the RGD peptide does not comprise any alanine residues.
  • the RGD peptide is between 8 and 40 amino acids. In some cases, the RGD peptide is more than 20 amino acids. In some cases, the RGD peptide is 21 amino acids.
  • the integrin-binding peptide includes the sequence RGDLX1X2LX4X5X6 (SEQ ID NO:52), wherein X1, X2, X4, X5, and X6 are independently selected amino acids.
  • X1, X2, X4, X5, and X6 are helix-promoting residues.
  • the helix- promoting residues can comprise naturally-occurring amino acids or unnatural amino acids such as artificial or modified amino acids.
  • the helix-promoting residues can be independently selected from the group consisting of Glu, Ala, Leu, Met, Gln, Lys, Arg, Val, Ile, His, Thr, Trp, Phe, and Asp.
  • the integrin-binding peptide includes the sequence RGDLX 1 X 2 LX 4 X 5 X 6 (SEQ ID NO:53), wherein X 1 , X 2 , X 4 , X 5 , and X 6 are independently selected from the group consisting of Glu, Ala, Leu, Met, Gln, Lys, Arg, Val, Ile, His, Thr, Trp, Phe, and Asp.
  • the integrin-binding peptide includes, from N- to C-terminus: an N-terminal segment comprising one or more amino acids which enhance hydrophobic interactions with a helix defined from LX1X2L and also enhances the RGD domain for binding, the sequence RGDLX 1 X 2 LX 4 X 5 X 6 (SEQ ID NO:54), and a C-terminal segment comprising one or more helix- promoting amino acids.
  • the N-terminal segment comprising between 1 and 35 amino acids.
  • the C-terminal segment comprises between 1 and 35 amino acids.
  • the length of the N-terminal segment is selected so that it is sufficiently long to facilitate a hydrophobic/non-covalent interacting core.
  • the exact nature of these residues depends on the general design of the region. In particular, it is preferred to have a mixture of hydrophobic interactions (from residues such as Val, Ile, Leu) and/or electrostatic interactions (using Asp, Glu, Lys, and/or Arg together with their counterpart ion-pair at X 1 and/or X2).
  • the integrin-binding peptide includes the amino acid sequence RGDLX 1 X 2 X 3 AQX 6 (SEQ ID NO:55), wherein X 6 is Lys (K) or Arg (R).
  • X6 is R.
  • X1 and X2 are independently selected amino acids
  • X3 is L or I.
  • the peptide comprises the RGD motif, RGDLX1X2X3AQX6 (SEQ ID NO:56), where X 1 and X 2 are independently selected from the group consisting of Glu, Ala, Leu, Met, Gln, Lys, Arg, Val, Ile, His, Thr, Trp, Phe, and Asp.
  • X1 is Q
  • X2 is V
  • X3 is L.
  • the integrin-binding peptide includes or consists of an amino acid sequence selected from the group consisting of NAVPNLRGDLQVLAQKVART (SEQ ID NO: 1), NAVPNLRGDLQVLAQRVART (SEQ ID NO: 2), GNGVPNLRGDLQVLGQRVGRT (SEQ ID NO: 3), GFTTGRRGDLATIHGMNRPF (SEQ ID NO: 4), YTASARGDLAHLTTTHARHL (SEQ ID NO: 5), and combinations thereof.
  • NAVPNLRGDLQVLAQKVART SEQ ID NO: 1
  • NAVPNLRGDLQVLAQRVART SEQ ID NO: 2
  • GNGVPNLRGDLQVLGQRVGRT SEQ ID NO: 3
  • GFTTGRRGDLATIHGMNRPF SEQ ID NO: 4
  • YTASARGDLAHLTTTHARHL SEQ ID NO: 5
  • the integrin-binding peptide includes or consists of an amino acid sequence selected from the group consisting of NAVPNLRGDLQVLAQKVART (SEQ ID NO: 1), NAVPNLRGDLQVLAQRVART (SEQ ID NO: 2), and GNGVPNLRGDLQVLGQRVGRT (SEQ ID NO: 3).
  • the RGD peptide comprises QX7VX8RT (SEQ ID NO:57) that is positioned C-terminally to the RGD motif, wherein X7 is R or K and X8 is A or G.
  • the RGD peptide comprises the amino acid sequence QRVGRT (SEQ ID NO: 6) positioned C- terminal to the RGD motif. In some cases, the RGD peptide includes the amino acid sequence RGDLQVLGQRVGRT (SEQ ID NO: 7). In certain embodiments, the RGD peptide includes or consists of the amino acid sequence GNGVPNLRGDLQVLGQRVGRT (SEQ ID NO: 3).
  • the integrin-binding peptide includes the amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:58-61), where m and n are independently 0 or 1; and X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are independently selected amino acids, provided that X 3 is not Q when X 4 is V.
  • the integrin-binding peptide includes the amino acid sequence RSD or VGD, e.g., the integrin-binding peptide includes the sequence RSDLTPLF (SEQ ID NO: 8), RSDLTPLFK (SEQ ID NO: 9), VGDLTYLK (SEQ ID NO: 10), VGDLTYLKK (SEQ ID NO: 11), or any of the integrin-binding peptide sequences disclosed in International Patent Application Publication Nos. WO 2015/160770, WO 2017/218569, and WO 2020/051549, each of which are incorporated herein by reference in their entirety.
  • the integrin-binding peptide includes amino acid sequences from N- to C-terminus X1X2DLX3X4LX5 and (Q)nKVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids where subscript n is 0 or 1; and X1, X2, X 3 , X 4 , and X 5 ,are independently selected amino acids, provided that X 3 is not Q when X 4 is V.
  • the integrin-binding peptide includes an amino acid sequences GX1X2DLX3X4LX5 (SEQ ID NO:64) and (Q)nKVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids, where); subscript n is 0 or 1; and X1, X2, X3, X4, and X5 are independently selected amino acids, provided that X3 is not Q when X4 is V.
  • the integrin-binding peptide includes an amino acid sequence X 1 X 2 DLX 3 X 4 LX 5 (X 6 ) m (Q) n KVART (SEQ ID NOs:58-61), where subscripts m and n are independently 0 or 1; and X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are independently selected amino acids, provided that X3 is not Q when X4 is V.
  • an integrin-binding peptide can include an amino acid sequence GX 1 X 2 DLX 3 X 4 LX 5 (X 6 ) m (Q) n KVART (SEQ ID NOs:65-68), where subscripts m and n are independently 0 or 1; and X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are independently selected amino acids, provided that X3 is not Q when X4 is V.
  • the integrin-binding peptide includes the amino acid sequences, from N- to C-terminus, X 1 X 2 DLX 3 X 4 LX 5 and_(Q) n KVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids, where X1 is an amino acid residue selected from the group consisting of E, D, G, A, I, L, M, C, Q, N, V, K, R, H, S, T, W, and F. In some embodiments, X 1 is an amino acid residue selected from the group consisting of G, A, I, L, M, C, V, K, R, and H.
  • X1 is an amino acid residue selected from the group consisting of V and R.
  • the integrin-binding peptide includes the amino acid sequences, from N- to C-terminus, X 1 X 2 DLX 3 X 4 LX 5 and (Q) n KVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids, where X2 is an amino acid residue selected from the group consisting of G, A, N, I, L, M, C, Q, E, D, K, R, V, H, S, T, W, F, and Y.
  • X2 is an amino acid residue selected from the group consisting of G, A, N, I, L, Q, E, D, V, S, and T.
  • X 2 is an amino acid residue selected from the group consisting of G, S, and T.
  • the integrin- binding peptide includes the amino acid sequences, from N- to C-terminus, X1X2DLX3X4LX5 and (Q) n KVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids, where X1 is V and X2 is G. In some embodiments, X1 is V and X2 is S.
  • X1 is V and X2 is T. In some embodiments, X1 is R and X2 is G. In some embodiments, X 1 is R and X 2 is S. In some embodiments, X 1 is R and X 2 is T.
  • the integrin-binding peptide includes the amino acid sequences, from N- to C-terminus, X1X2DLX3X4LX5 and (Q)nKVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids, where X3 is an amino acid residue selected from the group consisting of T, S, N, Q, M, C, V, L, I, A, G, R, H, K, Y, F, E, D, W, and P, provided that X3 is not Q when X4 is V.
  • X3 is an amino acid residue selected from the group consisting of T, S, M, C, V, L, I, A, G, R, K, Y, F, E, D, W, and P. In some embodiments, X 3 is an amino acid residue selected from the group consisting of T, M, A, R, Y, D, G, and P.
  • the integrin-binding peptide includes the amino acid sequences, from N- to C-terminus, X1X2DLX3X4LX5 and (Q)nKVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids, wherein X 4 is an amino acid residue selected from the group consisting of Y, W, K, H, R, D, E, P, G, A, C, M, V, I, L, N, Q, S, T, and F, provided that X4 is not V when X3 is Q.
  • X4 is an amino acid residue selected from the group consisting of Y, W, K, R, H, D, E, Q, N, P, S, and F.
  • X 4 is an amino acid residue selected from the group consisting of Y, K, D, E, P, S, R, and F.
  • the integrin-binding peptide includes the amino acid sequences, from N- to C-terminus, X1X2DLX3X4LX5 and (Q)nKVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids, where X 3 is T and X 4 is Y.
  • X 3 is T and X 4 is P. In some embodiments, X 3 is M and X 4 is K. In some embodiments, X3 is A and X4 is D. In some embodiments, X3 is R and X4 is E. In some embodiments, X 3 is Y and X 4 is K. In some embodiments, X 3 is P and X 4 is F. In some embodiments, X 3 is D and X 4 is S. In some embodiments, X 3 is G and X 4 is R.
  • the integrin-binding peptide includes the amino acid sequences, from N- to C-terminus X1X2DLX3X4LX5 and (Q)nKVART (SEQ ID NOs:62-63, immediately adjacent to each other or separated by 1 to 20, or more amino acids, where X 5 is an amino acid residue selected from the group consisting of K, H, A, G, P, I, L, V, R, F, Y, C, S, T, M, Q, N, E, D, and W. In some embodiments, X5 is an amino acid residue selected from the group consisting of K, A, G, R, F, Y, Q, N, E, D, C, and W.
  • X 5 is an amino acid residue selected from the group consisting of K, A, R, F, Q, C, and W.
  • the integrin- binding peptide includes the amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:69-70), where subscript m is 1 and X 6 is an amino acid residue selected from the group consisting of H, R, K, T, and Y. In some embodiments, subscript m is 1 and X 6 is an amino acid residue selected from the group consisting of R, K, T, and Y. In some embodiments, subscript m is 1 and X6 is amino acid residue K, T, and Y.
  • the integrin-binding peptide includes the amino acid sequence X 1 X 2 DLX 3 X 4 LX 5 (X 6 ) m (Q) n KVART (SEQ ID NOs:69-70), where X5 is K, subscript m is 1, and X6 is K. In some embodiments, X5 is K, subscript m is 1, and X6 is R. In some embodiments, X5 is A, subscript m is 1, and X6 is K. In some embodiments, X5 is A, subscript m is 1, and X 6 is R. In some embodiments, X 5 is A, subscript m is 1, and X 6 is Y.
  • X 5 is A, subscript m is 1, and X 6 is T.
  • X 5 is R, subscript m is 1, and X6 is K.
  • X5 is R, subscript m is 1, and X6 is T.
  • X 5 is R, subscript m is 1, and X 6 is Y.
  • X 5 is R, subscript m is 1, and X 6 is R.
  • X 5 is F, subscript m is 1, and X 6 is K.
  • X5 is F, subscript m is 1, and X6 is R.
  • X5 is Q, subscript m is 1, and X6 is K. In some embodiments, X5 is Q, subscript m is 1, and X6 is R. In some embodiments, X 5 is C, subscript m is 1, and X 6 is Y. In some embodiments, X 5 is C, subscript m is 1, and X6 is K. In some embodiments, X5 is C, subscript m is 1, and X6 is T. In some embodiments, X5 is C, subscript m is 1, and X6 is R. In some embodiments, X5 is W, subscript m is 1, and X 6 is K.
  • X 5 is W
  • subscript m is 1
  • X 6 is R.
  • the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:71-74), where subscripts m and n are independently 0 or 1;
  • X 1 is an amino acid residue selected from the group consisting of E, D, G, A, I, L, M, C, Q, N, V, K, R, H, S, T, W, and F;
  • X 2 is an amino acid residue selected from the group consisting of G, A, N, I, L, M, C, Q, E, D, K, R, V, H, S, T, W, F, and Y;
  • X3 is an amino acid residue selected from the group consisting of T, S, N, Q, M, C, V, L, I, A, G, R, H, K, Y, F, E
  • the integrin-binding peptide includes an amino acid sequence GX 1 X 2 DLX 3 X 4 LX 5 (X 6 ) m (Q) n KVART (SEQ ID NOs:75-78), where subscripts m and n are independently 0 or 1;
  • X 1 is an amino acid residue selected from the group consisting of E, D, G, A, I, L, M, C, Q, N, V, K, R, H, S, T, W, and F;
  • X2 is an amino acid residue selected from the group consisting of G, A, N, I, L, M, C, Q, E, D, K, R, V, H, S, T, W, F, and Y;
  • X3 is an amino acid residue selected from the group consisting of T, S, N, Q, M, C, V, L, I, A, G, R, H, K, Y, F, E, D, W, and P;
  • X4 is an amino acid residue selected
  • the integrin-binding peptide includes an amino acid sequence X 1 X 2 DLX 3 X 4 LX 5 (X 6 ) m (Q) n KVART, (SEQ ID NOs:79-82) where subscripts m and n are independently 0 or 1;
  • X1 is an amino acid residue selected from the group consisting of G, A, I, L, M, C, V, K, R, and H;
  • X2 is an amino acid residue selected from the group consisting of G, A, N, I, L, Q, E, D, V, S, and T;
  • X 3 is an amino acid residue selected from the group consisting of T, S, M, C, V, L, I, A, G, R, K, Y, F, E, D, W, and P;
  • X4 is an amino acid residue selected from the group consisting of Y, W, K, R, H, D, E, Q, N, P, S, and F;
  • X5 is an
  • the integrin-binding peptide includes an amino acid sequence GX 1 X 2 DLX 3 X 4 LX 5 (X 6 ) m (Q) n KVART (SEQ ID NOs:83-86), where subscripts m and n are independently 0 or 1;
  • X 1 is an amino acid residue selected from the group consisting of G, A, I, L, M, C, V, K, R, and H;
  • X2 is an amino acid residue selected from the group consisting of G, A, N, I, L, Q, E, D, V, S, and T;
  • X 3 is an amino acid residue selected from the group consisting of T, S, M, C, V, L, I, A, G, R, K, Y, F, E, D, W, and P;
  • X 4 is an amino acid residue selected from the group consisting of Y, W, K, R, H, D, E, Q, N, P, S, and F;
  • X5 is an
  • the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:87-90), where subscripts m and n are independently 0 or 1;
  • X 1 is an amino acid residue selected from the group consisting of V and R;
  • X2 is an amino acid residue selected from the group consisting of G, S, and T;
  • X3 is an amino acid residue selected from the group consisting of T, M, A, R, Y, D, G, and P;
  • X4 is an amino acid residue selected from the group consisting of Y, K, D, E, P, S, R, and F;
  • X 5 is an amino acid residue selected from the group consisting of K, A, R, F, Q, C, and W; and
  • X6 is K, T, and Y when m is 1.
  • the integrin-binding peptide includes an amino acid sequence GX1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:91-94), where subscripts m and n are independently 0 or 1;
  • X1 is an amino acid residue selected from the group consisting of V and R;
  • X 2 is an amino acid residue selected from the group consisting of G, S, and T;
  • X 3 is an amino acid residue selected from the group consisting of T, M, A, R, Y, D, G, and P;
  • X 4 is an amino acid residue selected from the group consisting of Y, K, D, E, P, S, R, and F;
  • X5 is an amino acid residue selected from the group consisting of K, A, R, F, Q, C, and W; and
  • X6 is K, T, and Y when m is 1.
  • the integrin-binding peptide includes the amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:58-61), where subscripts m and n are independently 0 or 1. In some embodiments, subscript m is 0 or 1. In some embodiments, subscript m is 0. In some embodiments, subscript m is 1. In some embodiments, subscript n is 0 or 1. In some embodiments, subscript n is 0. In some embodiments, subscript n is 1.
  • the integrin-binding peptide includes the amino acid sequence X 1 X 2 DLX 3 X 4 LX 5 (X 6 ) m (Q) n KVART (SEQ ID NOs:58-61), where subscript m is 0 and subscript n is 0. In some embodiments, subscript m is 1 and subscript n is 1. In some embodiments, subscript m is 1 and subscript n is 0. In some embodiments, subscript m is 0 and subscript n is 1.
  • the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:95-96), where subscript m is 0 or 1; subscript n is 1; X1 is an amino acid residue selected from the group consisting of V and R; X2 is an amino acid residue selected from the group consisting of G, T, and S; X 3 is an amino acid residue selected from the group consisting of T, A, D, and G; X4 is an amino acid residue selected from the group consisting of Y, D, P, S and R; X5 is an amino acid residue selected from the group consisting of K, R, F, and A; and X 6 is an amino acid residue selected from the group consisting of K, T, and Y when m is 1.
  • the integrin-binding peptide includes an amino acid sequence GX 1 X 2 DLX 3 X 4 LX 5 (X 6 ) m (Q) n KVART (SEQ ID NOs:97-98), where subscript m is 0 or 1; subscript n is 1; X1 is an amino acid residue selected from the group consisting of V and R; X2 is an amino acid residue selected from the group consisting of G, T, and S; X3 is an amino acid residue selected from the group consisting of T, A, D, and G; X 4 is an amino acid residue selected from the group consisting of Y, D, P, S and R; X5 is an amino acid residue selected from the group consisting of K, R, F, and A; and X6 is an amino acid residue selected from the group consisting of K, T, and Y when m is 1.
  • the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:99-100), where subscript m is 1; subscript n is 1; X 1 is an amino acid residue selected from the group consisting of V and R; X 2 is an amino acid residue selected from the group consisting of G, T, and S; X 3 is an amino acid residue selected from the group consisting of T, A, D, and G; X4 is an amino acid residue selected from the group consisting of Y, D, P, S and R; X5 is an amino acid residue selected from the group consisting of K, R, F, and A; and X 6 is an amino acid residue selected from the group consisting of K, T, and Y.
  • the integrin- binding peptide includes an amino acid sequence X 1 X 2 DLX 3 X 4 LX 5 (X 6 ) m (Q) n KVART (SEQ ID NO:101), where subscript m is 1; subscript n is 1; X 1 is R; X 2 is G; X 3 is A; X 4 is D; X 5 is R; and X6 is K.
  • the integrin-binding peptide includes an amino acid sequence X 1 X 2 DLX 3 X 4 LX 5 (X 6 ) m (Q) n KVART (SEQ ID NO:102), where subscript m is 0; subscript n is 1; X1 is an amino acid residue selected from the group consisting of V and R; X2 is an amino acid residue selected from the group consisting of G, T, and S; X3 is an amino acid residue selected from the group consisting of T, A, D, and G; X 4 is an amino acid residue selected from the group consisting of Y, D, P, S and R; and X5 is an amino acid residue selected from the group consisting of K, R, F, and A.
  • the integrin-binding peptide includes an amino acid sequence GX 1 X 2 DLX 3 X 4 LX 5 (X 6 ) m (Q) n KVART (SEQ ID NO:103), where subscript m is 0; subscript n is 1; X1 is an amino acid residue selected from the group consisting of V and R; X2 is an amino acid residue selected from the group consisting of G, T, and S; X3 is an amino acid residue selected from the group consisting of T, A, D, and G; X 4 is an amino acid residue selected from the group consisting of Y, D, P, S and R; and X 5 is an amino acid residue selected from the group consisting of K, R, F, and A.
  • the integrin-binding peptide includes an amino acid sequence X 1 X 2 DLX 3 X 4 LX 5 (X 6 ) m (Q) n KVART (SEQ ID NO:104), where subscript m is 0; subscript n is 1; X 1 is an amino acid residue selected from the group consisting of V and R; X2 is an amino acid residue selected from the group consisting of G and S; X3 is an amino acid residue selected from the group consisting of T and A; X4 is an amino acid residue selected from the group consisting of Y, D, and P; and X 5 is an amino acid residue selected from the group consisting of K, R, and F.
  • the integrin-binding peptide includes an amino acid sequence X 1 X 2 DLX 3 X 4 LX 5 (X 6 ) m (Q) n KVART (SEQ ID NO: 12), where subscript m is 0; subscript n is 1; X1 is V; X2 is G; X3 is T; X4 is Y; and X5 is K.
  • the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NO:21), where subscript m is 0; subscript n is 1; X 1 is R; X 2 is G; X 3 is A; X 4 is D; and X 5 is R.
  • the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NO:33), where subscript m is 0; subscript n is 1; X1 is R; X2 is S; X3 is T; X4 is P; and X5 is F.
  • the integrin-binding peptide includes an amino acid sequence X 1 X 2 DLX 3 X 4 LX 5 (X 6 ) m (Q) n KVART (SEQ ID NO:36), where subscript m is 0; subscript n is 1; X1 is R; X2 is T; X3 is D; X4 is S; and X5 is R.
  • the integrin-binding peptide includes an amino acid sequence GX 1 X 2 DLX 3 X 4 LX 5 (X 6 ) m (Q) n KVART (SEQ ID NO:42), where subscript m is 0; subscript n is 1; X1 is R; X2 is G; X3 is G; X4 is R; and X5 is A.
  • the integrin-binding peptide includes an amino acid sequence selected from the group consisting of VGDLTYLKQKVART (SEQ ID NO: 12), VGDLTYLKKQKVART (SEQ ID NO: 13), VGDLTYLKKKVART (SEQ ID NO: 14), RGDLTYLKQKVART (SEQ ID NO: 15), RGDLTYLKKQKVART (SEQ ID NO: 16), RGDLTYLKKKVART (SEQ ID NO: 17), RGDLMKLAQKVART (SEQ ID NO: 18), RGDLMKLAKQKVART (SEQ ID NO: 19), RGDLMKLAKKVART (SEQ ID NO: 20), RGDLADLRQKVART (SEQ ID NO: 21), RGDLADLRKQKVART (SEQ ID NO: 22), RGDLADLRKKVART (SEQ ID NO: 23), RGDLRELAQKVART (SEQ ID NO: 24), RGDLREL
  • the integrin-binding peptide is about 4 to about 80 amino acids in length, about 4 to about 50 amino acids in length, about 5 to about 80 amino acids in length, about 5 to about 75 amino acids in length, about 5 to about 45 amino acids in length, about 6 to about 60 amino acids in length, about 6 to about 40 amino acids in length, about 8 to about 50 amino acids in length, about 8 to about 30 amino acids in length, about 10 to about 50 amino acids in length, about 10 to about 35 amino acids in length, about 12 to about 45 amino acids in length, about 12 to about 40 amino acids in length, about 13 to about 60 amino acids in length, about 13 to about 40 amino acids in length, about 14 to about 55 amino acids in length, about 14 to about 35 amino acids in length, about 15 to about 45 amino acids in length, or about 15 to about 25 amino acids in length.
  • the peptide can be about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, or more amino acids in length.
  • the peptide is about 10 to about 20 amino acids in length.
  • the peptide is about 13 amino acids in length.
  • the peptide is about 14 amino acids in length.
  • the peptide is about 15 amino acids in length.
  • the integrin-binding peptide used in the conjugates described herein can also be a functional variant of any of the peptides as defined above, including peptides that possess at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more sequence identity with the peptides described above.
  • the integrin-binding peptide includes naturally- occurring amino acids and/or unnatural amino acids.
  • unnatural amino acids include, but are not limited to, D-amino acids, ornithine, diaminobutyric acid ornithine, norleucine ornithine, pyridylalanine, thienylalanine, naphthylalanine, phenylglycine, alpha and alpha- disubstituted amino acids, N-alkyl amino acids, lactic acid, halide derivatives of naturally- occurring amino acids (e.g., trifluorotyrosine, p-Cl-phenylalanine, p-Br-phenylalanine, p-I- phenylalanine, etc.), L-allylglycine, b-alanine, L-a-amino butyric acid, L-g-amino butyric acid, L- a-amino isobutyric acid, L-e-amino caproic acid, 7-amino heptanoic acid, L
  • the integrin-binding peptide can be further modified.
  • one or more amide bonds of the peptide can be replaced by ester or alkyl backbone bonds.
  • the peptide can additionally or alternatively include N- or C-alkyl substituents, side-chain modifications, or constraints such as disulfide bridges or side-chain amide or ester linkages.
  • the integrin-binding peptide can be prepared using methods known in the art.
  • the integrin-binding peptide can be produced by chemical synthesis, e.g., using solid phase techniques and/or automated peptide synthesizers, or by recombinant means.
  • the integrin-binding peptide can be synthesized using solid phase strategies on an automated multiple peptide synthesizer using 9-fluorenylmethyloxycarbonyl (Fmoc) chemistry.
  • the peptide conjugates of the provided systems generally further include a radionuclide.
  • the radionuclide can be, for example, an alpha-, beta-, and/or gamma-emitting radionuclide.
  • the radionuclide of the peptide conjugate is 3 H, 18 F, 32 P, 35 S, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Ga, 67 Cu, 67 Ga, 68 Ga, 82 Rb, 86 Y, 87 Y, 89 Sr, 90 Sr, 90 Y, 105 Rh, 111 Ag, 111 In, 124 I, 125 I, 131 I, 117m Sn, 99m Tc, 137 Cs, 149 Pm, 153 Sm, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 166 Ho, 177 Lu, 186 Re, 188 Re, 201 Tl, 211 At, 215 At, 217 At, 218 At, 209 Bi, 211 Bi, 212 Bi, 213 Bi, 203 Pb, 212 Pb, 210 Po, 211 Po, 212 Po, 214 Po, 215 Po, 216 Po, 218 Po
  • the radionuclide is 32 P, 47 Sc, 67 Cu, 89 Sr, 90 Y, 105 Rh, 111 Ag, 117m Sn, 131 I, 149 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 211 At, or 212 Bi.
  • the radionuclide is 177 Lu.
  • the conjugate also includes one or more polyethylene glycol (PEG) moieties covalently attached to the integrin-binding peptide.
  • the PEG moiety is attached to a terminus of the peptide, i.e., the N-terminus or the C-terminus.
  • the conjugate includes two PEG moieties, e.g., one PEG moiety covalently attached to the N-terminus of the peptide and one PEG moiety covalently attached to the C-terminus of the peptide.
  • the PEG moiety covalently attached to a terminus of the peptide terminates in an amide, a carboxyl group, or a hydroxyl group.
  • the one or more PEG moieties of the conjugate each independently have a molecular weight of less than about 5000 Daltons (Da). In particular embodiments, the one or more PEG moieties each independently have a molecular weight of less than about 3000 Da.
  • the PEG moieties are monodisperse PEG moieties having a defined chain length.
  • PEG moieties having a defined chain length generally include PEG molecules of discrete molecular weights with an exactly defined number of repeating ethylene glycol units.
  • Non-limiting examples of PEG moieties having a defined chain length include small, monodisperse PEG molecules having greater than about 90%, 91%, 92%, 93%, 94%, or 95% oligomer purity.
  • the one or more PEG moieties of the conjugate are each independently selected from the group consisting of PEG11, PEG12 (PEG 800), PEG28 (PEG 1500), and (PEG28)2 (PEG 1500 ⁇ 2).
  • the PEG moieties are the same.
  • the PEG moieties are both PEG 28 (PEG 1500).
  • PEG units suitable for use as one or both PEG moieties include PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 900, PEG 1000, PEG 1100, PEG 1200, PEG 1300, PEG 1400, PEG 1600, PEG 1700, PEG 1800, PEG 1900, PEG 2000, PEG 2100, PEG 2200, PEG 2300, PEG 2400, PEG 2500, PEG 2600, PEG 2700, PEG 2800, PEG 2900, PEG 3000, PEG 3250, PEG 3350, PEG 3500, PEG 3750, PEG 4000, PEG 4250, PEG 4500, PEG 4750, and PEG 5000, as well as derivatives thereof such as branched PEG derivatives.
  • these PEG molecules contain an exactly defined number of repeating units “n” and are monodisperse (e.g., having greater than about 95% oligomer purity).
  • PEG moieties suitable for use are commercially available from EMD Chemicals, Inc. (San Diego, Calif.) and Polypure AS (Oslo, Norway).
  • the radionuclide of the conjugate is attached via a prosthetic group to the integrin-binding peptide, a first PEG moiety, or a second PEG moiety.
  • the radionuclide is attached via a prosthetic group to the first PEG moiety.
  • the radionuclide is attached via a prosthetic group as the most N- terminal moiety in the conjugate.
  • prosthetic groups include benzoyl groups (e.g., fluorobenzoic acid (FBA)), fluoropropionic acid (FPA), pyridine (Py), dipyridyl- tetrazine (Tz), trans-cyclooctene (TCO), derivatives thereof, and combinations thereof.
  • the radionuclide is covalently attached to the first PEG moiety via a benzoyl group such as FBA.
  • the conjugate further includes a chelating moiety.
  • the chelating moiety is a dodecane tetraacetic acid (DOTA) moiety (1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid) covalently attached to the conjugate.
  • the radionuclide is attached via a chelating moiety to the integrin-binding protein, a first PEG moiety, or a second PEG moiety.
  • the radionuclide is attached via a chelating moiety to the first PEG moiety.
  • the radionuclide is attached via a chelating agent as the most N-terminal moiety in the conjugate.
  • the conjugate includes an albumin binding moiety (ABM) covalently attached to the conjugate.
  • ABM albumin binding moiety
  • the ABM can increase the half-life of the conjugate in serum, such as when administered to a subject.
  • the ABM is covalently attached to the peptide, a first PEG moiety, or a second PEG moiety.
  • the ABM includes a linker, such as a peptide linker that is covalently attached to the integrin-binding peptide, a first PEG moiety, or a second PEG moiety.
  • the ABM comprises 4-(4- iodophenyl)butyric acid (IPA) or a homolog thereof with a shorter alkyl chain such as, e.g., 4-(4- iodophenyl)propionic acid or 4-(4-iodophenyl)acetic acid, or the ABM comprises 4-(4- methylphenyl)butyric acid or 4-(4-bromophenyl)butyric acid or a homolog thereof with a shorter alkyl chain such as, e.g., a propionic acid or acetic acid homolog thereof.
  • IPA 4-(4- iodophenyl)butyric acid
  • IPA 4-(4- iodophenyl)butyric acid
  • a homolog thereof with a shorter alkyl chain such as, e.g., 4-(4- iodophenyl)propionic acid or 4-(4-iodophenyl)acetic acid
  • the ABM is covalently attached to the first and/or second PEG moiety via a linker such as a glutamic acid (E) linker, a peptide linker such as a lysine-aspartic acid-aminobutyric acid (K-D-Abu) linker, or other suitable linker (e.g., amino acid or peptide linker) known to one of skill in the art.
  • a linker such as a glutamic acid (E) linker, a peptide linker such as a lysine-aspartic acid-aminobutyric acid (K-D-Abu) linker, or other suitable linker (e.g., amino acid or peptide linker) known to one of skill in the art.
  • the ABM includes an ⁇ -(4-(4-iodophenyl)butyl amide)lysine-glutamic acid moiety (“K(IPA)E”), which corresponds to IPA that is covalently attached to the side-chain of the lysine residue of a lysine-glutamic acid peptide linker.
  • the ABM includes a K(D-Abu-iodophenylbutyryl) moiety, which corresponds to IPA that is covalently attached to the aminobutyric acid of a lysine-aspartic acid-aminobutyric acid (K-D-Abu) peptide linker.
  • the ABM including the K(IPA)E or K(D-Abu-iodophenylbutyryl) moiety is covalently attached to the first PEG moiety.
  • the peptide conjugate has the structure of Formula (I):
  • the DNA repair enzyme inhibitor of the provided system is a component of a solution or composition, e.g., a pharmaceutical composition.
  • the peptide conjugate of the system is a component of a solution or composition, e.g., a pharmaceutical composition.
  • a single solution or composition e.g., a single pharmaceutical composition, includes both the DNA repair enzyme inhibitor and the peptide conjugate.
  • Such pharmaceutical compositions can include one or both of the DNA repair enzyme inhibitor and the peptide conjugate, together with one or more pharmaceutically- acceptable excipients, e.g., excipients suitable for injection and/or infusion.
  • the provided systems, or one or more individual components thereof, can thus be formulated, for example, as compositions for administration in the form of a liquid.
  • the liquid can be useful for delivery by injection, such as intratumoral injection, or intravenous infusion.
  • a surfactant such as intratumoral injection, or intravenous infusion.
  • the liquid compositions can also include one or more of the following: sterile diluents such as water for injection, saline solution (preferably physiological saline), Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which can serve as the solvent or suspending medium, polyethylene glycols, glycerin, cyclodextrin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as amino acids, acetates, citrates or phosphates; detergents, such as nonionic surfactants, polyols; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • sterile diluents such as water for injection, saline solution (preferably physiological saline), Ringer's solution, is
  • the liquid compositions can include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • Aqueous solutions in saline are also conventionally used for injection.
  • Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • compositions for administration are preferably sterile.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and thimerosal.
  • Compositions for administration can be enclosed in ampoule, a disposable syringe or a multiple- dose vial made of glass, plastic, or other material.
  • excipients for use with the provided pharmaceutical compositions include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline, syrup, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and polyacrylic acids such as Carbopols, e.g., Carbopol 941, Carbopol 980, Carbopol 981, etc.
  • Carbopols e.g., Carbopol 941, Carbopol 980, Carbopol 981, etc.
  • compositions can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying agents; suspending agents; preserving agents such as methyl-, ethyl-, and propyl-hydroxy-benzoates (i.e., the parabens); pH adjusting agents such as inorganic and organic acids and bases; sweetening agents; coloring agents; and flavoring agents.
  • the compositions can also comprise biodegradable polymer beads, dextran, and cyclodextrin inclusion complexes.
  • the compositions can be in the form of tablets, lozenges, capsules, emulsions, suspensions, solutions, syrups, sprays, powders, and sustained-release formulations.
  • Suitable excipients for oral administration include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • the pharmaceutical compositions take the form of a pill, tablet, or capsule, and thus, the composition can contain, along with the DNA repair enzyme inhibitor and peptide conjugate, any of the following: a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as starch or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof.
  • the systems can also be formulated into a suppository disposed, for example, in a polyethylene glycol (PEG) carrier.
  • Liquid compositions can be prepared by dissolving or dispersing the DNA repair enzyme inhibitor and peptide conjugate and optionally one or more pharmaceutically acceptable adjuvants in a carrier such as, for example, aqueous saline (e.g., 0.9% w/v sodium chloride), aqueous dextrose, glycerol, ethanol, and the like, to form a solution or suspension, e.g., for oral, topical, or intravenous administration.
  • a carrier such as, for example, aqueous saline (e.g., 0.9% w/v sodium chloride), aqueous dextrose, glycerol, ethanol, and the like, to form a solution or suspension, e.g., for oral, topical, or intravenous administration.
  • a carrier such as, for example, aque
  • the compositions herein can be in the form of emulsions, lotions, gels, creams, jellies, solutions, suspensions, ointments, and transdermal patches.
  • the composition can be delivered as a dry powder or in liquid form via a nebulizer.
  • the compositions can be in the form of sterile injectable solutions and sterile packaged powders.
  • injectable solutions are formulated at a pH of about 4.5 to about 7.5.
  • the compositions described herein can also be provided in a lyophilized form.
  • compositions can include a buffer, e.g., bicarbonate, for reconstitution prior to administration, or the buffer can be included in the lyophilized composition for reconstitution with, e.g., water.
  • the lyophilized composition can further comprise a suitable vasoconstrictor, e.g., epinephrine.
  • the lyophilized composition can be provided in a syringe, optionally packaged in combination with the buffer for reconstitution, such that the reconstituted composition can be immediately administered to a patient.
  • the provided pharmaceutical composition includes one or more unit doses, wherein the amount of radioactivity present in a dose is between about 25 mCi and about 200 mCi.
  • the amount of radioactivity present in a dose of the peptide conjugate is between about 25 mCi and about 50 mCi, about 25 mCi and about 100 mCi, about 25 mCi and about 150 mCi, about 25 mCi and about 200 mCi, about 50 mCi and about 100 mCi, about 50 mCi and about 150 mCi, about 50 mCi and about 200 mCi, about 100 mCi and about 150 mCi, about 100 mCi and about 200 mCi, or about 150 mCi and about 200 mCi.
  • the amount of radioactivity present in a unit dose is about 25 mCi, about 50 mCi, about 100 mCi, about 150 mCi or about 200 mCi. In some embodiments, the amount of radioactivity present within a dose (e.g., a therapeutically effective dose) is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mCi. In some embodiments, the amount of peptide conjugate in each unit dose is no more than about 500 ⁇ g, about 400 ⁇ g, about 300 ⁇ g, about 200 ⁇ g, or about 100 ⁇ g of peptide.
  • the amount of peptide conjugate in each unit dose is no more than about 100 ⁇ g. IV.
  • Methods for Treating or Preventing a Disease [0099]
  • the present disclosure provides various methods of preventing or treating a disease, e.g., an integrin-related disease, in a subject. The particular details and combinations of the steps of the methods have been shown to result in surprising improvements, such as unexpectedly high therapeutic efficacies in addressing integrin-related cancers.
  • the methods generally include administering to the subject a therapeutically effective amount or dose of any of the DNA repair enzyme inhibitors disclosed herein, and a therapeutically effective amount or dose of any of the peptide conjugates disclosed herein.
  • the DNA repair enzyme inhibitor is administered before the peptide conjugate.
  • the DNA repair enzyme inhibitor and the peptide conjugate are administered concurrently, e.g., in the same composition.
  • the treating of the disease in the subject includes decreasing or eliminating one or more signs or symptoms of the disease.
  • diseases or disorders suitable for treatment with the systems and compositions described herein include, but are not limited to, allergy, anxiety disorder, autoimmune disease, behavioral disorder, birth defect, blood disorder, bone disease, cancer, chronic fibrosis, chronic obstructive pulmonary disease (COPD), chronic wounding skin disease, circulatory disease, tooth disease, depressive disorder, dissociative disorder, ear condition, eating disorder, eye condition, food allergy, food-borne illness, gastrointestinal disease, genetic disorder, heart disease, hormonal disorder, immune deficiency, infectious disease, inflammatory disease, insect-transmitted disease, nutritional disorder, kidney disease, leukodystrophy, liver disease, lung emphysema, mental health disorder, metabolic disease, mood disorder, musculodegenerative disorder, neurological disorder, neurodegenerative disorder, neuromuscular disorder, personality disorder, phobia, pregnancy complication, prion disease, prostate disease, psychological disorder, psychiatric disorder, respiratory disease, sexual disorder, skin condition, sleep disorder, speech-language disorder, sports injury, tropical disease, vestibular disorder, and
  • the ⁇ v ⁇ 6 integrin-mediated disease or disorder is cancer, an inflammatory disease, an autoimmune disease, chronic fibrosis, chronic obstructive pulmonary disease (COPD), lung emphysema, and chronic wounding skin disease (e.g., epidermolysis bullosa).
  • cancer generally includes any of various malignant neoplasms characterized by the proliferation of anaplastic cells that tend to invade surrounding tissue and metastasize to new body sites.
  • Non-limiting examples of different types of cancer suitable for treatment using the provided systems or compositions include ovarian cancer, breast cancer, lung cancer, bladder cancer, thyroid cancer, liver cancer, pleural cancer, pancreatic cancer, cervical cancer, prostate cancer, testicular cancer, colorectal cancer, colon cancer, anal cancer, bile duct cancer, gastrointestinal carcinoid tumors, esophageal cancer, gall bladder cancer, rectal cancer, appendix cancer, small intestine cancer, stomach (gastric) cancer, renal cancer (i.e., renal cell carcinoma), cancer of the central nervous system, skin cancer, oral squamous cell carcinoma, choriocarcinomas, head and neck cancers, bone cancer, osteogenic sarcomas, fibrosarcoma, neuroblastoma, glioma, melanoma, leukemia (e.g., acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia
  • the cancer is an ⁇ v ⁇ 6 integrin-mediated disease or disorder.
  • the cancer is lung cancer, breast cancer, colorectal cancer, pancreatic cancer, ovarian cancer, cervical cancer, oral squamous cell carcinoma, skin squamous cell carcinoma, stomach cancer, or endometrial cancer.
  • the subject has a primary lesion (e.g., a primary tumor).
  • the subject has a metastasis (e.g., a metastatic form of any of the cancer types described herein).
  • the subject has a primary lesion and a metastasis.
  • the subject has a pancreatic cancer such as locally advanced or metastatic pancreatic cancer, locally advanced, unresectable or metastatic pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma (PDAC).
  • a pancreatic cancer such as locally advanced or metastatic pancreatic cancer, locally advanced, unresectable or metastatic pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma (PDAC).
  • PDAC pancreatic ductal adenocarcinoma
  • Suitable anti-cancer agents for combination therapy include, without limitation, cytotoxins and agents such as antimetabolites, alkylating agents, anthracyclines, antibiotics, antimitotic agents, procarbazine, hydroxyurea, asparaginase, corticosteroids, interferons, radiopharmaceuticals, peptides with anti- tumor activity such as TNF- ⁇ , pharmaceutically acceptable salts thereof; derivatives thereof, prodrugs thereof, and combinations thereof.
  • a pharmaceutical composition comprising the provided DNA repair enzyme inhibitor and/or peptide conjugate can be administered to a patient before, during, or after administration of an anti-cancer agent or combination of anti-cancer agents either before, during, or after chemotherapy.
  • Treatment with the DNA repair enzyme inhibitor and/or peptide conjugate after chemotherapy can be particularly useful for reducing and/or preventing recurrence of the tumor or metastasis.
  • the anti-cancer agent can be covalently linked directly or indirectly (e.g., via liposomes or nanoparticles) to a peptide conjugate as described herein.
  • Inflammatory diseases typically include diseases or disorders characterized or caused by inflammation. Inflammation can result from a local response to cellular injury that is marked by capillary dilatation, leukocytic infiltration, redness, heat, and pain that serves as a mechanism initiating the elimination of noxious agents and damaged tissue.
  • the site of inflammation can include, for example, the lungs, the pleura, a tendon, a lymph node or gland, the uvula, the vagina, the brain, the spinal cord, nasal and pharyngeal mucous membranes, a muscle, the skin, bone or bony tissue, a joint, the urinary bladder, the retina, the cervix of the uterus, the canthus, the intestinal tract, the vertebrae, the rectum, the anus, a bursa, a follicle, and the like.
  • inflammatory diseases suitable for treatment using the provided systems and compositions include, but are not limited to, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), rheumatoid diseases such as rheumatoid arthritis, fibrositis, pelvic inflammatory disease, acne, psoriasis, actinomycosis, dysentery, biliary cirrhosis, Lyme disease, heat rash, Stevens-Johnson syndrome, mumps, pemphigus vulgaris, and blastomycosis.
  • inflammatory bowel disease e.g., Crohn's disease or ulcerative colitis
  • rheumatoid diseases such as rheumatoid arthritis, fibrositis, pelvic inflammatory disease, acne, psoriasis, actinomycosis, dysentery, biliary cirrhosis, Lyme disease, heat rash, Stevens-Johnson syndrome, mumps, pemph
  • Autoimmune diseases generally include diseases or disorders resulting from an immune response against a self-tissue or tissue component such as, e.g., a self-antibody response or cell- mediated response.
  • autoimmune diseases suitable for treatment using the provided systems and compositions include, without limitation, organ-specific autoimmune diseases, in which an autoimmune response is directed against a single tissue, such as Type I diabetes mellitus, myasthenia gravis, vitiligo, Graves' disease, Hashimoto's disease, Addison's disease, autoimmune gastritis, and autoimmune hepatitis; and non-organ specific autoimmune diseases, in which an autoimmune response is directed against a component present in several or many organs throughout the body, such as systemic lupus erythematosus, progressive systemic sclerosis and variants, polymyositis, and dermatomyositis.
  • autoimmune diseases include, for example, pernicious anemia, primary biliary cirrhosis, autoimmune thrombocytopenia, Sjögren's syndrome, and multiple sclerosis.
  • Suitable anti-inflammatory agents for combination therapy include, without limitation, corticosteroids, non-steroidal anti-inflammatory agents, antibodies such as infliximab, 5- aminosalicylates, antibiotics, pharmaceutically acceptable salts thereof; derivatives thereof, prodrugs thereof, and combinations thereof.
  • Suitable immunosuppressive agents for combination therapy include, without limitation, azathioprine and metabolites thereof, anti-metabolites such as methotrexate, immunosuppressive antibodies, mizoribine monophosphate, cyclosporine, scoparone, FK-506 (tacrolimus), FK-778, rapamycin (sirolimus), glatiramer acetate, mycopehnolate, pharmaceutically acceptable salts thereof, derivatives thereof, prodrugs thereof, and combinations thereof.
  • the provided systems and compositions are useful for treating an infection or infectious disease caused by, e.g., a virus, bacterium, fungus, parasite, or any other infectious agent.
  • Non-limiting examples of infectious diseases suitable for treatment include, but are not limited to, acquired immunodeficiency syndrome (AIDS/HIV) or HIV-related disorders, Alpers syndrome, anthrax, bovine spongiform encephalopathy (mad cow disease), chicken pox, cholera, conjunctivitis, Creutzfeldt-Jakob disease (CJD), dengue fever, Ebola, elephantiasis, encephalitis, fatal familial insomnia, Fifth's disease, Gerstmann-Straussler-Scheinker syndrome, hantavirus, helicobacter pylori, hepatitis (hepatitis A, hepatitis B, hepatitis C), herpes, influenza (e.g., avian influenza A (bird flu)), Kuru, leprosy, Lyme disease, malaria, hemorrhagic fever (e.g., Rift Valley fever, Crimean-Congo hemorrhagic fever, Lassa fever, Marburg virus disease,
  • the provided systems and compositions are useful for treating a neurological or musculoskeletal disorder.
  • disorders include, but are not limited to, Alzheimer's disease, Aicardi syndrome, amnesia, amyotrophic lateral sclerosis (Lou Gehrig's Disease), anencephaly, aphasia, arachnoiditis, Arnold Chiari malformation, ataxia telangiectasia, Batten disease, Bell's palsy, brachial plexus injury, brain injury, brain tumor, Charcol-Marie-Tooth disease, encephalitis, epilepsy, essential tremor, Guillain-Barre Syndrome, hydrocephalus, hyperhidrosis, Krabbes disease, meningitis, Moebius syndrome, muscular dystrophy, multiple sclerosis, Parkinson's disease, peripheral neuropathy, postural or orthostatic tachycardia syndrome, progressive supranuclear palsy, Reye's syndrome, shingles, Shy-Drager
  • Administration of the DNA repair enzyme inhibitors and peptide conjugates described herein with a suitable pharmaceutical excipient as necessary can be carried out via any of the accepted modes of administration.
  • administration can be, for example, intravenous, topical, subcutaneous, transcutaneous, transdermal, intramuscular, oral, intra-joint, parenteral, intra- arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, or by inhalation.
  • the DNA repair enzyme inhibitor and the peptide conjugate are administered intravenously.
  • the dose of the peptide conjugate administered to a subject contains between about 25 mCi and about 200 mCi radioactivity. In some embodiments, the dose of the conjugate contains between about 25 mCi and about 100 mCi radioactivity. In some embodiments, the dose of the therapeutic conjugate contains between about 25 mCi and about 150 mCi radioactivity. In some cases, the dose administered contains about 25 mCi, about 50 mCi, about 100 mCi, about 150 mCi, or about 200 mCi radioactivity.
  • the amount of peptide in the dose of the therapeutic conjugate is no more than about 500 ⁇ g, about 400 ⁇ g, about 300 ⁇ g, about 200 ⁇ g, or about 100 ⁇ g of peptide. In some cases, the amount of peptide administered in the dose of the therapeutic conjugate is no more than about 100 ⁇ g of peptide. In some embodiments, the dose of the therapeutic conjugate does not cause an adverse event (AE) in the subject, such as, e.g., an AE greater than or equal to grade 3 (i.e., severe AE). In some embodiments, the dose of the therapeutic conjugate does not exceed a radiation dose of about 23 Gy to the kidneys and/or a radiation dose of about 1.5 Gy to the bone marrow.
  • AE adverse event
  • the amount of the DNA repair enzyme inhibitor administered to a subject contains between about 1 mg and about 3500 mg of the DNA repair enzyme inhibitor, e.g., between about 1 mg and about 130 mg, between about 2.3 mg and about 300 mg, between about 5.1 mg and about 680 mg, between about 12 mg and about 1500 mg, or between about 26 mg and about 3500 mg.
  • the administered amount of the DNA repair enzyme inhibitor can be, for example, less than about 3500 mg, e.g., less than about 1500 mg, less than about 680 mg, less than about 300 mg, less than about 130 mg, less than about 59 mg, less than about 26 mg, less than about 12 mg, less than about 5.1 mg, or less than about 2.3 mg.
  • the administered amount of the DNA repair enzyme inhibitor can be, for example, greater than about 1 mg, e.g., greater than about 2.3 mg, greater than about 5.1 mg, greater than about 12 mg, greater than about 26 mg, greater than about 59 mg, greater than about 130 mg, greater than about 300 mg, greater than about 680 mg, or greater than about 1500 mg. Higher amounts, e.g., greater than about 3500 mg, and lower amounts, e.g., less than about 1 mg, are also contemplated.
  • the DNA repair enzyme inhibitor and peptide conjugate can be administered by infusion, such as over a period of time, such as minutes or hours.
  • the DNA repair enzyme inhibitor and peptide conjugate are infused over a period of minutes, such as about 1 minute, about 2 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, or about 55 minutes. In some embodiments, the DNA repair enzyme inhibitor and peptide conjugate are infused over a period of about 30 minutes. In some embodiments, the DNA repair enzyme inhibitor and peptide conjugate are infused over a period of hours, such as about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours.
  • the DNA repair enzyme inhibitor and peptide conjugate are infused over a period of about 4 hours. In some embodiments, the DNA repair enzyme inhibitor and peptide conjugate are co-infused with a solution of amino acids. In some cases, the infusion of the amino acid solution is commenced prior to the infusion of the DNA repair enzyme inhibitor and peptide conjugate. [0112] In some embodiments, the DNA repair enzyme inhibitor and/or peptide conjugate are administered to a subject once, twice, three times, four times, or five times over a course of treatment. Subsequent administration of the DNA repair enzyme inhibitor and/or peptide conjugate can occur at defined intervals of time, separated by days, weeks, or months.
  • the DNA repair enzyme inhibitor and/or peptide conjugate are administered at a subsequent time if a tumor or cancerous cells reappear, continue to grow, or otherwise are not fully treated after the first administration of the DNA repair enzyme inhibitor and peptide conjugate. In some cases, the DNA repair enzyme inhibitor and/or peptide conjugate are administered again at a subsequent time if the subject does not have a complete response to the first treatment, experiences a partial response, a stable response or progressive disease. [0113] In some embodiments, the dosimetry and/or biodistribution of the peptide conjugate is evaluated following administration of the peptide conjugate to a subject.
  • the dosimetry and biodistribution of the peptide conjugate can be evaluated using nuclear imaging at 1 day and/or 7 days after administration (e.g., infusion) to a subject.
  • the subject undergoes whole body planar imaging (e.g., anterior and posterior view) and single photon emission computerized tomography/computed tomography (SPECT/CT) (e.g., skull vertex extending through the perineum, terminating at the proximal thighs; approx. 2-4 bed positions) at about 24 and/or 168 hours following administration of the therapeutic conjugate.
  • whole body planar imaging e.g., anterior and posterior view
  • SPECT/CT single photon emission computerized tomography/computed tomography
  • serial blood samples are drawn at about 5, 15, 30, 60, 120 and/or 180 minutes following administration of the peptide conjugate, e.g., for evaluation of biodistribution.
  • full chemistry, hematology, liver function tests, and/or EKG are performed at 1 day and/or 7 days (e.g., ⁇ 48 hours) following administration of the peptide conjugate.
  • Methods for dosimetry analysis include, but are not limited to, descriptive statistics (e.g., mean, median, standard deviation, etc.) reported for AUC based on activity concentration-time curves of the therapeutic conjugate (e.g., separately for discernible thoracic and abdominal organs, target lesion, and blood), maximum uptake (e.g., achieved in %) at the target lesion and in discernible organs, specific absorbed dose per organ ( ⁇ Gy/MBq), and cumulative absorbed organ doses (Gy).
  • organs receiving the highest absorbed dose assessed by equivalent dose to tissue are tabulated using frequency and proportion.
  • graphic tools are used to describe the endpoints.
  • the distribution of the peptide conjugate is determined using whole-body planar SPECT/CT imaging.
  • radiation-absorbed doses to kidneys, stomach, uninvolved liver, bone marrow and the whole body together with any other organs displaying accumulation of the therapeutic conjugate are calculated based on the analysis of serial blood counts and SPECT/CT scans.
  • the SPECT/CT images are used to compute the volumetric absorbed radiation dose in the diseased and healthy tissues, e.g., activity concentration-time curves for normal tissues can be generated from region-of-interest (ROI) analysis from the SPECT/CT scans, activity concentration-time curves for red marrow and heart can be generated from blood activity concentration measured by a well scintillation counter, and/or volumes of interest (VOI) can be generated for each patient.
  • ROI region-of-interest
  • VOI volumes of interest
  • the activity concentration in red bone marrow is equal to that in blood.
  • activity concentration- time curves are integrated (e.g., either analytically or numerically as appropriate) to yield AUC values from which so-called residence times are generated.
  • these data are inputted into an organ dosimetry software (e.g., OLINDA/EXM) to generate absorbed dose estimates for normal tissues.
  • an organ dosimetry software e.g., OLINDA/EXM
  • a supplementary dosimetry assessment is performed including, e.g., lesion absorbed dose estimates based on image ROI analysis.
  • absorbed doses are normalized to administered activity and expressed in terms of mGy/MBq.
  • treatment with the DNA repair enzyme and peptide conjugate results in stable disease, partial remission or complete remission in the subject (e.g., the methods described herein comprise administering to the subject a dose of the DNA repair enzyme and peptide conjugate that kills or otherwise slows the growth or progression of cancer cells and leads to stable disease or to partial or complete remission of the cancer in the subject).
  • treatment with the DNA repair enzyme and peptide conjugate results in a reduction in metastases of the cancer in the subject (e.g., the methods described herein comprise administering to the subject a dose of the DNA repair enzyme and peptide conjugate that reduces metastases of the cancer in the subject).
  • treatment with the DNA repair enzyme and peptide conjugate results in a reduction in volume, size or growth of a tumor in the subject (e.g., the methods described herein comprise administering to the subject a dose of the DNA repair enzyme and peptide conjugate that reduces the volume, size or growth of a tumor in the subject).
  • treatment with the DNA repair enzyme and peptide conjugate results in an increased responsiveness of the cancer to a subsequently administered anti-cancer agent (e.g., the methods described herein comprise administering to the subject a dose of the DNA repair enzyme and peptide conjugate that increases responsiveness of the cancer to a subsequently administered anti-cancer agent).
  • the provided method further includes obtaining a test sample from the subject.
  • the test sample can include, for example, a blood sample, a tissue sample, a urine sample, a saliva sample, a cerebrospinal fluid sample, or a combination thereof.
  • the provided method further includes determining the level of one or more biomarkers in the obtained test sample. Determining the presence or level of biomarkers(s) can be used to, as non-limiting examples, determine response to treatment or to select an appropriate composition for the prevention or treatment of the disease.
  • the provided method further includes comparing the determined level of the one of more biomarkers in the obtained test sample to the level of the one or more biomarkers in a reference sample.
  • the reference sample can be obtained, for example, from the subject, with the reference sample being obtained prior to the obtaining of the test sample, e.g., prior to the administering to the subject of the therapeutically effective amount of the provided materials.
  • the reference sample can provide information about baseline levels of the biomarkers in the sample before the treatment
  • the test sample can provide information about levels of the biomarkers after the treatment.
  • the reference sample can be obtained, for example, from a different subject, e.g., a subject in which the treatment is not provided according to the provided methods. In this way, the reference sample can provide information about baseline levels of the biomarkers without treatment, and the test sample can provide information about levels of the biomarkers with treatment.
  • the reference sample can also be obtained, for example, from a population of subjects, e.g., subjects in which the treatment is not provided according to the provided method. In this way, the reference sample can provide population-averaged information about baseline levels of the biomarkers without treatment, and the test sample can provide information about levels of the biomarkers with treatment.
  • the reference sample can also be obtained from an individual or a population of individuals after treatment is provided according to the provided methods, and can serve as, for example, a positive control sample. In some embodiments, the reference sample is obtained from normal tissue. In some embodiments, the reference sample is obtained from abnormal tissue.
  • an increase or a decrease relative to a normal control or reference sample can be indicative of the presence of a disease, or response to treatment for a disease.
  • an increased level of a biomarker in a test sample, and hence the presence of a disease, e.g., an infectious disease or cancer, increased risk of the disease, or response to treatment is determined when the biomarker levels are at least, 1.1-fold, e.g., at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8- fold, at least 1.9-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 13-fold, at least 14-fold, at least 15-fold, at least
  • a decreased level of a biomarker in the test sample, and hence the presence of the disease, increased risk of the disease, or response to treatment is determined when the biomarker levels are at least 1.1-fold, e.g., at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 13-fold, at least 14-fold, at least 15-fold, at least 16-fold, at least 17-fold, at least 18-fold, at least 19-fold, or at least 20-fold lower in comparison to a negative control.
  • the biomarker levels can be detected using any method known in the art, including the use of antibodies specific for the biomarkers. Exemplary methods include, without limitation, polymerase chain reaction (PCR), Western Blot, dot blot, ELISA, radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, FACS analysis, electrochemiluminescence, and multiplex bead assays, e.g., using Luminex or fluorescent microbeads. In some instances, nucleic acid sequencing is employed.
  • PCR polymerase chain reaction
  • Western Blot Western Blot
  • dot blot ELISA
  • radioimmunoassay RIA
  • immunoprecipitation immunofluorescence
  • FACS analysis fluorescence
  • electrochemiluminescence electrochemiluminescence
  • multiplex bead assays e.g., using Luminex or fluorescent microbeads.
  • nucleic acid sequencing is employed.
  • the presence of decreased or increased levels of one or more biomarkers is indicated by a detectable signal, e.g., a blot, fluorescence, chemiluminescence, color, or radioactivity, in an immunoassay or PCR reaction, e.g., quantitative PCR.
  • a detectable signal e.g., a blot, fluorescence, chemiluminescence, color, or radioactivity
  • This detectable signal can be compared to the signal from a reference sample or to a threshold value.
  • the results of the biomarker level determinations are recorded in a tangible medium.
  • the results of diagnostic assays e.g., the observation of the presence or decreased or increased presence of one or more biomarkers, and the diagnosis of whether or not there is an increased risk or the presence of a disease, e.g., an infectious disease or cancer, or whether or not a subject is responding to treatment
  • a disease e.g., an infectious disease or cancer
  • the provided method further includes the step of providing to the subject a diagnosis and/or the results of treatment.
  • Kits are kits to facilitate and/or standardize the use of the systems and compositions described herein, as well as to facilitate the methods described herein. Materials and reagents to carry out these various methods can be provided in kits to facilitate execution of the methods.
  • kit includes a combination of articles that facilitates a process, assay, analysis, or manipulation.
  • kits comprising the conjugates or compositions of the conjugates can be stored and/or shipped to locations where the imaging is to be performed such as to a clinic or hospital.
  • Kits can contain chemical reagents as well as other components.
  • the kits containing the provided DNA repair enzyme and peptide conjugate can include, without limitation, instructions to the kit user.
  • Kits of the DNA repair enzyme and peptide conjugate or compositions thereof can also be packaged for convenient storage and safe shipping, for example, as ampules or other vials packaged in a box having a lid.
  • Embodiment 1 A system comprising: a DNA repair enzyme inhibitor; and a peptide conjugate comprising an integrin-binding peptide and a radionuclide.
  • Embodiment 2 An embodiment of embodiment 1, wherein the DNA repair enzyme inhibitor comprises a poly-ADP ribose polymerase (PARP) inhibitor.
  • PARP poly-ADP ribose polymerase
  • Embodiment 3 An embodiment of embodiment 2, wherein the PARP inhibitor comprises olaparib, niraparib, rucaparib, talazoparib, or a combination thereof.
  • Embodiment 4 An embodiment of embodiment 3, wherein the PARP inhibitor comprises olaparib.
  • Embodiment 5 An embodiment of any one of embodiments 1-4, wherein the integrin- binding peptide comprises an ⁇ v ⁇ 6 integrin-binding peptide.
  • Embodiment 6 An embodiment of any one of embodiments 1-5, wherein the integrin- binding peptide comprises the amino acid sequence RGDLX1X2X3 (SEQ ID NO:50), wherein: X1 and X 2 are each independently an amino acid; and X 3 is L or I.
  • Embodiment 7 An embodiment of any one of embodiments 1-6, wherein the integrin- binding peptide comprises the amino acid sequence of any one of SEQ ID NOs: 1-49.
  • Embodiment 8 An embodiment of embodiment 7, wherein the integrin-binding peptide comprises the amino acid sequence of SEQ ID NO: 3.
  • Embodiment 9 An embodiment of any one of embodiments 1-8, wherein the peptide conjugate further comprises a polyethylene glycol (PEG) moiety covalently attached to a terminus of the integrin-binding peptide.
  • Embodiment 10 An embodiment of embodiment 9, wherein the PEG moiety comprises PEG28 (PEG1500).
  • Embodiment 11 An embodiment of embodiment 9 or 10, wherein the peptide conjugate further comprises a second PEG moiety covalently attached to a second terminus of the integrin- binding peptide.
  • Embodiment 12 An embodiment of embodiment 11, wherein the second PEG moiety comprises PEG 28 (PEG1500).
  • Embodiment 13 An embodiment of any one of embodiments 1-12, wherein the radionuclide comprises 177 Lu, 3 H, 18 F, 32 P, 35 S, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Ga, 67 Cu, 67 Ga, 68 Ga, 82 Rb, 86 Y, 87 Y, 89 Sr, 90 Sr, 90 Y, 105 Rh, m Ag, m In, 124 I, 125 I, 131 I, 117m Sn, 99m Tc, 137 Cs, 149 Pm, 153 Sm, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 166 Ho, 186 Re, 188 Re, 201 T1, 211 At, 215 At, 217 At, 218 At, 209 Bi, 21 , 212 Bi, 213 Bi, 203 Pb, 212 Pb, 210 Po, 211 Po, 212 Po, 214 Po, 215
  • Embodiment 14 An embodiment of embodiment 13, wherein the radionuclide comprises 177 Lu, 32 P, 47 Sc, 67 Cu, 89 Sr, 90 Y, 105 Rh, m Ag, 117m Sn, 131 I, 149 Pm, 153 Sm, 166 Ho, 186 Re, 188 Re, 211 At, 212 Pb or 212 Bi.
  • Embodiment 15 An embodiment of embodiment 14, wherein the radionuclide comprises 177 Lu.
  • Embodiment 16 An embodiment of any one of embodiments 1-15, wherein the peptide conjugate further comprises a chelating moiety covalently attached to the integrin-binding peptide, wherein the radionuclide is complexed with the chelating moiety.
  • Embodiment 17 An embodiment of embodiment 16, wherein the chelating moiety comprises a dodecane tetraacetic acid (DOTA) moiety.
  • Embodiment 18 An embodiment of any one of embodiments 1-15, wherein the radionuclide is covalently attached directly or indirectly to the integrin-binding peptide.
  • DOTA dodecane tetraacetic acid
  • Embodiment 19 An embodiment of any one of embodiments 1-4, wherein the peptide conjugate has the structure of Formula (I): , wherein 5G is a PEG28-GNGVPNLRGDLQVLGQRVGRT (SEQ ID NO: 3)-PEG28-C(O)NH2 peptide.
  • Embodiment 20 An embodiment of any one of embodiments 1-19, wherein the ratio of the amount of the DNA repair enzyme inhibitor to the radioactivity of the peptide conjugate in the system is between 5 ⁇ g per mCi and 150 mg per mCi.
  • Embodiment 21 A composition comprising the system of any one of embodiments 1-20.
  • Embodiment 22 An embodiment of embodiment 21, wherein the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.
  • Embodiment 23 A cell comprising the system of any one of embodiments 1-20.
  • Embodiment 24 An embodiment of embodiment 23, wherein the cell is a mammalian cell.
  • Embodiment 25 An embodiment of embodiment 24, wherein the cell is a human cell.
  • Embodiment 26 A method of preventing or treating an integrin-related disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of a DNA repair enzyme inhibitor; and administering to the subject a therapeutically effective dose of a peptide conjugate comprising an integrin-binding peptide and a radionuclide.
  • Embodiment 27 An embodiment of embodiment 26, wherein the integrin-related disease comprises an integrin-related cancer.
  • Embodiment 28 An embodiment of embodiment 27, wherein the integrin-related cancer comprises an ⁇ v ⁇ 6 integrin-related cancer.
  • Embodiment 29 An embodiment of embodiment 28, wherein the ⁇ v ⁇ 6 integrin-related cancer comprises pancreatic cancer, breast cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, oral squamous cell carcinoma, skin squamous cell carcinoma, stomach cancer, or endometrial cancer.
  • Embodiment 30 An embodiment of any one of embodiments 27-29, wherein the integrin-related cancer comprises a metastatic cancer.
  • Embodiment 31 An embodiment of any one of embodiments 26-30, wherein the DNA repair enzyme inhibitor comprises a PARP inhibitor.
  • Embodiment 32 An embodiment of embodiment 31, wherein the PARP inhibitor comprises olaparib, niraparib, rucaparib, talazoparib, or a combination thereof.
  • Embodiment 33 An embodiment of embodiment 32, wherein the PARP inhibitor comprises olaparib.
  • Embodiment 34 An embodiment of any one of embodiments 26-33, wherein the integrin-binding peptide comprises an ⁇ v ⁇ 6 integrin-binding peptide.
  • Embodiment 35 An embodiment of any one of embodiments 26-34, wherein the integrin-binding peptide comprises the amino acid sequence RGDLX 1 X 2 X 3 (SEQ ID NO:50), wherein: X1 and X2 are each independently an amino acid; and X3 is L or I.
  • Embodiment 36 An embodiment of any one of embodiments 26-35, wherein the integrin-binding peptide comprises the amino acid sequence of any one of SEQ ID NOs: 1-49.
  • Embodiment 37 An embodiment of embodiment 36, wherein the integrin-binding peptide comprises the amino acid sequence of SEQ ID NO: 3.
  • Embodiment 38 An embodiment of any one of embodiments 26-37, wherein the peptide conjugate further comprises a polyethylene glycol (PEG) moiety covalently attached to a terminus of the integrin-binding peptide.
  • PEG polyethylene glycol
  • Embodiment 39 An embodiment of embodiment 38, wherein the PEG moiety comprises PEG28 (PEG1500).
  • Embodiment 40 An embodiment of embodiment 38 or 39, wherein the peptide conjugate further comprises a second PEG moiety covalently attached to a second terminus of the integrin- binding peptide.
  • Embodiment 41 An embodiment of embodiment 40, wherein the second PEG moiety comprises PEG28 (PEG1500).
  • Embodiment 42 An embodiment of any one of embodiments 26-41, wherein the radionuclide comprises 177 Lu, 3 H, 18 F, 32 P, 35 S, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Ga, 67 Cu, 67 Ga, 68 Ga, 82 Rb, 86 Y, 87 Y, 89 Sr, 90 Sr, 90 Y, 105 Rh, m Ag, m In, 124 I, 125 I, 131 I, 117m Sn, 99m Tc, 137 Cs, 149 Pm, 153 Sm, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 166 Ho, 186 Re, 188 Re, 201 T1, 211 At, 215 At, 217 At, 218 At, 209 Bi, 211 Bi, 212 Bi, 213 Bi, 203 Pb, 212 Pb, 210 Po, 211 Po, 212 Po, 214 Po,
  • Embodiment 43 An embodiment of embodiments 42, wherein the radionuclide comprises 177 Lu, 32 P, 47 Sc, 67 Cu, 89 Sr, 90 Y, 105 Rh, m Ag, 117m Sn, 131 I, 149 Pm, 153 Sm, 166 Ho, 186 Re, 188 Re, 211 At, 212 Pb or 212 Bi.
  • Embodiment 44 An embodiment of embodiment 43, wherein the radionuclide comprises 177 Lu.
  • Embodiment 45 An embodiment of any one of embodiments 26-44, wherein the peptide conjugate further comprises a chelating moiety covalently attached to the integrin-binding peptide, wherein the radionuclide is complexed with the chelating moiety.
  • Embodiment 46 An embodiment of embodiment 45, wherein the chelating moiety comprises a DOTA moiety.
  • Embodiment 47 An embodiment of any one of embodiments 26-44, wherein the radionuclide is covalently attached directly or indirectly to the integrin-binding peptide.
  • Embodiment 48 An embodiment of any one of embodiments 26-33, wherein the peptide conjugate has the structure of Formula (I): , wherein 5G is a PEG 28 -GNGVPNLRGDLQVLGQRVGRT (SEQ ID NO: 3)-PEG 28 -C(O)NH 2 peptide.
  • Embodiment 49 An embodiment of any one of embodiments 26-47, wherein the therapeutically effective dose of the peptide conjugate comprises a radioactivity between 25 mCi and 200 mCi.
  • Embodiment 50 An embodiment of any one of embodiments 26-49, wherein the therapeutically effective amount comprises between 1 mg and 3500 mg of the DNA repair enzyme inhibitor.
  • Embodiment 51 An embodiment of any one of embodiments 26-50, wherein the therapeutically effective amount of the DNA repair enzyme inhibitor is administered prior to the therapeutically effective dose of the peptide conjugate.
  • Embodiment 52 An embodiment of any one of embodiments 26-50, wherein the therapeutically effective amount of the DNA repair enzyme inhibitor is administered subsequent to the therapeutically effective dose of the peptide conjugate.
  • Embodiment 53 An embodiment of any one of embodiments 26-50, wherein the therapeutically effective amount of the DNA repair enzyme inhibitor is administered concurrently with the therapeutically effective dose of the peptide conjugate.
  • Embodiment 54 An embodiment of any one of embodiments 26-53, wherein the method further comprises administering one, two or three additional therapeutically effective amounts of the DNA repair enzyme inhibitor.
  • Embodiment 55 An embodiment of any one of embodiments 26-54, wherein the method further comprises administering one, two or three additional therapeutically effective doses of the peptide conjugate.
  • EXAMPLES [0184] The present disclosure will be better understood in view of the following non-limiting examples. The following examples are intended for illustrative purposes only and do not limit in any way the scope of the present invention. Example 1. Effect of provided therapeutic system on cell viability.
  • DOTA-ABM-5G The peptide conjugate DOTA-ABM-5G was synthesized using standard Fmoc chemistry and radiolabeled with the ⁇ -emitter lutetium-177.
  • DOTA refers to the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid moiety of the peptide conjugate
  • ABM refers to the K(D-Abu-iodophenylbutyryl) moiety of the peptide conjugate
  • 5G refers to a PEG 28 -GNGVPNLRGDLQVLGQRVGRT (SEQ ID NO: 3)-PEG 28 -C(O)NH 2 peptide.
  • the radiotherapy agent [ 177 Lu]Lu-DOTA-ABM-5G ( 177 Lu-1) was synthesized at 0.5-Ci/ ⁇ mol molar activity in > 98% radiochemical purity.
  • 177 Lu-1 were evaluated in the ⁇ v ⁇ 6 integrin-positive human pancreatic cancer Capan-1 cells. Rapid cell binding (52% at 1 h) and internalization (> 78% of bound at 1 h) of the 177 Lu-1 was observed in the Capan- 1 cells.
  • mice in Group 1 met the end point criteria (tumor ⁇ 2 cm in any direction and/or ulceration) by day 41 and all mice in Groups 2 and 3 met the end point criteria by days 70 and 73, respectively.
  • Group 4 had 22% survival, with 2/9 mice in the group still alive (FIG. 6B). The end point for the last remaining mouse in Group 4 was met at 110 days after the start of treatment. The median survival was 28 days for the mice in the control group (Group 1), 37 days for the mice in the Olaparib monotherapy group (Group 2), 44 days for the mice in the 177 Lu-1 monotherapy group (Group 3), and 65 days for the mice in the combination treatment group (Group 4). No evidence of treatment-related adverse effects (weight loss or signs of distress) was observed during the course of the study.

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Abstract

Provided herein are systems including a DNA repair enzyme inhibitor and a peptide conjugate, wherein the peptide conjugate includes an integrin-binding peptide and a radionuclide. The system is particularly useful as a therapy for treating or preventing integrin-related diseases such as integrin-related cancers. Also provided are compositions and cells including the systems, and methods for using the systems and compositions to treat or prevent an integrin-related disease.

Description

COMBINATION THERAPY WITH PEPTIDE RECEPTOR RADIONUCLIDE AND DNA REPAIR INHIBITOR CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Prov. Appl. 63/509,253, filed June 20, 2023, the entire contents of which are incorporated herein by reference. SEQUENCE LISTING The text of the computer readable sequence listing filed herewith, titled “UCDA_42326_601_SequenceListing.xml” created June 19, 2024, having a file size of 169,204 bytes, is hereby incorporated by reference in its entirety. BACKGROUND [0001] Cancers continue to be in need of new and more effective therapeutics. Particularly, some cancers and subsets within those cancer types are recalcitrant to current approaches. For example, despite exhaustive testing and some encouraging advances in first- and second-line treatments, pancreatic ductal adenocarcinoma (PDAC) remains the fourth leading cause of cancer-related deaths, with a 5-y survival below 10% (R.L. Siegel, K.D. Miller KD & A. Jemal, CA Cancer J Clin 68 (2018): 7; J.K. Thomas, et al., Cancer Biol. Ther.15, (2014):963). Therefore, there clearly remains an urgent unmet clinical need for more effective molecularly targeted diagnostics and therapeutics. [0002] The heterodimeric transmembrane receptor integrin αvβ6 has been identified as a potential molecular target; it is an epithelium-specific cell surface receptor that is undetectable in healthy adult epithelium but is significantly upregulated in a wide range of epithelium-derived cancers, including PDAC (A.S. Berghoff et al., Clin. Exp. Metastasis 31, (2014): 841; M.D. Allen, J.F. Marshall & J.L. Jones, Cancer Res. 74, (2014): 5942–5947; G.Y. Yang et al., World J. Gastroenterol. 21, (2015): 7457; J. Niu J & Z. Li, Cancer Lett. 403, (2017):128; C. Peng et al., Biosci. Rep. 38, (2018): BSR20180243; D.I. Cantor, H.R. Cheruku, E.C. Nice & M.S. Baker, Cancer Metastasis Rev. 34, (2015):715; N. Ahmed et al., Carcinogenesis 23, (2002): 237; A. Kawashima et al., Pathol. Res. Pract. 199, (2003): 57–64). In fact, αvβ6 integrin was initially identified in PDAC with nearly uniform high expression among patient samples screened; moreover, metastatic lesions demonstrate further highly upregulated expression of αvβ6 integrin when compared with the primary tumor, and αvβ6 integrin is undetectable in normal pancreas (C.S. Reader et al., J. Pathol. 249, (2019): 332). These traits further underscore the potential of αvβ6 integrin as an attractive target for targeted delivery of a therapeutic payload in PDAC. [0003] The practice of radiotheranostics combines molecular imaging with targeted radionuclide therapy, often using the same targeting ligand, and has shown efficacy in several cancers (K. Herrmann et al., Lancet Oncol. 21, (2020): e146; H. Jadvar, X. Chen, W. Cai & U. Mahmood, Radiology 286, (2018): 388). The last few years have seen an exponential growth in the development and acceptance of radiotheranostics for applications in oncology. For example, 68Ga- DOTATATE for imaging of neuroendocrine tumors and 177Lu-DOTATATE for peptide receptor radionuclide therapy were the first radiotheranostic peptides to be approved by the Food and Drug Administration, in 2018 (M.H. Maqsood, A. Tameez Ud Din & A.H. Khan, Cureus 11, (2019): e3986). More recently, 18F-DCFPyL and 68Ga-PSMA-11 gained approval for imaging, as did 177Lu-PSMA-617 for treatment of prostate-specific membrane antigen–positive metastatic castration-resistant prostate cancer (M. Sun, M.O. Niaz, A. Nelson, M. Skafida & M.J. Niaz, Cureus 12, (2020): e8921). [0004] Previous studies demonstrated that particular αvβ6 integrin-targeted radiotherapy agents can increase survival of mice bearing pancreatic cell xenograft tumors (T. Ganguly T et al., J. Nucl. Med. 64, (2023):639), and a Phase-1 clinical trial is currently evaluating one such agent in patients with metastatic or locally advanced pancreatic ductal adenocarcinoma (NCT04665947). Despite these positive findings, and in view of ongoing investigations, a need continues to exist for improved therapies and treatment methods to address integrin-associated malignancies. The present disclosure addresses this and other associated needs. BRIEF SUMMARY [0005] The following summary provides a high-level overview of various aspects of the invention and introduces some of the concepts that are described and illustrated in the present document and the accompanying figures. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used in isolation to determine the scope of the claimed subject matter. Covered embodiments of the disclosure are not defined by this summary. The subject matter should be understood by reference to appropriate portions of the entire specification, any or all figures, and each claim. Some of the exemplary embodiments of the present disclosure are discussed below. [0006] In one aspect, the disclosure provides a system including a DNA repair enzyme inhibitor and a peptide conjugate. The peptide conjugate includes an integrin-binding peptide and a radionuclide. [0007] In another aspect, the disclosure provides a composition, e.g., a pharmaceutical composition, including any of the systems disclosed herein. [0008] In another aspect, the disclosure provides a cell, e.g., a mammalian cell or a human cell, including any of the systems disclosed herein. [0009] In another aspect, the disclosure provides a method of preventing or treating an integrin- related disease in a subject. The method includes administering to the subject a therapeutically effective amount of a DNA repair enzyme inhibitor. The method further includes administering to the subject a therapeutically effective dose of a peptide conjugate. The peptide conjugate includes an integrin-binding peptide and a radionuclide. BRIEF DESCRIPTION OF THE DRAWINGS [0010] FIG. 1 presents a graph plotting Capan-1 cell viability data determined by WST-1 assay following incubation with Olaparib, 177Lu-1, or Olaparib + 177Lu-1 combination (* p = 0.03, ** p = 0.01). [0011] FIG. 2 presents a graph showing tissue uptake of 177Lu-1 determined by biodistribution and expressed as decay corrected percentage of injected dose per gram of tissue (% ID/g) in mice bearing integrin-positive αvβ6 + Capan-1 tumors (n = 4/group/time point). [0012] FIG.3 presents a graph plotting tumor volume in mice bearing Capan-1 tumors measured up to 16 days after start of study, i.e., day 0 of Olaparib treatment. Mice in Groups 2 and 4 received 50 mg/kg Olaparib once/day on days 0-6. Mice in Groups 3 and 4 received a single dose of 1 mCi 177Lu-1 on day 1. Mice in Group 1 received saline (vehicle) on day 1. [0013] FIG. 4A-B presents graphs showing cell viability and cell cycle analysis. (A) Capan-1 cell viability data determined by WST-1 assay following incubation with Olaparib, 177Lu-1, or Olaparib + 177Lu-1 combination (*** p = <0.001, **** p = <0.0001). (B) Cell cycle analysis of all groups at 72 h after start of treatment. [0014] FIG. 5A-D presents graphs with cell cycle analysis data. Complete analysis of all groups at 24 h (A) and 48 h (B) after start of treatment; G2/M fraction for all groups at 72 h after start of treatment (C); and Sub-G1 fraction over time for all groups (D). [0015] FIG. 6A-B provides graphs showing therapeutic efficacy of 177Lu-1 in mice bearing αvβ6 (+) Capan-1 tumors, as determined by (A) tumor growth (average tumor volume, up to 18 days after start of Olaparib treatment; * p = 0.009, ** p = 0.0003, *** p = 0.0001, # p = 0.006, ## p = 0.042), and (B) survival data. DETAILED DESCRIPTION I. General [0013] The present disclosure describes products and methods that include a combination of an inhibitor of a DNA repair enzyme, and a conjugate of an integrin-binding peptide and a radionuclide. The combination is demonstrated as providing significant advantages as a molecularly targeted therapy for integrin-related diseases and disorders. In particular, the DNA repair enzyme inhibitor and peptide conjugate are surprisingly effective in treating or preventing integrin-related cancers. Results presented in the examples herein show that the peptide conjugate of the combination can prime a patient to have a beneficially increased response to the DNA repair enzyme, such as a poly (ADP-ribose) polymerase (PARP) inhibitor. As a result, treatment effects with the combination are observed to be synergistically higher than expected based on the lower effects seen with treatment of the DNA repair enzyme or peptide conjugate individually. These improved treatment effects can include, for example, increased cancer cell death and decreased tumor growth, with reduced delay between treatment and outcome, and an advantageously slow washout time from a subject’s body. Further, the combination therapy is beneficially well- tolerated, causing, for example, no substantial weight loss in test subjects. II. Definitions [0014] Unless specifically indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this invention belongs. In addition, any method or material similar or equivalent to a method or material described herein can be used in the practice of the present disclosure. For purposes of the present disclosure, the following terms are defined. [0015] As used herein, the term “administering” refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to the subject. [0016] The term “amino acid” includes naturally-occurring α-amino acids and their stereoisomers, as well as unnatural amino acids and their stereoisomers. “Stereoisomers” of amino acids refers to mirror image isomers of the amino acids, such as L-amino acids or D-amino acids. For example, a stereoisomer of a naturally-occurring amino acid refers to the mirror image isomer of the naturally-occurring amino acid, i.e., the D-amino acid. [0017] Naturally-occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., α-carboxyglutamate and O-phosphoserine. Naturally- occurring α-amino acids include, without limitation, alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), arginine (Arg), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), and combinations thereof. Stereoisomers of a naturally-occurring α-amino acids include, without limitation, D-alanine (D-Ala), D-cysteine (D-Cys), D-aspartic acid (D-Asp), D-glutamic acid (D- Glu), D-phenylalanine (D-Phe), D-histidine (D-His), D-isoleucine (D-Ile), D-arginine (D-Arg), D- lysine (D-Lys), D-leucine (D-Leu), D-methionine (D-Met), D-asparagine (D-Asn), D-proline (D- Pro), D-glutamine (D-Gln), D-serine (D-Ser), D-threonine (D-Thr), D-valine (D-Val), D- tryptophan (D-Trp), D-tyrosine (D-Tyr), and combinations thereof. [0018] Unnatural amino acids include, without limitation, amino acid analogs, amino acid mimetics, synthetic amino acids, N-substituted glycines, and N-methyl amino acids in either the L- or D-configuration that function in a manner similar to the naturally-occurring amino acids. For example, “amino acid analogs” are unnatural amino acids that have the same basic chemical structure as naturally-occurring amino acids, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, but have modified R (i.e., side-chain) groups. [0019] Non-limiting examples of unnatural amino acids include 1-aminocyclopentane-1- carboxylic acid (Acp), 1-aminocyclobutane-1-carboxylic acid (Acb), 1-aminocyclopropane-1- carboxylic acid (Acpc), citrulline (Cit), homocitrulline (HoCit), α-aminohexanedioic acid (Aad), 3-(4-pyridyl)alanine (4-Pal), 3-(3-pyridyl)alanine (3-Pal), propargylglycine (Pra), α- aminoisobutyric acid (Aib), α-aminobutyric acid (Abu), norvaline (Nva), α,β-diaminopropionic acid (Dpr), α,γ-diaminobutyric acid (Dbu), α-tert-butylglycine (Bug), 3,5-dinitrotyrosine (Tyr(3,5- di NO2)), norleucine (Nle), 3-(2-naphthyl)alanine (Nal-2), 3-(1-naphthyl)alanine (Nal-1), cyclohexylalanine (Cha), di-n-propylglycine (Dpg), cyclopropylalanine (Cpa), homoleucine (Hle), homoserine (HoSer), homoarginine (Har), homocysteine (Hcy), methionine sulfoxide (Met(O)), methionine methylsulfonium (Met (S-Me)), α-cyclohexylglycine (Chg), 3-benzo-thienylalanine (Bta), taurine (Tau), hydroxyproline (Hyp), O-benzyl-hydroxyproline (Hyp(Bzl)), homoproline (HoPro), β-homoproline (βHoPro), thiazolidine-4-carboxylic acid (Thz), nipecotic acid (Nip), isonipecotic acid (IsoNip), 3-carboxymethyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (Cptd), tetrahydro-isoquinoline-3-carboxylic acid (3-Tic), 5H-thiazolo [3,2-a]pyridine-3-carboxylic acid (Btd), 3-aminobenzoic acid (3-Abz), 3-(2-thienyl)alanine (2-Thi), 3-(3-thienyl)alanine (3-Thi), α- aminooctanedioc acid (Asu), diethylglycine (Deg), 4-amino-4-carboxy-1,1-dioxo- tetrahydrothiopyran (Acdt), 1-amino-1-(4-hydroxycyclohexyl) carboxylic acid (Ahch), 1-amino- 1-(4-ketocyclohexyl)carboxylic acid (Akch), 4-amino-4-carboxytetrahydropyran (Actp), 3- nitrotyrosine (Tyr(3-NO2)), 1-amino-1-cyclohexane carboxylic acid (Ach), 1-amino-1-(3- piperidinyl)carboxylic acid (3-Apc), 1-amino-1-(4-piperidinyl)carboxylic acid (4-Apc), 2-amino- 3-(4-piperidinyl) propionic acid (4-App), 2-aminoindane-2-carboxylic acid (Aic), 2-amino-2- naphthylacetic acid (Ana), (2S, 5R)-5-phenylpyrrolidine-2-carboxylic acid (Ppca), 4- thiazoylalanine (Tha), 2-aminooctanoic acid (Aoa), 2-aminoheptanoic acid (Aha), ornithine (Orn), azetidine-2-carboxylic acid (Aca), α-amino-3-chloro-4,5-dihydro-5-isoazoleacetic acid (Acdi), thiazolidine-2-carboxylic acid (Thz(2-COOH)), allylglycine (Agl), 4-cyano-2-aminobutyric acid (Cab), 2-pyridylalanine (2-Pal), 2-quinoylalanine (2-Qal), cyclobutylalanine (Cba), a phenylalanine analog, derivatives of lysine, ornithine (Orn) and α,γ-diaminobutyric acid (Dbu), stereoisomers thereof, and combinations thereof (see, e.g., Liu et al., Anal. Biochem. 295, (2001): 9). As such, the unnatural α-amino acids are present either as unnatural L-α-amino acids, unnatural D-α-amino acids, or combinations thereof. [0020] “Amino acid mimetics” are chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that function in a manner similar to a naturally-occurring amino acid. Suitable amino acid mimetics include, without limitation, β-amino acids and γ-amino acids. In β-amino acids, the amino group is bonded to the β-carbon atom of the carboxyl group such that there are two carbon atoms between the amino and carboxyl groups. In γ-amino acids, the amino group is bonded to the γ-carbon atom of the carboxyl group such that there are three carbon atoms between the amino and carboxyl groups. Suitable R groups for β- or γ-amino acids include, but are not limited to, side-chains present in naturally-occurring amino acids and unnatural amino acids. [0021] “N-substituted glycines” are unnatural amino acids based on glycine, where an amino acid side-chain is attached to the glycine nitrogen atom. Suitable amino acid side-chains (e.g., R groups) include, but are not limited to, side chains present in naturally-occurring amino acids and side-chains present in unnatural amino acids such as amino acid analogs. Non-limiting examples of N-substituted glycines include N-(2-aminoethyl)glycine, N-(3-aminopropyl)glycine, N-(2- methoxyethyl)glycine, N-benzylglycine, (S)-N-(1-phenylethyl)glycine, N- cyclohexylmethylglycine, N-(2-phenylethyl)glycine, N-(3-phenylpropyl)glycine, N-(6- aminogalactosyl)glycine, N-(2-(3′-indolylethyl)glycine, N-(2-(p-methoxyphenylethyl))glycine, N-(2-(p-chlorophenylethyl)glycine, and N-[2-(p-hydroxyphenylethyl)]glycine. N-substituted glycine oligomers, referred to herein as “peptoids,” have been shown to be protease resistant (see, e.g., Miller et al., Drug Dev. Res., 35:20-32 (1995)). [0022] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. For example, an L-amino acid may be represented herein by its commonly known three letter symbol (e.g., Arg for L-arginine) or by an upper-case one-letter amino acid symbol (e.g., R for L-arginine). A D-amino acid may be represented herein by its commonly known three letter symbol (e.g., D-Arg for D-arginine) or by a lower-case one-letter amino acid symbol (e.g., r for D-arginine). [0023] With respect to amino acid sequences, one of skill in the art will recognize that individual substitutions, additions, or deletions to a peptide, polypeptide, or protein sequence which alters, adds, or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a “conservatively modified variant” where the alteration results in the substitution of an amino acid with a chemically similar amino acid. The chemically similar amino acid includes, without limitation, a naturally-occurring amino acid such as an L-amino acid, a stereoisomer of a naturally occurring amino acid such as a D-amino acid, and an unnatural amino acid such as an amino acid analog, amino acid mimetic, synthetic amino acid, N-substituted glycine, and N-methyl amino acid. [0024] Conservative substitution tables providing functionally similar amino acids are well known in the art. For example, substitutions may be made wherein an aliphatic amino acid (e.g., G, A, I, L, or V) is substituted with another member of the group. Similarly, an aliphatic polar- uncharged group such as C, S, T, M, N, or Q, may be substituted with another member of the group; and basic residues, e.g., K, R, or H, may be substituted for one another. In some embodiments, an amino acid with an acidic side chain, e.g., E or D, may be substituted with its uncharged counterpart, e.g., Q or N, respectively; or vice versa. Each of the following eight groups contains other exemplary amino acids that are conservative substitutions for one another (see, e.g., Creighton, Proteins, 1993): 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M). [0025] As used herein, the term “composition” refers to a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. A “pharmaceutical composition” or “pharmaceutically acceptable composition” is one in which each ingredient, e.g., a carrier, diluent, or excipient, is compatible with the other ingredients of a formulation composition and not deleterious to the recipient thereof. [0026] As used herein, the term “conjugate” refers to a chemical compound that has been formed by the joining or attachment of two or more compounds. For example, in the context of the present disclosure, a conjugate can comprise a peptide as described herein (e.g., an integrin-binding peptide) and a radionuclide. Therefore, in the context of the present disclosure, a conjugate may be referred to as a “peptide conjugate.” [0027] As used herein, the term “integrin” refers to a class of cell surface receptor proteins. Such class of proteins are heterodimers, which contain two different chains, called α subunit and β subunit respectively. Non-limiting examples of integrins include α1β1, α2β1, α3β1, α4β1, α5β1, α6β1, α7β1, α8β1, α9β1, α10β1, α11β1, αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, αIIbβ3, α4β7, αEβ7, α6β4, αLβ2, αMβ2, αXβ2, αDβ2, etc. [0028] As used herein, the term “peptide” refers to a polymer made up of a single chain of D- or L-amino acids or a mixture of D- and L-amino acids joined by covalent peptide bonds. [0029] As used herein, the terms “integrin-binding peptide” and “binds to an integrin,” and variations thereof, refer to the binding/interaction of a peptide which shows the capacity of specific interaction with a specific integrin or a specific group of integrins. In certain embodiments, the terms refer to the ability of a peptide or a portion thereof to interact with and/or bind to a target integrin (e.g., αvβ6 integrin) without cross-reacting with molecules of similar sequences or structures. In some instances, a peptide specifically binds to a target integrin when it binds to the target integrin with a substantially lower dissociation constant (i.e., tighter binding) than a molecule of similar sequence or structure. For example, in certain instances, a specific binding occurs when the peptide binds to the target integrin with an about 2, 3, 4, 5, 6, 8, 10, 15, 20, 25, 30, 40, 50, 100, or 1000-fold or greater affinity than a related molecule. The binding of the peptide to a site on the target integrin may occur via intermolecular forces such as ionic bonds, hydrogen bonds, hydrophobic interactions, dipole-dipole bonds, and/or Van der Waals forces. Cross- reactivity may be tested, for example, by assessing binding of the peptide under conventional conditions to the target integrin as well as to a number of more or less (e.g., structurally and/or functionally) closely related molecules. These methods may include, without limitation, binding studies, blocking and competition studies with closely related molecules, FACS analysis, surface plasmon resonance (e.g., with BIAcore), analytical ultracentrifugation, isothermal titration calorimetry, fluorescence anisotropy, fluorescence spectroscopy, radiolabeled ligand binding assays, and combinations thereof. [0030] The term “RGD peptide” refers to the binding/interaction of a peptide motif in a conjugate described herein which shows the capacity of specific interaction with αvβ6 integrin. In some embodiments, the RGD peptide interacts with and/or binds to αvβ6 integrin without cross- reacting with molecules of similar sequences or structures. In some instances, the RGD peptide specifically binds to αvβ6 integrin when it binds with a substantially lower dissociation constant (i.e., tighter binding) than a molecule of similar sequence or structure. [0031] As used herein, the terms “pharmaceutically acceptable carrier” and “pharmaceutically acceptable excipient” refer to a substance that aids the administration of an active agent to and absorption by a subject and may be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable excipients and carriers include water, NaCl, normal saline solutions, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, and the like. One of skill in the art will recognize that other pharmaceutically acceptable excipients and carriers are useful in the present disclosure. [0032] As used herein, the terms “polyethylene glycol” and “PEG” refer to a polymer containing ethylene glycol monomer units of formula –O–CH2–CH2–. Suitable polyethylene glycols may have a free hydroxyl group at each end of the polymer molecule, or may have one or more hydroxyl groups etherified with a lower alkyl, e.g., a methyl group. Also suitable are derivatives of polyethylene glycols having carboxy groups or amide groups. Polyethylene glycols useful in the present invention can be polymers of any chain length or molecular weight, and can include branching, the details of which are provided herein. [0033] As used herein, the term “PEGylation” refers to the process of covalently coupling a polyethylene glycol (PEG) molecule to another molecule, e.g., an RGD peptide, which is then referred to as “PEGylated.” As a non-limiting example, an RGD peptide may be PEGylated at both the amino-terminus and the carboxyl terminus with monodisperse PEG molecules having a defined chain length to generate bi-terminal PEGylated peptide conjugates. Monodisperse PEG molecules typically comprise discrete molecular weights with an exactly defined number of repeating ethylene glycol units. PEG moieties suitable for use are commercially available from Polypure AS (Oslo, Norway), which supplies monodisperse PEG molecules and PEG derivatives thereof consisting of substantially one oligomer only (e.g., greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% oligomer purity). In particular embodiments, the RGD peptide is PEGylated at both ends with a single type or mixtures of different types of monodisperse PEG moieties having a molecular weight of less than about 5,000 Daltons (Da) (e.g., less than about 5,000, 4,000, or 3,000 Da), such as, e.g., PEG11, PEG12 (PEG 800), PEG28 (PEG 1500), and/or (PEG28)2 (PEG 1500×2). [0034] As used herein, the term “radionuclide” refers to any nuclide that exhibits radioactivity. A “nuclide” is a type of atom specified by its atomic number, atomic mass, and energy state, such as carbon 14 (14C). “Radioactivity” refers to the radiation, including alpha particles, beta particles, nucleons, electrons, positrons, neutrinos, and gamma rays, emitted by a radioactive substance. Examples of radionuclides suitable for use in the conjugates described herein include, but are not limited to, tritium (3H), fluorine 18 (18F), phosphorus 32 (32P), sulfur 35 (35S), scandium 47 (47Sc), cobalt 55 (55Co), copper 60 (60Cu), copper 61 (61Cu), copper 62 (62Cu), copper 64 (64Cu), gallium 66 (66Ga), copper 67 (67Cu), gallium 67 (67Ga), gallium 68 (68Ga), rubidium 82 (82Rb), yttrium 86 (86Y), yttrium 87 (87Y), strontium 89 (89Sr), strontium 90 (90Sr), yttrium 90 (90Y), rhodium 105 (105Rh), silver 111 (111Ag), indium 111 (111In), iodine 124 (124I), iodine 125 (125I), iodine 131 (131I), tin 117m (117mSn), technetium 99m (99mTc), cesium 137 (137Cs), promethium 149 (149Pm), samarium 153 (153Sm), terbium 149 (149Tb), terbium 152 (152Tb), terbium 155 (155Tb), terbium 161 (161Tb), holmium 166 (166Ho), lutetium 177 (177Lu), rhenium 186 (186Re), rhenium 188 (188Re), thallium 201 (201Tl), astatine 211 (211At), astatine 215 (215At), astatine 217 (217At), astatine 218 (218At), bismuth 209 (209Bi), bismuth 211 (211Bi), bismuth 212 (212Bi), bismuth 213 (213Bi), lead 203 (203Pb), lead 212 (212Pb), polonium 210 (210Po), polonium 211 (211Po), polonium 212 (212Po), polonium 214 (214Po), polonium 215 (215Po), polonium 216 (216Po), polonium 218 (218Po), radon 218 (218Rn), radon 219 (219Rn), radon 220 (220Rn), radon 222 (222Rn), radon 226 (226Rn), francium 221 (221Fr), radium 223 (223Ra), radium 224 (224Ra), radium 226 (226Ra), actinium 225 (225Ac), actinium 227 (227Ac), thorium 227 (227Th), thorium 228 (228Th), thorium 229 (229Th), thorium 230 (230Th), thorium 232 (232Th), protactinium 231 (231Pa), uranium 233 (233U), uranium 234 (234U), uranium 235 (235U), uranium 236 (236U), uranium 238 (238U), neptunium 237 (237Np), plutonium 238 (238Pu), plutonium 239 (239Pu), plutonium 240 (240Pu), plutonium 244 (244Pu), americium 241 (241Am), curium 244 (244Cm), curium 245 (245Cm), curium 248 (248Cm), californium 249 (249Cf), and californium 252 (252Cf). As used herein, the “m” in 117mSn and 99mTc stands for the meta state. Additionally, naturally-occurring radioactive elements such as uranium, radium, and thorium, which typically represent mixtures of radioisotopes, are suitable examples of radionuclides. 67Cu, 131I, 177Lu, and 186Re are beta- and gamma-emitting radionuclides. 212Bi is an alpha- and beta- emitting radionuclide.
Figure imgf000013_0002
is an alpha- and gamma-emitting radionuclide.
Figure imgf000013_0001
1At, 215At, 217At, 218At, 209Bi, 211Bi, 213Bi, 210Po, 211Po, 212Po, 214Po, 215Po, 216Po, 218Po, 218Rn, 219Rn, 220Rn, 222Rn, 226Rn, 221Fr, 223Ra, 224Ra, 225Ac, 227Ac, 227Th, 228Th, 229Th, 230Th, 232Th, 231Pa, 233U, 234U, 235U, 236U, 238U, 237Np, 238Pu, 239Pu, 240Pu, 244Pu, 241Am, 244Cm, 245Cm, 248Cm, 249Cf, and 252Cf are examples of alpha-emitting radionuclides. 3H, 32P, 35S, 47Sc, 89Sr, 90Sr, 90Y, 105Rh, 111Ag, 117mSn, 149Pm, 153Sm, 166Ho, and 188Re are examples of beta-emitting radionuclides. 67Ga, 111In, 99mTc, 137Cs, and 201Tl are examples of gamma-emitting radionuclides.55Co, 60Cu, 61Cu, 62Cu, 66Ga, 68Ga, 82Rb, and 86Y are examples of positron-emitting radionuclides. 64Cu is a beta- and positron- emitting radionuclide. [0035] As used herein, the term “subject” refers to a vertebrate, and preferably to a mammal. Mammalian subjects for which the provided composition is suitable include, but are not limited to, mice, rats, simians, humans, farm animals, sport animals, and pets. In some embodiments, the subject is human. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is an adult. In some embodiments, the subject is an adolescent. In some embodiments, the subject is a child. In some embodiments, the subject is above 10 years of age, e.g., above 20 years of age, above 30 years of age, above 40 years of age, above 50 years of age, above 60 years of age, above 70 years of age, or above 80 years of age. In some embodiments, the subject is less than 80 years of age, e.g., less than 70 years of age, less than 60 years of age, less than 50 years of age, less than 40 years of age, less than 30 years of age, less than 20 years of age, or less than 10 years of age. [0036] As used herein, the term “therapeutically effective amount” refers to an amount or dose of a compound, composition, or formulation that produces therapeutic effects for which it is administered. The exact amount or dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques. [0037] As used herein, the terms “treat,” “treating,” and “treatment” refer to a procedure resulting in any indicia of success in the elimination or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of one or more symptoms. The treatment or amelioration of symptoms can be based on any objective or subjective parameter, including, e.g., the result of a physical examination or laboratory test. [0038] As used herein, the terms “including,” “comprising,” “having,” “containing,” and variations thereof, are inclusive and open-ended and do not exclude additional, unrecited elements or method steps beyond those explicitly recited. As used herein, the phrase “consisting of” is closed and excludes any element, step, or ingredient not explicitly specified. As used herein, the phrase “consisting essentially of” limits the scope of the described feature to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the disclosed feature. [0039] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a DNA repair ezyme inhibitor” optionally includes a combination of two or more DNA repair enzyme inhibitors, and the like. [0040] As used herein, the term “about” denotes a range of value that is +/- 10% of a specified value. For instance, “about 10” denotes the value range of 9 to 11 (10 +/- 1). III. Systems and Pharmaceutical Compositions [0041] In one aspect, the present disclosure provides various systems that include a DNA repair enzyme inhibitor and a peptide conjugate. The particular selections and relative amounts of these components provide the system with surprisingly improved characteristics, especially when the system is used as a therapy for the treatment or prevention of integrin-related disorders, such as integrin-related cancers. For example, the provided systems are demonstrated herein as exhibiting substantially greater therapeutic efficacy against integrin-related cancers than the efficacy of either the DNA repair enzyme inhibitor or the peptide conjugate alone. [0042] The relative amounts of the DNA repair enzyme inhibitor and the peptide conjugate in the system can be selected to provide the system with its advantageous therapeutic properties. For example, the ratio of the amount of the DNA repair enzyme inhibitor to the amount of radioactivity of the peptide conjugate in the system can be between about 5 µg of the inhibitor per mCi of the conjugate, and about 150 mg of the inhibitor per mCi of the conjugate, e.g., between about 5 µg per mCi and about 2.4 mg per mCi, between about 14 µg per mCi and about 6.8 mg per mCi, between about 39 µg per mCi and about 19 mg per mCi, between about 110 µg per mCi and about 54 mg per mCi, or about 310 µg per mCi and about 150 mg per mCi. In terms of upper limits, the ratio of the DNA repair enzyme inhibitor to the peptide conjugate can be, for example, less than about 150 mg per mCi, e.g., less than about 54 mg per mCi, less than about 19 mg per mCi, less than about 6.8 mg per mCi, less than about 2.4 mg per mCi, less than about 870 µg per mCi, less than about 310 µg per mCi, less than about 110 µg per mCi, less than about 39 µg per mCi, or less than about 14 µg per mCi. In terms of lower limits, the ratio of the DNA repair enzyme inhibitor to the peptide conjugate can be, for example, greater than about 5 µg per mCi, e.g., greater than about 14 µg per mCi, greater than about 39 µg per mCi, greater than about 110 µg per mCi, greater than about 310 µg per mCi, greater than about 870 µg per mCi, greater than about 2.4 mg per mCi, greater than about 6.8 mg per mCi, greater than about 19 mg per mCi, or greater than about 54 mg per mCi. Higher ratios, e.g., greater than 150 mg per mCi, and lower ratios, e.g., less than about 5 µg per mCi, are also contemplated. 1. DNA repair enzyme inhibitors [0043] The provided systems generally include a DNA repair enzyme inhibitor. In some embodiments, the system includes only one species of DNA repair enzyme inhibitor. Alternatively, the system can include two or more structurally and/or functionally different species of DNA repair enzyme inhibitors. A provided system can include, for example, two or more different species of DNA repair enzyme inhibitors, e.g., three or more, four or more, five or more, six or more, seven or more, seven or more, eight or more, nine or more, or ten or more. [0044] DNA repair enzyme inhibitors are compounds that interfere with the activity of enzymes that are involved in repairing damaged DNA. DNA damage can occur due to various factors, such as exposure to radiation, chemicals, oxidative stress, replication errors and spontaneous hydrolysis. DNA damage can lead to mutations, chromosomal aberrations and genomic instability, which can compromise cell functions and viability, and contribute to various diseases, especially cancer. Accordingly, DNA repair mechanisms can be important for maintaining genome integrity and preventing disease. [0045] However, DNA repair mechanisms can also pose a challenge for cancer therapy, as they can protect tumor cells from the cytotoxic effects of DNA-damaging agents, such as radiation and chemotherapy. These therpaeutic agents can be used to induce DNA double-strand breaks (DSBs), which are the most lethal form of DNA damage. DSBs can be repaired by two major pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). HR requires a sister chromatid as a template and is active during the S and G2 phases of the cell cycle. NHEJ directly ligates the broken ends without a template and is active throughout the cell cycle. [0046] One of the key enzymes involved in NHEJ is DNA-dependent protein kinase (DNA-PK), which includes a catalytic subunit (DNA-PKcs) and a Ku70–Ku80 heterodimer. DNA-PKcs is a serine/threonine kinase that phosphorylates itself and other proteins involved in NHEJ, such as XRCC4, Ligase IV and Artemis. DNA-PKcs also regulates cell cycle checkpoints and apoptosis in response to DNA damage. DNA-PKcs is overexpressed in many tumor cells and is associated with resistance to radiation and chemotherapy. [0047] Another important enzyme involved in DNA repair is poly(ADP-ribose) polymerase (PARP), which is abundant and ubiquitous in the nucleus of cells. PARP detects and signals single- strand breaks (SSBs) in DNA, which can arise from various sources or be intermediates of other repair pathways. PARP catalyzes the transfer of ADP-ribose units from NAD+ to itself and other proteins, forming poly(ADP-ribose) chains that recruit and modulate the activity of other repair factors, such as XRCC1, Ligase III and Pol beta. PARP also regulates chromatin structure, gene expression and cell death in response to DNA damage. PARP is therefore important for the repair of SSBs and the maintenance of genomic stability. [0048] DNA repair enzyme inhibitors are agents designed or selected for their ability to block the activity of these enzymes and sensitize tumor cells to DNA-damaging agents. For example, by inhibiting DNA-PKcs, NHEJ is impaired and DSBs accumulate in tumor cells, leading to cell death or genomic instability. By inhibiting PARP, SSBs are not repaired and can be converted into DSBs during replication, which can overwhelm the HR capacity of tumor cells. Further, PARP inhibitors can sensitize cells to DNA damage from treatments such as radiotherapy (N.J. Curtin et al., Mol. Asp. Med. 34, (2013): 1217) by inhibiting repair mechanisms and increasing the number of DNA double strand breaks. Thus, DNA repair enzyme inhibitors can exploit the synthetic lethality between different repair pathways and selectively kill tumor cells while sparing normal cells. [0049] DNA repair enzyme inhibitors suitable for use with the provided systems can include, for example, DNA-PKcs inhibitors, PARP inhibitors, alkylating agents, novobiocin, APE1 inhibitors, RAD51 inhibitors, ATM inhibitors, Ataxia Telangiectasia and Rad3-related protein (ATR) inhibitors, O6-methylguanine-DNA methyltransferase (MGMT) inhibitors, DNA ligase inhibitors, ERCC1-XPF endonuclease inhibitors, Werner syndrome RecQ helicase (WRN) inhibitors, DNA glycolase inhibitors, Fanconi anemia complementation group M protein (FANCM) inhibitors, and combinations thereof. In some embodiments, the DNA repair enzyme inhibitor of the provided system includes or consists of one or more PARP inhibitors. Examples of PARP inhibitors suitable for use in the provided systems include those described by Rose et al, Front. Cell Dev. Biol. 8, (2020): 564601, which is incorporated herein by reference. [0050] In some embodiments, the PARP inhibitor of the provided system includes or consists of olaparib (3-aminobenzamide, 4-(3-(1-(cyclopropanecarbonyl)piperazine-4-carbonyl)-4- fluorobenzyl)phthalazin-1(2H)-one; AZD-2281; AstraZeneca). In some embodiments, the PARP inhibitor of the provided system includes or consists of rucaparib (6-fluoro-2-[4- (methylaminomethyl)phenyl]-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraen-9-one; Clovis Oncology, Inc.). In some embodiments, the PARP inhibitor of the provided system includes or consists of niraparib tosylate ((S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide hydrochloride; MK-4827; GSK). In some embodiments, the PARP inhibitor of the provided system includes or consists of talazoparib (11S,12R)-7-fluoro-11-(4-fluorophenyl)-12-(2-methyl- 1,2,4-triazol-3-yl)-2,3,10-triazatricyclo[7.3.1.05,13]trideca-1,5(13),6,8-tetraen-4-one; BMN-673; Pfizer). In some embodiments, the PARP inhibitor of the provided system includes or consists of fluzoparib (4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7- carbonyl]phenyl]methyl]-2H-phthalazin-1-one; Jiangsu Hengrui Pharmaceuticals). In some embodiments, the PARP inhibitor of the provided system includes or consists of veliparib (2- [(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide dihydrochloride benzimidazole carboxamide; ABT-888; Abbvie). In some embodiments, the PARP inhibitor of the provided system includes or consists of pamiparib (2R)-14-fluoro-2-methyl-6,9,10,19- tetrazapentacyclo[14.2.1.02,6.08,18.012,17]nonadeca-1(18),8,12(17),13,15-pentaen-11-one; BGB-290; BeiGene). In some embodiments, the PARP inhibitor of the provided system includes or consists of CEP-8983 and/or CEP 9722, a small-molecule prodrug of CEP-8983, a 4-methoxy- carbazole inhibitor (CheckPoint Therapeutics). In some embodiments, the PARP inhibitor of the provided system includes or consists of E7016 (Eisai), In some embodiments, the PARP inhibitor of the provided system includes or consists of PJ34 (2-(dimethylamino)-N-(6-oxo-5H- phenanthridin-2-yl)acetamide;hydrochloride). In some embodiments, the PARP inhibitor of the provided system includes or consists of 3-aminobenzamide. In some embodiments, the PARP inhibitor of the provided system includes or consists of any combination of the PARP inhibitors described herein. 2. Peptide conjugates [0051] The provided systems further generally include a peptide conjugate. In some embodiments, the system includes only one species of peptide conjugate. Alternatively, the system can include two or more structurally and/or functionally different species of peptide conjugates. A provided system can include, for example, two or more different species of peptide conjugates, e.g., three or more, four or more, five or more, six or more, seven or more, seven or more, eight or more, nine or more, or ten or more. a) Integrin-binding peptides [0052] The peptide conjugates of the provided systems generally include an integrin-binding peptide. The integrins are a superfamily of cell adhesion receptors that bind to extracellular matrix ligands, cell-surface ligands, and soluble ligands. Integrins are transmembrane αβ heterodimers and at least 18 α and eight β subunits are known in humans, generating 24 heterodimers. The α and β subunits have distinct domain structures, with extracellular domains from each subunit contributing to the ligand-binding site of the heterodimer. Non-limiting examples of integrins include α1β1, α2β1, α3β1, α4β1, α5β1, α6β1, α7β1, α8β1, α9β1, α10β1, α11β1, αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, αIIbβ3, α4β7, αEβ7, α6β4, αLβ2, αMβ2, αXβ2, αDβ2, and combinations thereof. In some embodiments, the integrin bound by the integrin-binding peptide is αvβ3 integrin, αIIbβ3 integrin, or αvβ6 integrin. In particular embodiments, the integrin-binding peptide binds to (e.g., targets) αvβ6 integrin. [0053] The αvβ6 integrin, which is a receptor for fibronectin, tenascin, vitronectin, the latency associated peptide (LAP) of TGF-β, and viral capsid protein (VP1) of foot-and-mouth disease virus (FMDV), is expressed at very low or undetectable levels in only a subset of epithelial cells in normal adult tissues (Breuss et al., J. Cell Sci. 108, (1995): 2241). However, αvβ6 integrin expression is increased dramatically during development, following injury or inflammation, or in a variety of epithelial neoplasms. For example, keratinocytes show de novo expression of αvβ6 integrin in both oral and skin wounds (Breuss et al., J. Cell Sci. 108, (1995): 2241; Clark et al., Am. J. Path. 148, (1996): 1407). In addition, αvβ6 integrin plays an active role in tumor invasion because its expression is often higher at the invasive margins of oral squamous cell carcinomas. As a result, αvβ6 integrin is an attractive target for therapy of diseases or disorders such as pancreatic cancer, oral cancer, ovarian cancer, breast cancer, and colon cancer. [0054] In some embodiments, the integrin-binding peptide of the peptide conjugate is an RGD peptide that is selective for binding αvβ6 integrin. In some embodiments, the peptide comprises the RGD motif, RGDLX1X2X3 (SEQ ID NO:50), where X1 and X2 are independently selected amino acids, and X3 is L or I. In some instances, the peptide comprises the RGD motif, RGDLX1X2X3 (SEQ ID NO:51), where X1 and X2 are independently selected from the group consisting of Glu, Ala, Leu, Met, Gln, Lys, Arg, Val, Ile, His, Thr, Trp, Phe, and Asp. In certain embodiments, X1 is Q, X2 is V, and X3 is L. In certain embodiments, the RGD peptide does not comprise any alanine residues. In certain embodiments, the RGD peptide is between 8 and 40 amino acids. In some cases, the RGD peptide is more than 20 amino acids. In some cases, the RGD peptide is 21 amino acids. [0055] In other embodiments, the integrin-binding peptide includes the sequence RGDLX1X2LX4X5X6 (SEQ ID NO:52), wherein X1, X2, X4, X5, and X6 are independently selected amino acids. In certain instances, X1, X2, X4, X5, and X6 are helix-promoting residues. The helix- promoting residues can comprise naturally-occurring amino acids or unnatural amino acids such as artificial or modified amino acids. For example, the helix-promoting residues can be independently selected from the group consisting of Glu, Ala, Leu, Met, Gln, Lys, Arg, Val, Ile, His, Thr, Trp, Phe, and Asp. Thus, in some embodiments, the integrin-binding peptide includes the sequence RGDLX1X2LX4X5X6 (SEQ ID NO:53), wherein X1, X2, X4, X5, and X6 are independently selected from the group consisting of Glu, Ala, Leu, Met, Gln, Lys, Arg, Val, Ile, His, Thr, Trp, Phe, and Asp. [0056] In further embodiments, the integrin-binding peptide includes, from N- to C-terminus: an N-terminal segment comprising one or more amino acids which enhance hydrophobic interactions with a helix defined from LX1X2L and also enhances the RGD domain for binding, the sequence RGDLX1X2LX4X5X6 (SEQ ID NO:54), and a C-terminal segment comprising one or more helix- promoting amino acids. In some embodiments, the N-terminal segment comprising between 1 and 35 amino acids. In some embodiments, the C-terminal segment comprises between 1 and 35 amino acids. In particular embodiments, the length of the N-terminal segment is selected so that it is sufficiently long to facilitate a hydrophobic/non-covalent interacting core. The exact nature of these residues depends on the general design of the region. In particular, it is preferred to have a mixture of hydrophobic interactions (from residues such as Val, Ile, Leu) and/or electrostatic interactions (using Asp, Glu, Lys, and/or Arg together with their counterpart ion-pair at X1 and/or X2). [0057] In certain embodiments, the integrin-binding peptide includes the amino acid sequence RGDLX1X2X3AQX6 (SEQ ID NO:55), wherein X6 is Lys (K) or Arg (R). In particular embodiments, X6 is R. In some embodiments, X1 and X2 are independently selected amino acids, and X3 is L or I. In some instances, the peptide comprises the RGD motif, RGDLX1X2X3AQX6 (SEQ ID NO:56), where X1 and X2 are independently selected from the group consisting of Glu, Ala, Leu, Met, Gln, Lys, Arg, Val, Ile, His, Thr, Trp, Phe, and Asp. In certain embodiments, X1 is Q, X2 is V, and X3 is L. In some embodiments, the integrin-binding peptide includes or consists of an amino acid sequence selected from the group consisting of NAVPNLRGDLQVLAQKVART (SEQ ID NO: 1), NAVPNLRGDLQVLAQRVART (SEQ ID NO: 2), GNGVPNLRGDLQVLGQRVGRT (SEQ ID NO: 3), GFTTGRRGDLATIHGMNRPF (SEQ ID NO: 4), YTASARGDLAHLTTTHARHL (SEQ ID NO: 5), and combinations thereof. In particular embodiments, the integrin-binding peptide includes or consists of an amino acid sequence selected from the group consisting of NAVPNLRGDLQVLAQKVART (SEQ ID NO: 1), NAVPNLRGDLQVLAQRVART (SEQ ID NO: 2), and GNGVPNLRGDLQVLGQRVGRT (SEQ ID NO: 3). [0058] In certain embodiments, the RGD peptide comprises QX7VX8RT (SEQ ID NO:57) that is positioned C-terminally to the RGD motif, wherein X7 is R or K and X8 is A or G. In some cases, the RGD peptide comprises the amino acid sequence QRVGRT (SEQ ID NO: 6) positioned C- terminal to the RGD motif. In some cases, the RGD peptide includes the amino acid sequence RGDLQVLGQRVGRT (SEQ ID NO: 7). In certain embodiments, the RGD peptide includes or consists of the amino acid sequence GNGVPNLRGDLQVLGQRVGRT (SEQ ID NO: 3). [0059] In some embodiments, the integrin-binding peptide includes the amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:58-61), where m and n are independently 0 or 1; and X1, X2, X3, X4, X5, and X6 are independently selected amino acids, provided that X3 is not Q when X4 is V. In some embodiments, the integrin-binding peptide includes the amino acid sequence RSD or VGD, e.g., the integrin-binding peptide includes the sequence RSDLTPLF (SEQ ID NO: 8), RSDLTPLFK (SEQ ID NO: 9), VGDLTYLK (SEQ ID NO: 10), VGDLTYLKK (SEQ ID NO: 11), or any of the integrin-binding peptide sequences disclosed in International Patent Application Publication Nos. WO 2015/160770, WO 2017/218569, and WO 2020/051549, each of which are incorporated herein by reference in their entirety. [0060] In some embodiments, the integrin-binding peptide includes amino acid sequences from N- to C-terminus X1X2DLX3X4LX5 and (Q)nKVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids where subscript n is 0 or 1; and X1, X2, X3, X4, and X5,are independently selected amino acids, provided that X3 is not Q when X4 is V. In some embodiments, the integrin-binding peptide includes an amino acid sequences GX1X2DLX3X4LX5 (SEQ ID NO:64) and (Q)nKVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids, where); subscript n is 0 or 1; and X1, X2, X3, X4, and X5 are independently selected amino acids, provided that X3 is not Q when X4 is V. In some embodiments, the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:58-61), where subscripts m and n are independently 0 or 1; and X1, X2, X3, X4, X5, and X6 are independently selected amino acids, provided that X3 is not Q when X4 is V. For example, an integrin-binding peptide can include an amino acid sequence GX1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:65-68), where subscripts m and n are independently 0 or 1; and X1, X2, X3, X4, X5, and X6 are independently selected amino acids, provided that X3 is not Q when X4 is V. [0061] In some embodiments, the integrin-binding peptide includes the amino acid sequences, from N- to C-terminus, X1X2DLX3X4LX5 and_(Q)nKVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids, where X1 is an amino acid residue selected from the group consisting of E, D, G, A, I, L, M, C, Q, N, V, K, R, H, S, T, W, and F. In some embodiments, X1 is an amino acid residue selected from the group consisting of G, A, I, L, M, C, V, K, R, and H. In some embodiments, X1 is an amino acid residue selected from the group consisting of V and R. In some embodiments, the integrin-binding peptide includes the amino acid sequences, from N- to C-terminus, X1X2DLX3X4LX5 and (Q)nKVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids, where X2 is an amino acid residue selected from the group consisting of G, A, N, I, L, M, C, Q, E, D, K, R, V, H, S, T, W, F, and Y. In some embodiments, X2 is an amino acid residue selected from the group consisting of G, A, N, I, L, Q, E, D, V, S, and T. In some embodiments, X2 is an amino acid residue selected from the group consisting of G, S, and T. In some embodiments, the integrin- binding peptide includes the amino acid sequences, from N- to C-terminus, X1X2DLX3X4LX5 and (Q)nKVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids, where X1 is V and X2 is G. In some embodiments, X1 is V and X2 is S. In some embodiments, X1 is V and X2 is T. In some embodiments, X1 is R and X2 is G. In some embodiments, X1 is R and X2 is S. In some embodiments, X1 is R and X2 is T. [0062] In some embodiments, the integrin-binding peptide includes the amino acid sequences, from N- to C-terminus, X1X2DLX3X4LX5 and (Q)nKVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids, where X3 is an amino acid residue selected from the group consisting of T, S, N, Q, M, C, V, L, I, A, G, R, H, K, Y, F, E, D, W, and P, provided that X3 is not Q when X4 is V. In some embodiments, X3 is an amino acid residue selected from the group consisting of T, S, M, C, V, L, I, A, G, R, K, Y, F, E, D, W, and P. In some embodiments, X3 is an amino acid residue selected from the group consisting of T, M, A, R, Y, D, G, and P. In some embodiments, the integrin-binding peptide includes the amino acid sequences, from N- to C-terminus, X1X2DLX3X4LX5 and (Q)nKVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids, wherein X4 is an amino acid residue selected from the group consisting of Y, W, K, H, R, D, E, P, G, A, C, M, V, I, L, N, Q, S, T, and F, provided that X4 is not V when X3 is Q. In some embodiments, X4 is an amino acid residue selected from the group consisting of Y, W, K, R, H, D, E, Q, N, P, S, and F. In some embodiments, X4 is an amino acid residue selected from the group consisting of Y, K, D, E, P, S, R, and F. In some embodiments, the integrin-binding peptide includes the amino acid sequences, from N- to C-terminus, X1X2DLX3X4LX5 and (Q)nKVART (SEQ ID NOs:62-63), immediately adjacent to each other or separated by 1 to 20, or more amino acids, where X3 is T and X4 is Y. In some embodiments, X3 is T and X4 is P. In some embodiments, X3 is M and X4 is K. In some embodiments, X3 is A and X4 is D. In some embodiments, X3 is R and X4 is E. In some embodiments, X3 is Y and X4 is K. In some embodiments, X3 is P and X4 is F. In some embodiments, X3 is D and X4 is S. In some embodiments, X3 is G and X4 is R. [0063] In some embodiments, the integrin-binding peptide includes the amino acid sequences, from N- to C-terminus X1X2DLX3X4LX5 and (Q)nKVART (SEQ ID NOs:62-63, immediately adjacent to each other or separated by 1 to 20, or more amino acids, where X5 is an amino acid residue selected from the group consisting of K, H, A, G, P, I, L, V, R, F, Y, C, S, T, M, Q, N, E, D, and W. In some embodiments, X5 is an amino acid residue selected from the group consisting of K, A, G, R, F, Y, Q, N, E, D, C, and W. In some embodiments, X5 is an amino acid residue selected from the group consisting of K, A, R, F, Q, C, and W. In some embodiments, the integrin- binding peptide includes the amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:69-70), where subscript m is 1 and X6 is an amino acid residue selected from the group consisting of H, R, K, T, and Y. In some embodiments, subscript m is 1 and X6 is an amino acid residue selected from the group consisting of R, K, T, and Y. In some embodiments, subscript m is 1 and X6 is amino acid residue K, T, and Y. In some embodiments, the integrin-binding peptide includes the amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:69-70), where X5 is K, subscript m is 1, and X6 is K. In some embodiments, X5 is K, subscript m is 1, and X6 is R. In some embodiments, X5 is A, subscript m is 1, and X6 is K. In some embodiments, X5 is A, subscript m is 1, and X6 is R. In some embodiments, X5 is A, subscript m is 1, and X6 is Y. In some embodiments, X5 is A, subscript m is 1, and X6 is T. In some embodiments, X5 is R, subscript m is 1, and X6 is K. In some embodiments, X5 is R, subscript m is 1, and X6 is T. In some embodiments, X5 is R, subscript m is 1, and X6 is Y. In some embodiments, X5 is R, subscript m is 1, and X6 is R. In some embodiments, X5 is F, subscript m is 1, and X6 is K. In some embodiments, X5 is F, subscript m is 1, and X6 is R. In some embodiments, X5 is Q, subscript m is 1, and X6 is K. In some embodiments, X5 is Q, subscript m is 1, and X6 is R. In some embodiments, X5 is C, subscript m is 1, and X6 is Y. In some embodiments, X5 is C, subscript m is 1, and X6 is K. In some embodiments, X5 is C, subscript m is 1, and X6 is T. In some embodiments, X5 is C, subscript m is 1, and X6 is R. In some embodiments, X5 is W, subscript m is 1, and X6 is K. In some embodiments, X5 is W, subscript m is 1, and X6 is R. [0064] In some embodiments, the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:71-74), where subscripts m and n are independently 0 or 1; X1 is an amino acid residue selected from the group consisting of E, D, G, A, I, L, M, C, Q, N, V, K, R, H, S, T, W, and F; X2 is an amino acid residue selected from the group consisting of G, A, N, I, L, M, C, Q, E, D, K, R, V, H, S, T, W, F, and Y; X3 is an amino acid residue selected from the group consisting of T, S, N, Q, M, C, V, L, I, A, G, R, H, K, Y, F, E, D, W, and P; X4 is an amino acid residue selected from the group consisting of Y, W, K, H, R, D, E, P, G, A, C, M, V, I, L, N, Q, S, T, and F; X5 is an amino acid residue selected from the group consisting of K, H, A, G, P, I, L, V, R, F, Y, C, S, T, M, Q, N, E, D, and W; and X6 is an amino acid residue selected from the group consisting of H, R, K, T, and Y when m is 1, provided that X3 is not Q when X4 is V. [0065] In some embodiments, the integrin-binding peptide includes an amino acid sequence GX1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:75-78), where subscripts m and n are independently 0 or 1; X1 is an amino acid residue selected from the group consisting of E, D, G, A, I, L, M, C, Q, N, V, K, R, H, S, T, W, and F; X2 is an amino acid residue selected from the group consisting of G, A, N, I, L, M, C, Q, E, D, K, R, V, H, S, T, W, F, and Y; X3 is an amino acid residue selected from the group consisting of T, S, N, Q, M, C, V, L, I, A, G, R, H, K, Y, F, E, D, W, and P; X4 is an amino acid residue selected from the group consisting of Y, W, K, H, R, D, E, P, G, A, C, M, V, I, L, N, Q, S, T, and F; X5 is an amino acid residue selected from the group consisting of K, H, A, G, P, I, L, V, R, F, Y, C, S, T, M, Q, N, E, D, and W; and X6 is an amino acid residue selected from the group consisting of H, R, K, T and Y when m is 1, provided that X3 is not Q when X4 is V. [0066] In some embodiments, the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART, (SEQ ID NOs:79-82) where subscripts m and n are independently 0 or 1; X1 is an amino acid residue selected from the group consisting of G, A, I, L, M, C, V, K, R, and H; X2 is an amino acid residue selected from the group consisting of G, A, N, I, L, Q, E, D, V, S, and T; X3 is an amino acid residue selected from the group consisting of T, S, M, C, V, L, I, A, G, R, K, Y, F, E, D, W, and P; X4 is an amino acid residue selected from the group consisting of Y, W, K, R, H, D, E, Q, N, P, S, and F; X5 is an amino acid residue selected from the group consisting of K, A, G, R, F, Y, Q, N, E, D, C, and W; and X6 is an amino acid residue selected from the group consisting of R, K, T and Y when m is 1. [0067] In some embodiments, the integrin-binding peptide includes an amino acid sequence GX1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:83-86), where subscripts m and n are independently 0 or 1; X1 is an amino acid residue selected from the group consisting of G, A, I, L, M, C, V, K, R, and H; X2 is an amino acid residue selected from the group consisting of G, A, N, I, L, Q, E, D, V, S, and T; X3 is an amino acid residue selected from the group consisting of T, S, M, C, V, L, I, A, G, R, K, Y, F, E, D, W, and P; X4 is an amino acid residue selected from the group consisting of Y, W, K, R, H, D, E, Q, N, P, S, and F; X5 is an amino acid residue selected from the group consisting of K, A, G, R, F, Y, Q, N, E, D, C, and W; and X6 is an amino acid residue selected from the group consisting of R, K, T and Y when m is 1. [0068] In some embodiments, the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:87-90), where subscripts m and n are independently 0 or 1; X1 is an amino acid residue selected from the group consisting of V and R; X2 is an amino acid residue selected from the group consisting of G, S, and T; X3 is an amino acid residue selected from the group consisting of T, M, A, R, Y, D, G, and P; X4 is an amino acid residue selected from the group consisting of Y, K, D, E, P, S, R, and F; X5 is an amino acid residue selected from the group consisting of K, A, R, F, Q, C, and W; and X6 is K, T, and Y when m is 1. [0069] In some embodiments, the integrin-binding peptide includes an amino acid sequence GX1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:91-94), where subscripts m and n are independently 0 or 1; X1 is an amino acid residue selected from the group consisting of V and R; X2 is an amino acid residue selected from the group consisting of G, S, and T; X3 is an amino acid residue selected from the group consisting of T, M, A, R, Y, D, G, and P; X4 is an amino acid residue selected from the group consisting of Y, K, D, E, P, S, R, and F; X5 is an amino acid residue selected from the group consisting of K, A, R, F, Q, C, and W; and X6 is K, T, and Y when m is 1. [0070] In some embodiments, the integrin-binding peptide includes the amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:58-61), where subscripts m and n are independently 0 or 1. In some embodiments, subscript m is 0 or 1. In some embodiments, subscript m is 0. In some embodiments, subscript m is 1. In some embodiments, subscript n is 0 or 1. In some embodiments, subscript n is 0. In some embodiments, subscript n is 1. In some embodiments, the integrin-binding peptide includes the amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:58-61), where subscript m is 0 and subscript n is 0. In some embodiments, subscript m is 1 and subscript n is 1. In some embodiments, subscript m is 1 and subscript n is 0. In some embodiments, subscript m is 0 and subscript n is 1. [0071] In some embodiments, the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:95-96), where subscript m is 0 or 1; subscript n is 1; X1 is an amino acid residue selected from the group consisting of V and R; X2 is an amino acid residue selected from the group consisting of G, T, and S; X3 is an amino acid residue selected from the group consisting of T, A, D, and G; X4 is an amino acid residue selected from the group consisting of Y, D, P, S and R; X5 is an amino acid residue selected from the group consisting of K, R, F, and A; and X6 is an amino acid residue selected from the group consisting of K, T, and Y when m is 1. [0072] In some embodiments, the integrin-binding peptide includes an amino acid sequence GX1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:97-98), where subscript m is 0 or 1; subscript n is 1; X1 is an amino acid residue selected from the group consisting of V and R; X2 is an amino acid residue selected from the group consisting of G, T, and S; X3 is an amino acid residue selected from the group consisting of T, A, D, and G; X4 is an amino acid residue selected from the group consisting of Y, D, P, S and R; X5 is an amino acid residue selected from the group consisting of K, R, F, and A; and X6 is an amino acid residue selected from the group consisting of K, T, and Y when m is 1. [0073] In some embodiments, the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NOs:99-100), where subscript m is 1; subscript n is 1; X1 is an amino acid residue selected from the group consisting of V and R; X2 is an amino acid residue selected from the group consisting of G, T, and S; X3 is an amino acid residue selected from the group consisting of T, A, D, and G; X4 is an amino acid residue selected from the group consisting of Y, D, P, S and R; X5 is an amino acid residue selected from the group consisting of K, R, F, and A; and X6 is an amino acid residue selected from the group consisting of K, T, and Y. In some embodiments, subscript m is 1; subscript n is 1; X1 is an amino acid residue selected from the group consisting of V and R; X2 is an amino acid residue selected from the group consisting of G and S; X3 is an amino acid residue selected from the group consisting of T and A; X4 is an amino acid residue selected from the group consisting of Y, D, and P; X5 is an amino acid residue selected from the group consisting of K, R, and F; and X6 is K. In some embodiments, the integrin- binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NO:101), where subscript m is 1; subscript n is 1; X1 is R; X2 is G; X3 is A; X4 is D; X5 is R; and X6 is K. [0074] In some embodiments, the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NO:102), where subscript m is 0; subscript n is 1; X1 is an amino acid residue selected from the group consisting of V and R; X2 is an amino acid residue selected from the group consisting of G, T, and S; X3 is an amino acid residue selected from the group consisting of T, A, D, and G; X4 is an amino acid residue selected from the group consisting of Y, D, P, S and R; and X5 is an amino acid residue selected from the group consisting of K, R, F, and A. In some embodiments, the integrin-binding peptide includes an amino acid sequence GX1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NO:103), where subscript m is 0; subscript n is 1; X1 is an amino acid residue selected from the group consisting of V and R; X2 is an amino acid residue selected from the group consisting of G, T, and S; X3 is an amino acid residue selected from the group consisting of T, A, D, and G; X4 is an amino acid residue selected from the group consisting of Y, D, P, S and R; and X5 is an amino acid residue selected from the group consisting of K, R, F, and A. In some embodiments, the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NO:104), where subscript m is 0; subscript n is 1; X1 is an amino acid residue selected from the group consisting of V and R; X2 is an amino acid residue selected from the group consisting of G and S; X3 is an amino acid residue selected from the group consisting of T and A; X4 is an amino acid residue selected from the group consisting of Y, D, and P; and X5 is an amino acid residue selected from the group consisting of K, R, and F. [0075] In some embodiments, the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NO: 12), where subscript m is 0; subscript n is 1; X1 is V; X2 is G; X3 is T; X4 is Y; and X5 is K. In some embodiments, the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NO:21), where subscript m is 0; subscript n is 1; X1 is R; X2 is G; X3 is A; X4 is D; and X5 is R. In some embodiments, the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NO:33), where subscript m is 0; subscript n is 1; X1 is R; X2 is S; X3 is T; X4 is P; and X5 is F. In some embodiments, the integrin-binding peptide includes an amino acid sequence X1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NO:36), where subscript m is 0; subscript n is 1; X1 is R; X2 is T; X3 is D; X4 is S; and X5 is R. In some embodiments, the integrin-binding peptide includes an amino acid sequence GX1X2DLX3X4LX5(X6)m(Q)nKVART (SEQ ID NO:42), where subscript m is 0; subscript n is 1; X1 is R; X2 is G; X3 is G; X4 is R; and X5 is A. [0076] In some embodiments, the integrin-binding peptide includes an amino acid sequence selected from the group consisting of VGDLTYLKQKVART (SEQ ID NO: 12), VGDLTYLKKQKVART (SEQ ID NO: 13), VGDLTYLKKKVART (SEQ ID NO: 14), RGDLTYLKQKVART (SEQ ID NO: 15), RGDLTYLKKQKVART (SEQ ID NO: 16), RGDLTYLKKKVART (SEQ ID NO: 17), RGDLMKLAQKVART (SEQ ID NO: 18), RGDLMKLAKQKVART (SEQ ID NO: 19), RGDLMKLAKKVART (SEQ ID NO: 20), RGDLADLRQKVART (SEQ ID NO: 21), RGDLADLRKQKVART (SEQ ID NO: 22), RGDLADLRKKVART (SEQ ID NO: 23), RGDLRELAQKVART (SEQ ID NO: 24), RGDLRELAKQKVART (SEQ ID NO: 25), RGDLRELAKKVART (SEQ ID NO: 26), RTDLYKLQQKVART (SEQ ID NO: 27), RTDLYKLQKQKVART (SEQ ID NO: 28), RTDLYKLQKKVART (SEQ ID NO: 29), RGDLPFLWQKVART (SEQ ID NO: 30), RGDLPFLWKQKVART (SEQ ID NO: 31), RGDLPFLWKKVART (SEQ ID NO: 32), RSDLTPLFQKVART (SEQ ID NO: 33), RSDLTPLFKQKVART (SEQ ID NO: 34), RSDLTPLFKKVART (SEQ ID NO: 35), RTDLDSLRQKVART (SEQ ID NO: 36), RTDLDSLRTQKVART (SEQ ID NO: 37), RTDLDSLRTKVART (SEQ ID NO: 38), GRGDLGRLCQKVART (SEQ ID NO: 39), GRGDLGRLCYQKVART (SEQ ID NO: 40), GRGDLGRLCYKVART (SEQ ID NO: 41), GRGDLGRLAQKVART (SEQ ID NO: 42), GRGDLGRLAYQKVART (SEQ ID NO: 43), GRGDLGRLAYKVART (SEQ ID NO: 44), and GRGDLGRLAKVART (SEQ ID NO: 45), RGDLMKLAK (SEQ ID NO: 46), RGDLADLRK (SEQ ID NO: 47), GIDLTSLTK (SEQ ID NO: 48), and RGDLRELAK (SEQ ID NO: 49). [0077] In some embodiments, the integrin-binding peptide is about 4 to about 80 amino acids in length, about 4 to about 50 amino acids in length, about 5 to about 80 amino acids in length, about 5 to about 75 amino acids in length, about 5 to about 45 amino acids in length, about 6 to about 60 amino acids in length, about 6 to about 40 amino acids in length, about 8 to about 50 amino acids in length, about 8 to about 30 amino acids in length, about 10 to about 50 amino acids in length, about 10 to about 35 amino acids in length, about 12 to about 45 amino acids in length, about 12 to about 40 amino acids in length, about 13 to about 60 amino acids in length, about 13 to about 40 amino acids in length, about 14 to about 55 amino acids in length, about 14 to about 35 amino acids in length, about 15 to about 45 amino acids in length, or about 15 to about 25 amino acids in length. For example, the peptide can be about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, or more amino acids in length. In some embodiments, the peptide is about 10 to about 20 amino acids in length. In some embodiments, the peptide is about 13 amino acids in length. In some embodiments, the peptide is about 14 amino acids in length. In some embodiments, the peptide is about 15 amino acids in length. [0078] The integrin-binding peptide used in the conjugates described herein can also be a functional variant of any of the peptides as defined above, including peptides that possess at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more sequence identity with the peptides described above. In certain instances, the integrin-binding peptide includes naturally- occurring amino acids and/or unnatural amino acids. Examples of unnatural amino acids include, but are not limited to, D-amino acids, ornithine, diaminobutyric acid ornithine, norleucine ornithine, pyridylalanine, thienylalanine, naphthylalanine, phenylglycine, alpha and alpha- disubstituted amino acids, N-alkyl amino acids, lactic acid, halide derivatives of naturally- occurring amino acids (e.g., trifluorotyrosine, p-Cl-phenylalanine, p-Br-phenylalanine, p-I- phenylalanine, etc.), L-allylglycine, b-alanine, L-a-amino butyric acid, L-g-amino butyric acid, L- a-amino isobutyric acid, L-e-amino caproic acid, 7-amino heptanoic acid, L methionine sulfone, L-norleucine, L-norvaline, p-nitro-L-phenylalanine, L-hydroxyproline, L-thioproline, methyl derivatives of phenylalanine (e.g., 1-methyl-Phe, pentamethyl-Phe, L-Phe (4-amino), L-Tyr (methyl), L-Phe(4-isopropyl), L-Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxyl acid), L- diaminopropionic acid, L-Phe (4-benzyl), etc.). The integrin-binding peptide can be further modified. For example, one or more amide bonds of the peptide can be replaced by ester or alkyl backbone bonds. The peptide can additionally or alternatively include N- or C-alkyl substituents, side-chain modifications, or constraints such as disulfide bridges or side-chain amide or ester linkages. [0079] The integrin-binding peptide can be prepared using methods known in the art. For example, the integrin-binding peptide can be produced by chemical synthesis, e.g., using solid phase techniques and/or automated peptide synthesizers, or by recombinant means. In certain instances, the integrin-binding peptide can be synthesized using solid phase strategies on an automated multiple peptide synthesizer using 9-fluorenylmethyloxycarbonyl (Fmoc) chemistry. b) Radionuclides [0080] The peptide conjugates of the provided systems generally further include a radionuclide. The radionuclide can be, for example, an alpha-, beta-, and/or gamma-emitting radionuclide. In some embodiments, the radionuclide of the peptide conjugate is 3H, 18F, 32P, 35S, 47Sc, 55Co, 60Cu, 61Cu, 62Cu, 64Cu, 66Ga, 67Cu, 67Ga, 68Ga, 82Rb, 86Y, 87Y, 89Sr, 90Sr, 90Y, 105Rh, 111Ag, 111In, 124I, 125I, 131I, 117mSn, 99mTc, 137Cs, 149Pm,153Sm, 149Tb, 152Tb, 155Tb, 161Tb, 166Ho, 177Lu, 186Re, 188Re, 201Tl, 211At, 215At, 217At, 218At, 209Bi, 211Bi, 212Bi, 213Bi, 203Pb, 212Pb, 210Po, 211Po, 212Po, 214Po, 215Po, 216Po, 218Po, 218Rn, 219Rn, 220Rn, 222Rn, 226Rn, 221Fr, 223Ra, 224Ra, 226Ra, 225Ac, 227Ac, 227Th, 228Th, 229Th, 230Th, 232Th, 231Pa, 233U, 234U, 235U, 236U, 238U, 237Np, 238Pu, 239Pu, 240Pu, 244Pu, 241Am, 244Cm, 245Cm, 248Cm, 249Cf, or 252Cf. In some embodiments, the radionuclide is 32P, 47Sc, 67Cu, 89Sr, 90Y, 105Rh, 111Ag, 117mSn, 131I, 149Pm, 153Sm, 166Ho, 177Lu, 186Re, 188Re, 211At, or 212Bi. In particular embodiments, the radionuclide is 177Lu. c) PEG moieties [0081] In some embodiments, the conjugate also includes one or more polyethylene glycol (PEG) moieties covalently attached to the integrin-binding peptide. In some instances, the PEG moiety is attached to a terminus of the peptide, i.e., the N-terminus or the C-terminus. In some cases, the conjugate includes two PEG moieties, e.g., one PEG moiety covalently attached to the N-terminus of the peptide and one PEG moiety covalently attached to the C-terminus of the peptide. In some embodiments, the PEG moiety covalently attached to a terminus of the peptide terminates in an amide, a carboxyl group, or a hydroxyl group. [0082] In some embodiments, the one or more PEG moieties of the conjugate each independently have a molecular weight of less than about 5000 Daltons (Da). In particular embodiments, the one or more PEG moieties each independently have a molecular weight of less than about 3000 Da. In certain embodiments, the PEG moieties are monodisperse PEG moieties having a defined chain length. PEG moieties having a defined chain length generally include PEG molecules of discrete molecular weights with an exactly defined number of repeating ethylene glycol units. Non-limiting examples of PEG moieties having a defined chain length include small, monodisperse PEG molecules having greater than about 90%, 91%, 92%, 93%, 94%, or 95% oligomer purity. [0083] In certain instances, the one or more PEG moieties of the conjugate are each independently selected from the group consisting of PEG11, PEG12 (PEG 800), PEG28 (PEG 1500), and (PEG28)2 (PEG 1500×2). In certain embodiments, the PEG moieties are the same. In particular embodiments, the PEG moieties are both PEG28 (PEG 1500). Other non-limiting examples of PEG units suitable for use as one or both PEG moieties include PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 900, PEG 1000, PEG 1100, PEG 1200, PEG 1300, PEG 1400, PEG 1600, PEG 1700, PEG 1800, PEG 1900, PEG 2000, PEG 2100, PEG 2200, PEG 2300, PEG 2400, PEG 2500, PEG 2600, PEG 2700, PEG 2800, PEG 2900, PEG 3000, PEG 3250, PEG 3350, PEG 3500, PEG 3750, PEG 4000, PEG 4250, PEG 4500, PEG 4750, and PEG 5000, as well as derivatives thereof such as branched PEG derivatives. In particular embodiments, these PEG molecules contain an exactly defined number of repeating units “n” and are monodisperse (e.g., having greater than about 95% oligomer purity). PEG moieties suitable for use are commercially available from EMD Chemicals, Inc. (San Diego, Calif.) and Polypure AS (Oslo, Norway). [0084] In some embodiments, the radionuclide of the conjugate is attached via a prosthetic group to the integrin-binding peptide, a first PEG moiety, or a second PEG moiety. In certain embodiments, the radionuclide is attached via a prosthetic group to the first PEG moiety. In particular embodiments, the radionuclide is attached via a prosthetic group as the most N- terminal moiety in the conjugate. Non-limiting examples of prosthetic groups include benzoyl groups (e.g., fluorobenzoic acid (FBA)), fluoropropionic acid (FPA), pyridine (Py), dipyridyl- tetrazine (Tz), trans-cyclooctene (TCO), derivatives thereof, and combinations thereof. In some embodiments, the radionuclide is covalently attached to the first PEG moiety via a benzoyl group such as FBA. d) Chelating moieties [0085] In some embodiments, the conjugate further includes a chelating moiety. In some instances, the chelating moiety is a dodecane tetraacetic acid (DOTA) moiety (1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid) covalently attached to the conjugate. In some embodiments, the radionuclide is attached via a chelating moiety to the integrin-binding protein, a first PEG moiety, or a second PEG moiety. In certain embodiments, the radionuclide is attached via a chelating moiety to the first PEG moiety. In particular embodiments, the radionuclide is attached via a chelating agent as the most N-terminal moiety in the conjugate. e) Albumin binding moieties [0086] In some embodiments, the conjugate includes an albumin binding moiety (ABM) covalently attached to the conjugate. The ABM can increase the half-life of the conjugate in serum, such as when administered to a subject. In some embodiments, the ABM is covalently attached to the peptide, a first PEG moiety, or a second PEG moiety. In some embodiments, the ABM includes a linker, such as a peptide linker that is covalently attached to the integrin-binding peptide, a first PEG moiety, or a second PEG moiety. In certain embodiments, the ABM comprises 4-(4- iodophenyl)butyric acid (IPA) or a homolog thereof with a shorter alkyl chain such as, e.g., 4-(4- iodophenyl)propionic acid or 4-(4-iodophenyl)acetic acid, or the ABM comprises 4-(4- methylphenyl)butyric acid or 4-(4-bromophenyl)butyric acid or a homolog thereof with a shorter alkyl chain such as, e.g., a propionic acid or acetic acid homolog thereof. In certain instances, the ABM is covalently attached to the first and/or second PEG moiety via a linker such as a glutamic acid (E) linker, a peptide linker such as a lysine-aspartic acid-aminobutyric acid (K-D-Abu) linker, or other suitable linker (e.g., amino acid or peptide linker) known to one of skill in the art. In certain embodiments, the ABM includes an ε-(4-(4-iodophenyl)butyl amide)lysine-glutamic acid moiety (“K(IPA)E”), which corresponds to IPA that is covalently attached to the side-chain of the lysine residue of a lysine-glutamic acid peptide linker. In certain other embodiments, the ABM includes a K(D-Abu-iodophenylbutyryl) moiety, which corresponds to IPA that is covalently attached to the aminobutyric acid of a lysine-aspartic acid-aminobutyric acid (K-D-Abu) peptide linker. In some embodiments, the ABM including the K(IPA)E or K(D-Abu-iodophenylbutyryl) moiety is covalently attached to the first PEG moiety. [0087] In some embodiments, the peptide conjugate has the structure of Formula (I):
Figure imgf000034_0001
(Formula I), designated [177Lu]Lu-DOTA-ABM-5G, where DOTA refers to the 1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid moiety of Formula (I), ABM refers to the K(D- Abu-iodophenylbutyryl) moiety of Formula (I), and 5G refers to a PEG28- GNGVPNLRGDLQVLGQRVGRT (SEQ ID NO: 3) -PEG28-C(O)NH2 peptide. 3. Pharmaceutical Compositions [0088] In some embodiments, the DNA repair enzyme inhibitor of the provided system is a component of a solution or composition, e.g., a pharmaceutical composition. In some embodiments, the peptide conjugate of the system is a component of a solution or composition, e.g., a pharmaceutical composition. In some embodiments, a single solution or composition, e.g., a single pharmaceutical composition, includes both the DNA repair enzyme inhibitor and the peptide conjugate. Such pharmaceutical compositions can include one or both of the DNA repair enzyme inhibitor and the peptide conjugate, together with one or more pharmaceutically- acceptable excipients, e.g., excipients suitable for injection and/or infusion. [0089] The provided systems, or one or more individual components thereof, can thus be formulated, for example, as compositions for administration in the form of a liquid. The liquid can be useful for delivery by injection, such as intratumoral injection, or intravenous infusion. In a composition for administration by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer (e.g., radioprotectant), and isotonic agent can also be included. [0090] The liquid compositions, whether they are solutions, suspensions or other like form, can also include one or more of the following: sterile diluents such as water for injection, saline solution (preferably physiological saline), Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which can serve as the solvent or suspending medium, polyethylene glycols, glycerin, cyclodextrin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as amino acids, acetates, citrates or phosphates; detergents, such as nonionic surfactants, polyols; and agents for the adjustment of tonicity such as sodium chloride or dextrose. The liquid compositions can include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. [0091] The provided pharmaceutical compositions for administration are preferably sterile. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and thimerosal. Compositions for administration can be enclosed in ampoule, a disposable syringe or a multiple- dose vial made of glass, plastic, or other material. [0092] Additional examples of suitable excipients for use with the provided pharmaceutical compositions include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline, syrup, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and polyacrylic acids such as Carbopols, e.g., Carbopol 941, Carbopol 980, Carbopol 981, etc. The compositions can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying agents; suspending agents; preserving agents such as methyl-, ethyl-, and propyl-hydroxy-benzoates (i.e., the parabens); pH adjusting agents such as inorganic and organic acids and bases; sweetening agents; coloring agents; and flavoring agents. The compositions can also comprise biodegradable polymer beads, dextran, and cyclodextrin inclusion complexes. [0093] For oral administration, the compositions can be in the form of tablets, lozenges, capsules, emulsions, suspensions, solutions, syrups, sprays, powders, and sustained-release formulations. Suitable excipients for oral administration include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like. [0094] In some embodiments, the pharmaceutical compositions take the form of a pill, tablet, or capsule, and thus, the composition can contain, along with the DNA repair enzyme inhibitor and peptide conjugate, any of the following: a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as starch or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof. The systems can also be formulated into a suppository disposed, for example, in a polyethylene glycol (PEG) carrier. [0095] Liquid compositions can be prepared by dissolving or dispersing the DNA repair enzyme inhibitor and peptide conjugate and optionally one or more pharmaceutically acceptable adjuvants in a carrier such as, for example, aqueous saline (e.g., 0.9% w/v sodium chloride), aqueous dextrose, glycerol, ethanol, and the like, to form a solution or suspension, e.g., for oral, topical, or intravenous administration. The systems can also be formulated into a retention enema. [0096] For topical administration, the compositions herein can be in the form of emulsions, lotions, gels, creams, jellies, solutions, suspensions, ointments, and transdermal patches. For delivery by inhalation, the composition can be delivered as a dry powder or in liquid form via a nebulizer. For parenteral administration, the compositions can be in the form of sterile injectable solutions and sterile packaged powders. Preferably, injectable solutions are formulated at a pH of about 4.5 to about 7.5. [0097] The compositions described herein can also be provided in a lyophilized form. Such compositions can include a buffer, e.g., bicarbonate, for reconstitution prior to administration, or the buffer can be included in the lyophilized composition for reconstitution with, e.g., water. The lyophilized composition can further comprise a suitable vasoconstrictor, e.g., epinephrine. The lyophilized composition can be provided in a syringe, optionally packaged in combination with the buffer for reconstitution, such that the reconstituted composition can be immediately administered to a patient. [0098] In some embodiments, the provided pharmaceutical composition includes one or more unit doses, wherein the amount of radioactivity present in a dose is between about 25 mCi and about 200 mCi. In certain embodiments, the amount of radioactivity present in a dose of the peptide conjugate is between about 25 mCi and about 50 mCi, about 25 mCi and about 100 mCi, about 25 mCi and about 150 mCi, about 25 mCi and about 200 mCi, about 50 mCi and about 100 mCi, about 50 mCi and about 150 mCi, about 50 mCi and about 200 mCi, about 100 mCi and about 150 mCi, about 100 mCi and about 200 mCi, or about 150 mCi and about 200 mCi. In some cases, the amount of radioactivity present in a unit dose is about 25 mCi, about 50 mCi, about 100 mCi, about 150 mCi or about 200 mCi. In some embodiments, the amount of radioactivity present within a dose (e.g., a therapeutically effective dose) is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mCi. In some embodiments, the amount of peptide conjugate in each unit dose is no more than about 500 µg, about 400 µg, about 300 µg, about 200 µg, or about 100 µg of peptide. In some cases, the amount of peptide conjugate in each unit dose is no more than about 100 μg. IV. Methods for Treating or Preventing a Disease [0099] In another aspect, the present disclosure provides various methods of preventing or treating a disease, e.g., an integrin-related disease, in a subject. The particular details and combinations of the steps of the methods have been shown to result in surprising improvements, such as unexpectedly high therapeutic efficacies in addressing integrin-related cancers. The methods generally include administering to the subject a therapeutically effective amount or dose of any of the DNA repair enzyme inhibitors disclosed herein, and a therapeutically effective amount or dose of any of the peptide conjugates disclosed herein. In some embodiments, the DNA repair enzyme inhibitor is administered before the peptide conjugate. Alternatively, it can be beneficial in some instances to administer the peptide conjugate before the DNA repair enzyme inhibitor. In still other cases, e.g., to further improve therapeutic outcomes and/or to streamline the process, the DNA repair enzyme inhibitor and the peptide conjugate are administered concurrently, e.g., in the same composition. In some embodiments, the treating of the disease in the subject includes decreasing or eliminating one or more signs or symptoms of the disease. [0100] The systems and compositions disclosed herein are particularly useful for treating diseases and disorders that are associated with the expression, overexpression, or activation of an integrin (e.g., αvβ6 integrin). Examples of diseases or disorders suitable for treatment with the systems and compositions described herein include, but are not limited to, allergy, anxiety disorder, autoimmune disease, behavioral disorder, birth defect, blood disorder, bone disease, cancer, chronic fibrosis, chronic obstructive pulmonary disease (COPD), chronic wounding skin disease, circulatory disease, tooth disease, depressive disorder, dissociative disorder, ear condition, eating disorder, eye condition, food allergy, food-borne illness, gastrointestinal disease, genetic disorder, heart disease, hormonal disorder, immune deficiency, infectious disease, inflammatory disease, insect-transmitted disease, nutritional disorder, kidney disease, leukodystrophy, liver disease, lung emphysema, mental health disorder, metabolic disease, mood disorder, musculodegenerative disorder, neurological disorder, neurodegenerative disorder, neuromuscular disorder, personality disorder, phobia, pregnancy complication, prion disease, prostate disease, psychological disorder, psychiatric disorder, respiratory disease, sexual disorder, skin condition, sleep disorder, speech-language disorder, sports injury, tropical disease, vestibular disorder, and wasting disease. Preferably, the αvβ6 integrin-mediated disease or disorder is cancer, an inflammatory disease, an autoimmune disease, chronic fibrosis, chronic obstructive pulmonary disease (COPD), lung emphysema, and chronic wounding skin disease (e.g., epidermolysis bullosa). [0101] In particular embodiments, the compositions and systems described herein are used for the prevention or treatment of cancer. Cancer generally includes any of various malignant neoplasms characterized by the proliferation of anaplastic cells that tend to invade surrounding tissue and metastasize to new body sites. Non-limiting examples of different types of cancer suitable for treatment using the provided systems or compositions include ovarian cancer, breast cancer, lung cancer, bladder cancer, thyroid cancer, liver cancer, pleural cancer, pancreatic cancer, cervical cancer, prostate cancer, testicular cancer, colorectal cancer, colon cancer, anal cancer, bile duct cancer, gastrointestinal carcinoid tumors, esophageal cancer, gall bladder cancer, rectal cancer, appendix cancer, small intestine cancer, stomach (gastric) cancer, renal cancer (i.e., renal cell carcinoma), cancer of the central nervous system, skin cancer, oral squamous cell carcinoma, choriocarcinomas, head and neck cancers, bone cancer, osteogenic sarcomas, fibrosarcoma, neuroblastoma, glioma, melanoma, leukemia (e.g., acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, or hairy cell leukemia), lymphoma (e.g., non-Hodgkin's lymphoma, Hodgkin's lymphoma, B-cell lymphoma, or Burkitt's lymphoma), and multiple myeloma. In some embodiments, the cancer is an αvβ6 integrin-mediated disease or disorder. In certain embodiments, the cancer is lung cancer, breast cancer, colorectal cancer, pancreatic cancer, ovarian cancer, cervical cancer, oral squamous cell carcinoma, skin squamous cell carcinoma, stomach cancer, or endometrial cancer. In some cases, the subject has a primary lesion (e.g., a primary tumor). In some cases, the subject has a metastasis (e.g., a metastatic form of any of the cancer types described herein). In some cases, the subject has a primary lesion and a metastasis. In some embodiments, the subject has a pancreatic cancer such as locally advanced or metastatic pancreatic cancer, locally advanced, unresectable or metastatic pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma (PDAC). [0102] One skilled in the art will also appreciate that the provided systems and compositions can be co-administered with other therapeutic agents for the treatment of cancer. Suitable anti-cancer agents for combination therapy include, without limitation, cytotoxins and agents such as antimetabolites, alkylating agents, anthracyclines, antibiotics, antimitotic agents, procarbazine, hydroxyurea, asparaginase, corticosteroids, interferons, radiopharmaceuticals, peptides with anti- tumor activity such as TNF-α, pharmaceutically acceptable salts thereof; derivatives thereof, prodrugs thereof, and combinations thereof. For example, a pharmaceutical composition comprising the provided DNA repair enzyme inhibitor and/or peptide conjugate can be administered to a patient before, during, or after administration of an anti-cancer agent or combination of anti-cancer agents either before, during, or after chemotherapy. Treatment with the DNA repair enzyme inhibitor and/or peptide conjugate after chemotherapy can be particularly useful for reducing and/or preventing recurrence of the tumor or metastasis. In some embodiments, the anti-cancer agent can be covalently linked directly or indirectly (e.g., via liposomes or nanoparticles) to a peptide conjugate as described herein. [0103] Inflammatory diseases typically include diseases or disorders characterized or caused by inflammation. Inflammation can result from a local response to cellular injury that is marked by capillary dilatation, leukocytic infiltration, redness, heat, and pain that serves as a mechanism initiating the elimination of noxious agents and damaged tissue. The site of inflammation can include, for example, the lungs, the pleura, a tendon, a lymph node or gland, the uvula, the vagina, the brain, the spinal cord, nasal and pharyngeal mucous membranes, a muscle, the skin, bone or bony tissue, a joint, the urinary bladder, the retina, the cervix of the uterus, the canthus, the intestinal tract, the vertebrae, the rectum, the anus, a bursa, a follicle, and the like. Examples of inflammatory diseases suitable for treatment using the provided systems and compositions include, but are not limited to, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), rheumatoid diseases such as rheumatoid arthritis, fibrositis, pelvic inflammatory disease, acne, psoriasis, actinomycosis, dysentery, biliary cirrhosis, Lyme disease, heat rash, Stevens-Johnson syndrome, mumps, pemphigus vulgaris, and blastomycosis. [0104] Autoimmune diseases generally include diseases or disorders resulting from an immune response against a self-tissue or tissue component such as, e.g., a self-antibody response or cell- mediated response. Examples of autoimmune diseases suitable for treatment using the provided systems and compositions include, without limitation, organ-specific autoimmune diseases, in which an autoimmune response is directed against a single tissue, such as Type I diabetes mellitus, myasthenia gravis, vitiligo, Graves' disease, Hashimoto's disease, Addison's disease, autoimmune gastritis, and autoimmune hepatitis; and non-organ specific autoimmune diseases, in which an autoimmune response is directed against a component present in several or many organs throughout the body, such as systemic lupus erythematosus, progressive systemic sclerosis and variants, polymyositis, and dermatomyositis. Additional autoimmune diseases include, for example, pernicious anemia, primary biliary cirrhosis, autoimmune thrombocytopenia, Sjögren's syndrome, and multiple sclerosis. [0105] One skilled in the art will appreciate that the provided systems and compositions can be co-administered with other therapeutic agents for the treatment of inflammatory or autoimmune diseases. Suitable anti-inflammatory agents for combination therapy include, without limitation, corticosteroids, non-steroidal anti-inflammatory agents, antibodies such as infliximab, 5- aminosalicylates, antibiotics, pharmaceutically acceptable salts thereof; derivatives thereof, prodrugs thereof, and combinations thereof. Suitable immunosuppressive agents for combination therapy include, without limitation, azathioprine and metabolites thereof, anti-metabolites such as methotrexate, immunosuppressive antibodies, mizoribine monophosphate, cyclosporine, scoparone, FK-506 (tacrolimus), FK-778, rapamycin (sirolimus), glatiramer acetate, mycopehnolate, pharmaceutically acceptable salts thereof, derivatives thereof, prodrugs thereof, and combinations thereof. [0106] In another embodiment, the provided systems and compositions are useful for treating an infection or infectious disease caused by, e.g., a virus, bacterium, fungus, parasite, or any other infectious agent. Non-limiting examples of infectious diseases suitable for treatment include, but are not limited to, acquired immunodeficiency syndrome (AIDS/HIV) or HIV-related disorders, Alpers syndrome, anthrax, bovine spongiform encephalopathy (mad cow disease), chicken pox, cholera, conjunctivitis, Creutzfeldt-Jakob disease (CJD), dengue fever, Ebola, elephantiasis, encephalitis, fatal familial insomnia, Fifth's disease, Gerstmann-Straussler-Scheinker syndrome, hantavirus, helicobacter pylori, hepatitis (hepatitis A, hepatitis B, hepatitis C), herpes, influenza (e.g., avian influenza A (bird flu)), Kuru, leprosy, Lyme disease, malaria, hemorrhagic fever (e.g., Rift Valley fever, Crimean-Congo hemorrhagic fever, Lassa fever, Marburg virus disease, and Ebola hemorrhagic fever), measles, meningitis (viral, bacterial), mononucleosis, nosocomial infections, otitis media, pelvic inflammatory disease (PID), plague, pneumonia, polio, prion disease, rabies, rheumatic fever, roseola, Ross River virus infection, rubella, salmonellosis, septic arthritis, sexually transmitted diseases (STDs), shingles, smallpox, strep throat, tetanus, toxic shock syndrome, toxoplasmosis, trachoma, tuberculosis, tularemia, typhoid fever, valley fever, whooping cough, and yellow fever. [0107] In certain embodiments, the provided systems and compositions are useful for treating a neurological or musculoskeletal disorder. Examples of such disorders include, but are not limited to, Alzheimer's disease, Aicardi syndrome, amnesia, amyotrophic lateral sclerosis (Lou Gehrig's Disease), anencephaly, aphasia, arachnoiditis, Arnold Chiari malformation, ataxia telangiectasia, Batten disease, Bell's palsy, brachial plexus injury, brain injury, brain tumor, Charcol-Marie-Tooth disease, encephalitis, epilepsy, essential tremor, Guillain-Barre Syndrome, hydrocephalus, hyperhidrosis, Krabbes disease, meningitis, Moebius syndrome, muscular dystrophy, multiple sclerosis, Parkinson's disease, peripheral neuropathy, postural or orthostatic tachycardia syndrome, progressive supranuclear palsy, Reye's syndrome, shingles, Shy-Drager Syndrome, spasmodic torticollis, spina bifida, spinal muscular atrophy, Stiff Man syndrome, synesthesia, syringomyelia, thoracic outlet syndrome, Tourette syndrome, toxoplasmosis, and trigeminal neuralgia. [0108] Administration of the DNA repair enzyme inhibitors and peptide conjugates described herein with a suitable pharmaceutical excipient as necessary can be carried out via any of the accepted modes of administration. Thus, administration can be, for example, intravenous, topical, subcutaneous, transcutaneous, transdermal, intramuscular, oral, intra-joint, parenteral, intra- arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, or by inhalation. In some embodiments here, the DNA repair enzyme inhibitor and the peptide conjugate are administered intravenously. [0109] In some embodiments, the dose of the peptide conjugate administered to a subject contains between about 25 mCi and about 200 mCi radioactivity. In some embodiments, the dose of the conjugate contains between about 25 mCi and about 100 mCi radioactivity. In some embodiments, the dose of the therapeutic conjugate contains between about 25 mCi and about 150 mCi radioactivity. In some cases, the dose administered contains about 25 mCi, about 50 mCi, about 100 mCi, about 150 mCi, or about 200 mCi radioactivity. In some embodiments, the amount of peptide in the dose of the therapeutic conjugate is no more than about 500 µg, about 400 µg, about 300 µg, about 200 µg, or about 100 µg of peptide. In some cases, the amount of peptide administered in the dose of the therapeutic conjugate is no more than about 100 μg of peptide. In some embodiments, the dose of the therapeutic conjugate does not cause an adverse event (AE) in the subject, such as, e.g., an AE greater than or equal to grade 3 (i.e., severe AE). In some embodiments, the dose of the therapeutic conjugate does not exceed a radiation dose of about 23 Gy to the kidneys and/or a radiation dose of about 1.5 Gy to the bone marrow. [0110] In some embodiments, the amount of the DNA repair enzyme inhibitor administered to a subject contains between about 1 mg and about 3500 mg of the DNA repair enzyme inhibitor, e.g., between about 1 mg and about 130 mg, between about 2.3 mg and about 300 mg, between about 5.1 mg and about 680 mg, between about 12 mg and about 1500 mg, or between about 26 mg and about 3500 mg. In terms of upper limits, the administered amount of the DNA repair enzyme inhibitor can be, for example, less than about 3500 mg, e.g., less than about 1500 mg, less than about 680 mg, less than about 300 mg, less than about 130 mg, less than about 59 mg, less than about 26 mg, less than about 12 mg, less than about 5.1 mg, or less than about 2.3 mg. In terms of lower limits, the administered amount of the DNA repair enzyme inhibitor can be, for example, greater than about 1 mg, e.g., greater than about 2.3 mg, greater than about 5.1 mg, greater than about 12 mg, greater than about 26 mg, greater than about 59 mg, greater than about 130 mg, greater than about 300 mg, greater than about 680 mg, or greater than about 1500 mg. Higher amounts, e.g., greater than about 3500 mg, and lower amounts, e.g., less than about 1 mg, are also contemplated. [0111] The DNA repair enzyme inhibitor and peptide conjugate can be administered by infusion, such as over a period of time, such as minutes or hours. In some embodiments, the DNA repair enzyme inhibitor and peptide conjugate are infused over a period of minutes, such as about 1 minute, about 2 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, or about 55 minutes. In some embodiments, the DNA repair enzyme inhibitor and peptide conjugate are infused over a period of about 30 minutes. In some embodiments, the DNA repair enzyme inhibitor and peptide conjugate are infused over a period of hours, such as about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours. In some embodiments, the DNA repair enzyme inhibitor and peptide conjugate are infused over a period of about 4 hours. In some embodiments, the DNA repair enzyme inhibitor and peptide conjugate are co-infused with a solution of amino acids. In some cases, the infusion of the amino acid solution is commenced prior to the infusion of the DNA repair enzyme inhibitor and peptide conjugate. [0112] In some embodiments, the DNA repair enzyme inhibitor and/or peptide conjugate are administered to a subject once, twice, three times, four times, or five times over a course of treatment. Subsequent administration of the DNA repair enzyme inhibitor and/or peptide conjugate can occur at defined intervals of time, separated by days, weeks, or months. In some cases, the DNA repair enzyme inhibitor and/or peptide conjugate are administered at a subsequent time if a tumor or cancerous cells reappear, continue to grow, or otherwise are not fully treated after the first administration of the DNA repair enzyme inhibitor and peptide conjugate. In some cases, the DNA repair enzyme inhibitor and/or peptide conjugate are administered again at a subsequent time if the subject does not have a complete response to the first treatment, experiences a partial response, a stable response or progressive disease. [0113] In some embodiments, the dosimetry and/or biodistribution of the peptide conjugate is evaluated following administration of the peptide conjugate to a subject. As a non-limiting example, the dosimetry and biodistribution of the peptide conjugate can be evaluated using nuclear imaging at 1 day and/or 7 days after administration (e.g., infusion) to a subject. In some cases, the subject undergoes whole body planar imaging (e.g., anterior and posterior view) and single photon emission computerized tomography/computed tomography (SPECT/CT) (e.g., skull vertex extending through the perineum, terminating at the proximal thighs; approx. 2-4 bed positions) at about 24 and/or 168 hours following administration of the therapeutic conjugate. In some cases, serial blood samples are drawn at about 5, 15, 30, 60, 120 and/or 180 minutes following administration of the peptide conjugate, e.g., for evaluation of biodistribution. In some cases, full chemistry, hematology, liver function tests, and/or EKG are performed at 1 day and/or 7 days (e.g., ± 48 hours) following administration of the peptide conjugate. [0114] Methods for dosimetry analysis are known in the art and include, but are not limited to, descriptive statistics (e.g., mean, median, standard deviation, etc.) reported for AUC based on activity concentration-time curves of the therapeutic conjugate (e.g., separately for discernible thoracic and abdominal organs, target lesion, and blood), maximum uptake (e.g., achieved in %) at the target lesion and in discernible organs, specific absorbed dose per organ (μGy/MBq), and cumulative absorbed organ doses (Gy). In some cases, organs receiving the highest absorbed dose assessed by equivalent dose to tissue are tabulated using frequency and proportion. In some cases, graphic tools are used to describe the endpoints. [0115] In some embodiments, the distribution of the peptide conjugate is determined using whole-body planar SPECT/CT imaging. As a non-limiting example, radiation-absorbed doses to kidneys, stomach, uninvolved liver, bone marrow and the whole body together with any other organs displaying accumulation of the therapeutic conjugate are calculated based on the analysis of serial blood counts and SPECT/CT scans. In some cases, the SPECT/CT images are used to compute the volumetric absorbed radiation dose in the diseased and healthy tissues, e.g., activity concentration-time curves for normal tissues can be generated from region-of-interest (ROI) analysis from the SPECT/CT scans, activity concentration-time curves for red marrow and heart can be generated from blood activity concentration measured by a well scintillation counter, and/or volumes of interest (VOI) can be generated for each patient. In some cases, the activity concentration in red bone marrow is equal to that in blood. In some cases, activity concentration- time curves are integrated (e.g., either analytically or numerically as appropriate) to yield AUC values from which so-called residence times are generated. In some cases, these data are inputted into an organ dosimetry software (e.g., OLINDA/EXM) to generate absorbed dose estimates for normal tissues. In some cases, a supplementary dosimetry assessment is performed including, e.g., lesion absorbed dose estimates based on image ROI analysis. In some cases, absorbed doses are normalized to administered activity and expressed in terms of mGy/MBq. [0116] In some embodiments, treatment with the DNA repair enzyme and peptide conjugate results in stable disease, partial remission or complete remission in the subject (e.g., the methods described herein comprise administering to the subject a dose of the DNA repair enzyme and peptide conjugate that kills or otherwise slows the growth or progression of cancer cells and leads to stable disease or to partial or complete remission of the cancer in the subject). In some embodiments, treatment with the DNA repair enzyme and peptide conjugate results in a reduction in metastases of the cancer in the subject (e.g., the methods described herein comprise administering to the subject a dose of the DNA repair enzyme and peptide conjugate that reduces metastases of the cancer in the subject). In some embodiments, treatment with the DNA repair enzyme and peptide conjugate results in a reduction in volume, size or growth of a tumor in the subject (e.g., the methods described herein comprise administering to the subject a dose of the DNA repair enzyme and peptide conjugate that reduces the volume, size or growth of a tumor in the subject). In some embodiments, treatment with the DNA repair enzyme and peptide conjugate results in an increased responsiveness of the cancer to a subsequently administered anti-cancer agent (e.g., the methods described herein comprise administering to the subject a dose of the DNA repair enzyme and peptide conjugate that increases responsiveness of the cancer to a subsequently administered anti-cancer agent). [0117] In some embodiments, the provided method further includes obtaining a test sample from the subject. The test sample can include, for example, a blood sample, a tissue sample, a urine sample, a saliva sample, a cerebrospinal fluid sample, or a combination thereof. In some embodiments, the provided method further includes determining the level of one or more biomarkers in the obtained test sample. Determining the presence or level of biomarkers(s) can be used to, as non-limiting examples, determine response to treatment or to select an appropriate composition for the prevention or treatment of the disease. [0118] In some embodiments, the provided method further includes comparing the determined level of the one of more biomarkers in the obtained test sample to the level of the one or more biomarkers in a reference sample. The reference sample can be obtained, for example, from the subject, with the reference sample being obtained prior to the obtaining of the test sample, e.g., prior to the administering to the subject of the therapeutically effective amount of the provided materials. In this way, the reference sample can provide information about baseline levels of the biomarkers in the sample before the treatment, and the test sample can provide information about levels of the biomarkers after the treatment. [0119] Alternatively, the reference sample can be obtained, for example, from a different subject, e.g., a subject in which the treatment is not provided according to the provided methods. In this way, the reference sample can provide information about baseline levels of the biomarkers without treatment, and the test sample can provide information about levels of the biomarkers with treatment. The reference sample can also be obtained, for example, from a population of subjects, e.g., subjects in which the treatment is not provided according to the provided method. In this way, the reference sample can provide population-averaged information about baseline levels of the biomarkers without treatment, and the test sample can provide information about levels of the biomarkers with treatment. [0120] The reference sample can also be obtained from an individual or a population of individuals after treatment is provided according to the provided methods, and can serve as, for example, a positive control sample. In some embodiments, the reference sample is obtained from normal tissue. In some embodiments, the reference sample is obtained from abnormal tissue. [0121] Depending on the biomarker, an increase or a decrease relative to a normal control or reference sample can be indicative of the presence of a disease, or response to treatment for a disease. In some embodiments, an increased level of a biomarker in a test sample, and hence the presence of a disease, e.g., an infectious disease or cancer, increased risk of the disease, or response to treatment is determined when the biomarker levels are at least, 1.1-fold, e.g., at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8- fold, at least 1.9-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 13-fold, at least 14-fold, at least 15-fold, at least 16-fold, at least 17-fold, at least 18-fold, at least 19-fold, or at least 20-fold higher in comparison to a negative control. In other embodiments, a decreased level of a biomarker in the test sample, and hence the presence of the disease, increased risk of the disease, or response to treatment is determined when the biomarker levels are at least 1.1-fold, e.g., at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 13-fold, at least 14-fold, at least 15-fold, at least 16-fold, at least 17-fold, at least 18-fold, at least 19-fold, or at least 20-fold lower in comparison to a negative control. [0122] The biomarker levels can be detected using any method known in the art, including the use of antibodies specific for the biomarkers. Exemplary methods include, without limitation, polymerase chain reaction (PCR), Western Blot, dot blot, ELISA, radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, FACS analysis, electrochemiluminescence, and multiplex bead assays, e.g., using Luminex or fluorescent microbeads. In some instances, nucleic acid sequencing is employed. [0123] In certain embodiments, the presence of decreased or increased levels of one or more biomarkers is indicated by a detectable signal, e.g., a blot, fluorescence, chemiluminescence, color, or radioactivity, in an immunoassay or PCR reaction, e.g., quantitative PCR. This detectable signal can be compared to the signal from a reference sample or to a threshold value. [0124] In some embodiments, the results of the biomarker level determinations are recorded in a tangible medium. For example, the results of diagnostic assays, e.g., the observation of the presence or decreased or increased presence of one or more biomarkers, and the diagnosis of whether or not there is an increased risk or the presence of a disease, e.g., an infectious disease or cancer, or whether or not a subject is responding to treatment can be recorded, for example, on paper or on electronic media, e.g., audio tape, a computer disk, a CD-ROM, or a flash drive. [0125] In some embodiments, the provided method further includes the step of providing to the subject a diagnosis and/or the results of treatment. V. Kits [0126] Also provided herein are kits to facilitate and/or standardize the use of the systems and compositions described herein, as well as to facilitate the methods described herein. Materials and reagents to carry out these various methods can be provided in kits to facilitate execution of the methods. As used herein, the term “kit” includes a combination of articles that facilitates a process, assay, analysis, or manipulation. In particular, kits comprising the conjugates or compositions of the conjugates can be stored and/or shipped to locations where the imaging is to be performed such as to a clinic or hospital. [0127] Kits can contain chemical reagents as well as other components. In addition, the kits containing the provided DNA repair enzyme and peptide conjugate can include, without limitation, instructions to the kit user. Kits of the DNA repair enzyme and peptide conjugate or compositions thereof can also be packaged for convenient storage and safe shipping, for example, as ampules or other vials packaged in a box having a lid. VI. Exemplary Embodiments [0128] The following embodiments are contemplated. All combinations of features and embodiments are contemplated. [0129] Embodiment 1: A system comprising: a DNA repair enzyme inhibitor; and a peptide conjugate comprising an integrin-binding peptide and a radionuclide. [0130] Embodiment 2: An embodiment of embodiment 1, wherein the DNA repair enzyme inhibitor comprises a poly-ADP ribose polymerase (PARP) inhibitor. [0131] Embodiment 3: An embodiment of embodiment 2, wherein the PARP inhibitor comprises olaparib, niraparib, rucaparib, talazoparib, or a combination thereof. [0132] Embodiment 4: An embodiment of embodiment 3, wherein the PARP inhibitor comprises olaparib. [0133] Embodiment 5: An embodiment of any one of embodiments 1-4, wherein the integrin- binding peptide comprises an αvβ6 integrin-binding peptide. [0134] Embodiment 6: An embodiment of any one of embodiments 1-5, wherein the integrin- binding peptide comprises the amino acid sequence RGDLX1X2X3 (SEQ ID NO:50), wherein: X1 and X2 are each independently an amino acid; and X3 is L or I. [0135] Embodiment 7: An embodiment of any one of embodiments 1-6, wherein the integrin- binding peptide comprises the amino acid sequence of any one of SEQ ID NOs: 1-49. [0136] Embodiment 8: An embodiment of embodiment 7, wherein the integrin-binding peptide comprises the amino acid sequence of SEQ ID NO: 3. [0137] Embodiment 9: An embodiment of any one of embodiments 1-8, wherein the peptide conjugate further comprises a polyethylene glycol (PEG) moiety covalently attached to a terminus of the integrin-binding peptide. [0138] Embodiment 10: An embodiment of embodiment 9, wherein the PEG moiety comprises PEG28 (PEG1500). [0139] Embodiment 11: An embodiment of embodiment 9 or 10, wherein the peptide conjugate further comprises a second PEG moiety covalently attached to a second terminus of the integrin- binding peptide. [0140] Embodiment 12: An embodiment of embodiment 11, wherein the second PEG moiety comprises PEG28 (PEG1500). [0141] Embodiment 13: An embodiment of any one of embodiments 1-12, wherein the radionuclide comprises 177Lu, 3H, 18F, 32P, 35S, 47Sc, 55Co, 60Cu, 61Cu, 62Cu, 64Cu, 66Ga, 67Cu, 67Ga, 68Ga, 82Rb, 86Y, 87Y, 89Sr, 90Sr, 90Y, 105Rh, mAg, mIn, 124I, 125I, 131I, 117mSn, 99mTc, 137Cs, 149Pm, 153Sm, 149Tb, 152Tb, 155Tb, 161Tb, 166Ho, 186Re, 188Re, 201T1, 211At, 215At, 217At, 218At, 209Bi, 21 , 212Bi, 213Bi, 203Pb, 212Pb, 210Po, 211Po, 212Po, 214Po, 215Po, 216Po, 218Po, 218Rn, 219Rn, 220Rn, 222Rn, 226Rn, 221Fr, 223Ra, 224Ra, 226Ra, 225Ac, 227Ac, 227Th, 228Th, 229Th, 230Th, 232Th, 231Pa, 23U, 234U, 235U, 236U, 238U, 237Np, 238Pu, 239Pu, 240Pu, 244Pu, 241Am, 244Cm, 245Cm, 248Cm, 249Cf, or 252Cf. [0142] Embodiment 14: An embodiment of embodiment 13, wherein the radionuclide comprises 177Lu, 32P, 47Sc, 67Cu, 89Sr, 90Y, 105Rh, mAg, 117mSn, 131I, 149Pm, 153Sm, 166Ho, 186Re, 188Re, 211At, 212Pb or 212Bi. [0143] Embodiment 15: An embodiment of embodiment 14, wherein the radionuclide comprises 177Lu. [0144] Embodiment 16: An embodiment of any one of embodiments 1-15, wherein the peptide conjugate further comprises a chelating moiety covalently attached to the integrin-binding peptide, wherein the radionuclide is complexed with the chelating moiety. [0145] Embodiment 17: An embodiment of embodiment 16, wherein the chelating moiety comprises a dodecane tetraacetic acid (DOTA) moiety. [0146] Embodiment 18: An embodiment of any one of embodiments 1-15, wherein the radionuclide is covalently attached directly or indirectly to the integrin-binding peptide. [0147] Embodiment 19: An embodiment of any one of embodiments 1-4, wherein the peptide conjugate has the structure of Formula (I):
Figure imgf000050_0001
, wherein 5G is a PEG28-GNGVPNLRGDLQVLGQRVGRT (SEQ ID NO: 3)-PEG28-C(O)NH2 peptide. [0148] Embodiment 20: An embodiment of any one of embodiments 1-19, wherein the ratio of the amount of the DNA repair enzyme inhibitor to the radioactivity of the peptide conjugate in the system is between 5 µg per mCi and 150 mg per mCi. [0149] Embodiment 21: A composition comprising the system of any one of embodiments 1-20. [0150] Embodiment 22: An embodiment of embodiment 21, wherein the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. [0151] Embodiment 23: A cell comprising the system of any one of embodiments 1-20. [0152] Embodiment 24: An embodiment of embodiment 23, wherein the cell is a mammalian cell. [0153] Embodiment 25: An embodiment of embodiment 24, wherein the cell is a human cell. [0154] Embodiment 26: A method of preventing or treating an integrin-related disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of a DNA repair enzyme inhibitor; and administering to the subject a therapeutically effective dose of a peptide conjugate comprising an integrin-binding peptide and a radionuclide. [0155] Embodiment 27: An embodiment of embodiment 26, wherein the integrin-related disease comprises an integrin-related cancer. [0156] Embodiment 28: An embodiment of embodiment 27, wherein the integrin-related cancer comprises an αvβ6 integrin-related cancer. [0157] Embodiment 29: An embodiment of embodiment 28, wherein the αvβ6 integrin-related cancer comprises pancreatic cancer, breast cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, oral squamous cell carcinoma, skin squamous cell carcinoma, stomach cancer, or endometrial cancer. [0158] Embodiment 30: An embodiment of any one of embodiments 27-29, wherein the integrin-related cancer comprises a metastatic cancer. [0159] Embodiment 31: An embodiment of any one of embodiments 26-30, wherein the DNA repair enzyme inhibitor comprises a PARP inhibitor. [0160] Embodiment 32: An embodiment of embodiment 31, wherein the PARP inhibitor comprises olaparib, niraparib, rucaparib, talazoparib, or a combination thereof. [0161] Embodiment 33: An embodiment of embodiment 32, wherein the PARP inhibitor comprises olaparib. [0162] Embodiment 34: An embodiment of any one of embodiments 26-33, wherein the integrin-binding peptide comprises an αvβ6 integrin-binding peptide. [0163] Embodiment 35: An embodiment of any one of embodiments 26-34, wherein the integrin-binding peptide comprises the amino acid sequence RGDLX1X2X3 (SEQ ID NO:50), wherein: X1 and X2 are each independently an amino acid; and X3 is L or I. [0164] Embodiment 36: An embodiment of any one of embodiments 26-35, wherein the integrin-binding peptide comprises the amino acid sequence of any one of SEQ ID NOs: 1-49. [0165] Embodiment 37: An embodiment of embodiment 36, wherein the integrin-binding peptide comprises the amino acid sequence of SEQ ID NO: 3. [0166] Embodiment 38: An embodiment of any one of embodiments 26-37, wherein the peptide conjugate further comprises a polyethylene glycol (PEG) moiety covalently attached to a terminus of the integrin-binding peptide. [0167] Embodiment 39: An embodiment of embodiment 38, wherein the PEG moiety comprises PEG28 (PEG1500). [0168] Embodiment 40: An embodiment of embodiment 38 or 39, wherein the peptide conjugate further comprises a second PEG moiety covalently attached to a second terminus of the integrin- binding peptide. [0169] Embodiment 41: An embodiment of embodiment 40, wherein the second PEG moiety comprises PEG28 (PEG1500). [0170] Embodiment 42: An embodiment of any one of embodiments 26-41, wherein the radionuclide comprises 177Lu, 3H, 18F, 32P, 35S, 47Sc, 55Co, 60Cu, 61Cu, 62Cu, 64Cu, 66Ga, 67Cu, 67Ga, 68Ga, 82Rb, 86Y, 87Y, 89Sr, 90Sr, 90Y, 105Rh, mAg, mIn, 124I, 125I, 131I, 117mSn, 99mTc, 137Cs, 149Pm, 153Sm, 149Tb, 152Tb, 155Tb, 161Tb, 166Ho, 186Re, 188Re, 201T1, 211At, 215At, 217At, 218At, 209Bi, 211Bi, 212Bi, 213Bi, 203Pb, 212Pb, 210Po, 211Po, 212Po, 214Po, 215Po, 216Po, 218Po, 218Rn, 219Rn, 220Rn, 222Rn, 226Rn, 221Fr, 223Ra, 224Ra, 226Ra, 225Ac, 227Ac, 227Th, 228Th, 229Th, 230Th, 232Th, 231Pa, 23U, 234U, 235U, 236U, 238U, 237Np, 238Pu, 239Pu, 240Pu, 244Pu, 241Am, 244Cm, 245Cm, 248Cm, 249Cf, or 252Cf. [0171] Embodiment 43: An embodiment of embodiments 42, wherein the radionuclide comprises 177Lu, 32P, 47Sc, 67Cu, 89Sr, 90Y, 105Rh, mAg, 117mSn, 131I, 149Pm, 153Sm, 166Ho, 186Re, 188Re, 211At, 212Pb or 212Bi. [0172] Embodiment 44: An embodiment of embodiment 43, wherein the radionuclide comprises 177Lu. [0173] Embodiment 45: An embodiment of any one of embodiments 26-44, wherein the peptide conjugate further comprises a chelating moiety covalently attached to the integrin-binding peptide, wherein the radionuclide is complexed with the chelating moiety. [0174] Embodiment 46: An embodiment of embodiment 45, wherein the chelating moiety comprises a DOTA moiety. [0175] Embodiment 47: An embodiment of any one of embodiments 26-44, wherein the radionuclide is covalently attached directly or indirectly to the integrin-binding peptide. [0176] Embodiment 48: An embodiment of any one of embodiments 26-33, wherein the peptide conjugate has the structure of Formula (I):
Figure imgf000053_0001
, wherein 5G is a PEG28-GNGVPNLRGDLQVLGQRVGRT (SEQ ID NO: 3)-PEG28-C(O)NH2 peptide. [0177] Embodiment 49: An embodiment of any one of embodiments 26-47, wherein the therapeutically effective dose of the peptide conjugate comprises a radioactivity between 25 mCi and 200 mCi. [0178] Embodiment 50: An embodiment of any one of embodiments 26-49, wherein the therapeutically effective amount comprises between 1 mg and 3500 mg of the DNA repair enzyme inhibitor. [0179] Embodiment 51: An embodiment of any one of embodiments 26-50, wherein the therapeutically effective amount of the DNA repair enzyme inhibitor is administered prior to the therapeutically effective dose of the peptide conjugate. [0180] Embodiment 52: An embodiment of any one of embodiments 26-50, wherein the therapeutically effective amount of the DNA repair enzyme inhibitor is administered subsequent to the therapeutically effective dose of the peptide conjugate. [0181] Embodiment 53: An embodiment of any one of embodiments 26-50, wherein the therapeutically effective amount of the DNA repair enzyme inhibitor is administered concurrently with the therapeutically effective dose of the peptide conjugate. [0182] Embodiment 54: An embodiment of any one of embodiments 26-53, wherein the method further comprises administering one, two or three additional therapeutically effective amounts of the DNA repair enzyme inhibitor. [0183] Embodiment 55: An embodiment of any one of embodiments 26-54, wherein the method further comprises administering one, two or three additional therapeutically effective doses of the peptide conjugate. EXAMPLES [0184] The present disclosure will be better understood in view of the following non-limiting examples. The following examples are intended for illustrative purposes only and do not limit in any way the scope of the present invention. Example 1. Effect of provided therapeutic system on cell viability. [0185] The peptide conjugate DOTA-ABM-5G was synthesized using standard Fmoc chemistry and radiolabeled with the β-emitter lutetium-177. As described above, DOTA refers to the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid moiety of the peptide conjugate, ABM refers to the K(D-Abu-iodophenylbutyryl) moiety of the peptide conjugate, and 5G refers to a PEG28-GNGVPNLRGDLQVLGQRVGRT (SEQ ID NO: 3)-PEG28-C(O)NH2 peptide. The radiotherapy agent [177Lu]Lu-DOTA-ABM-5G (177Lu-1) was synthesized at 0.5-Ci/μmol molar activity in > 98% radiochemical purity. In vitro cell binding and internalization of 177Lu-1 were evaluated in the αvβ6 integrin-positive human pancreatic cancer Capan-1 cells. Rapid cell binding (52% at 1 h) and internalization (> 78% of bound at 1 h) of the 177Lu-1 was observed in the Capan- 1 cells. [0186] Cytotoxicity was also evaluated by using a 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4- disulfophenyl)-2H-tetrazolium, monosodium salt (WST-1) assay in Capan-1 cells. The cells were incubated with Olaparib, 177Lu-1, or Olaparib + 177Lu-1 combination for 24, 72, and 120 h. Results are shown in FIG. 1In the WST-1 assay, the combination of Olaparib + 177Lu-1 resulted in significantly decreased cell viability at 120 h post treatment, p ≤ 0.01; 29% viability vs. 42% for 177Lu-1 alone and 45% for Olaparib alone. Example 2. In vivo biodistribution of provided therapeutic system. [0187] In vivo biodistribution of 177Lu-1 in mice bearing Capan-1 tumors was evaluated at 4, 24, 48, and 72 h post injection. The biodistribution study demonstrated uptake and slow washout over time of 177Lu-1 in the Capan-1 tumor (decay-corrected percentage of injected dose per gram of tissue, % ID/g: 4.4±0.5% ID/g at 4 h and 3.4±0.3% ID/g at 72 h; FIG. 2). Kidneys were the predominant clearance route with 18.0±1.5% ID/g at 4 h and 10.6±2.8% ID/g at 72 h. Example 3. Therapeutic efficacy of provided therapeutic system. [0188] Therapeutic efficacy was evaluated in mice bearing Capan-1 tumors by assigning them randomly into the following groups: Saline control (Group 1), Olaparib (Group 2), 1 mCi 177Lu-1 (Group 3), and Olaparib +1 mCi 177Lu-1 (Group 4).50 mg/kg of Olaparib was administered orally once per day on days 0-6 (Groups 2 and 4), and 1 mCi 177Lu-1 was injected intravenously on day 1 (Groups 3 and 4). [0189] As shown in FIG. 3, initial treatment results (at 34 d post tumor implantation, corresponding to 16 d post treatment initiation) showed a steady increase in tumor volume for the saline control Group 1. In comparison, a significant delay in tumor growth was observed for the treatment Groups 2-4, most notably in Group 4 that had received the combination Olaparib + 177Lu- 1 treatment (Group 1 vs. Group 2: p = 0.009; Group 1 vs. Group 3: p = 0.0003; Group 1 vs. Group 4: p = 0.0001). No noticeable changes in body weight or skin appearance were observed in any group during this period. Example 4. Additional data related to therapeutic efficiency of provided therapeutic system. [0193] WST-1 assay. In the WST-1 cell viability assay, the combination of 177Lu-1 and Olaparib resulted in significantly decreased cell viability at 72h and 120h post-exposure in comparison to either monotherapy alone (p-values ≤ 0.001) (72h: 62% viable cells vs.85% for 177Lu-1 alone and 82% for Olaparib alone; 120h: 30% viable cells vs. 61% for 177Lu-1 alone and 47% for Olaparib alone) (FIG.4A). [0194] Cell cycle analysis. In the cell cycle analysis assay at 72h post-exposure, there was a significant increase in the percentage of cells in the sub-G1 and G2/M phases in the 177Lu-1 and Olaparib combination treatment in comparison to either monotherapy alone (p-values ≤ 0.002) (19% sub-G1 cells vs. 14% for 177Lu-1 alone and 17% for Olaparib alone; 34% G2/M cells vs. 22% for 177Lu-1 alone and 27% for Olaparib alone) (FIGs. 4B and 5A-D). [0195] Therapeutic efficacy. At 18 days after the start of treatment, (all groups had 100% viability at the start of treatment), a significant delay in tumor growth was observed in the groups that received treatment as compared to the saline control group (Group 1), which continued to demonstrate rapid growth: Group 1 vs. Group 2: p = 0.009; Group 1 vs. Group 3: p = 0.0003; Group 1 vs. Group 4: p = 0.0001 (FIG.6A). All mice in Group 1 met the end point criteria (tumor ≥2 cm in any direction and/or ulceration) by day 41 and all mice in Groups 2 and 3 met the end point criteria by days 70 and 73, respectively. At 73 days after start of treatment, Group 4 had 22% survival, with 2/9 mice in the group still alive (FIG. 6B). The end point for the last remaining mouse in Group 4 was met at 110 days after the start of treatment. The median survival was 28 days for the mice in the control group (Group 1), 37 days for the mice in the Olaparib monotherapy group (Group 2), 44 days for the mice in the 177Lu-1 monotherapy group (Group 3), and 65 days for the mice in the combination treatment group (Group 4). No evidence of treatment-related adverse effects (weight loss or signs of distress) was observed during the course of the study. [0190] Although the foregoing disclosure has been described in some detail by way of illustration and example for purpose of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications within the spirit and scope of the disclosure may be practiced, e.g., within the scope of the appended claims. It should also be understood that aspects of the disclosure and portions of various recited embodiments and features can be combined or interchanged either in whole or in part. In the foregoing descriptions of the various embodiments, those embodiments which refer to another embodiment may be appropriately combined with other embodiments as will be appreciated by one of skill in the art. Furthermore, those of ordinary skill in the art will appreciate that the foregoing description is by way of example only and is not intended to limit the disclosure. In addition, each reference provided herein is incorporated by reference in its entirety for all purposes to the same extent as if each reference was individually incorporated by reference. INFORMAL SEQUENCE LISTING
Figure imgf000057_0001
Figure imgf000058_0001

Claims

WHAT IS CLAIMED IS: 1. A system comprising: a DNA repair enzyme inhibitor; and a peptide conjugate comprising an integrin-binding peptide and a radionuclide.
2. The system of claim 1, wherein the DNA repair enzyme inhibitor comprises a poly-ADP ribose polymerase (PARP) inhibitor.
3. The system of claim 2, wherein the PARP inhibitor comprises olaparib, niraparib, rucaparib, talazoparib, or a combination thereof.
4. The system of claim 3, wherein the PARP inhibitor comprises olaparib.
5. The system of any one of claims 1-4, wherein the integrin-binding peptide comprises an αvβ6 integrin-binding peptide.
6. The system of any one of claims 1-5, wherein the integrin-binding peptide comprises the amino acid sequence RGDLX1X2X3 (SEQ ID NO:50), wherein: X1 and X2 are each independently an amino acid; and X3 is L or I.
7. The system of any one of claims 1-6, wherein the integrin-binding peptide comprises the amino acid sequence of any one of SEQ ID NOs: 1-49.
8. The system of claim 7, wherein the integrin-binding peptide comprises the amino acid sequence of SEQ ID NO: 3.
9. The system of any one of claims 1-8, wherein the peptide conjugate further comprises a polyethylene glycol (PEG) moiety covalently attached to a terminus of the integrin- binding peptide.
10. The system of claim 9, wherein the PEG moiety comprises PEG28 (PEG1500).
11. The system of claim 9 or 10, wherein the peptide conjugate further comprises a second PEG moiety covalently attached to a second terminus of the integrin-binding peptide.
12. The system of claim 11, wherein the second PEG moiety comprises PEG28 (PEG1500).
13. The system of any one of claims 1-12, wherein the radionuclide comprises
Figure imgf000060_0001
14. The system of claim 13, wherein the radionuclide comprises
Figure imgf000060_0002
, , ,
Figure imgf000060_0003
15. The system of claim 14, wherein the radionuclide comprises 177Lu.
16. The system of any one of claims 1-15, wherein the peptide conjugate further comprises a chelating moiety covalently attached to the integrin-binding peptide, wherein the radionuclide is complexed with the chelating moiety.
17. The system of claim 16, wherein the chelating moiety comprises a dodecane tetraacetic acid (DOTA) moiety.
18. The system of any one of claims 1-15, wherein the radionuclide is covalently attached directly or indirectly to the integrin-binding peptide.
19. The system of any one of claims 1-4, wherein the peptide conjugate has the structure of Formula (I):
Figure imgf000061_0001
(Formula I), wherein 5G is a PEG28-GNGVPNLRGDLQVLGQRVGRT (SEQ ID NO:3) - PEG28-C(O)NH2 peptide.
20. The system of any one of claims 1-19, wherein the ratio of the amount of the DNA repair enzyme inhibitor to the radioactivity of the peptide conjugate in the system is between 5 µg per mCi and 150 mg per mCi.
21. A composition comprising the system of any one of claims 1-20.
22. The composition of claim 21, wherein the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.
23. A cell comprising the system of any one of claims 1-20.
24. The cell of claim 23, wherein the cell is a mammalian cell.
25. The cell of claim 24, wherein the cell is a human cell.
26. A method of preventing or treating an integrin-related disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of a DNA repair enzyme inhibitor; and administering to the subject a therapeutically effective dose of a peptide conjugate comprising an integrin-binding peptide and a radionuclide.
27. The method of claim 26, wherein the integrin-related disease comprises an integrin-related cancer.
28. The method of claim 27, wherein the integrin-related cancer comprises an αvβ6 integrin-related cancer.
29. The method of claim 28, wherein the αvβ6 integrin-related cancer comprises pancreatic cancer, breast cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, oral squamous cell carcinoma, skin squamous cell carcinoma, stomach cancer, or endometrial cancer.
30. The method of any one of claims 27-29, wherein the integrin-related cancer comprises a metastatic cancer.
31. The method of any one of claims 26-30, wherein the DNA repair enzyme inhibitor comprises a PARP inhibitor.
32. The method of claim 31, wherein the PARP inhibitor comprises olaparib, niraparib, rucaparib, talazoparib, or a combination thereof.
33. The method of claim 32, wherein the PARP inhibitor comprises olaparib.
34. The method of any one of claims 26-33, wherein the integrin-binding peptide comprises an αvβ6 integrin-binding peptide.
35. The method of any one of claims 26-34, wherein the integrin-binding peptide comprises the amino acid sequence RGDLX1X2X3 (SEQ ID NO:50), wherein: X1 and X2 are each independently an amino acid; and X3 is L or I.
36. The method of any one of claims 26-35, wherein the integrin-binding peptide comprises the amino acid sequence of any one of SEQ ID NOs: 1-49.
37. The method of claim 36, wherein the integrin-binding peptide comprises the amino acid sequence of SEQ ID NO: 3.
38. The method of any one of claims 26-37, wherein the peptide conjugate further comprises a polyethylene glycol (PEG) moiety covalently attached to a terminus of the integrin-binding peptide.
39. The method of claim 38, wherein the PEG moiety comprises PEG28 (PEG1500).
40. The method of claim 38 or 39, wherein the peptide conjugate further comprises a second PEG moiety covalently attached to a second terminus of the integrin-binding peptide.
41. The method of claim 40, wherein the second PEG moiety comprises PEG28 (PEG1500).
42. The method of any one of claims 26-41, wherein the radionuclide comprises 177Lu, 3H, 18F, 32P, 35S, 47Sc, 55Co, 60Cu, 61Cu, 62Cu, 64Cu, 66Ga, 67Cu, 67Ga, 68Ga, 82Rb, 86Y, 87Y, 89Sr, 90Sr, 90Y, 105Rh, mAg, mIn, 124I, 125I, 131I, 117mSn, 99mTc, 137Cs, 149Pm, 153Sm, 149Tb, 152Tb, 155Tb, 161Tb, 166Ho, 186Re, 188Re, 201T1, 211At, 215At, 217At, 218At, 209Bi, 211Bi, 212Bi, 213Bi, 203Pb, 212Pb, 210Po, 211Po, 212Po, 214Po, 215Po, 216Po, 218Po, 218Rn, 219Rn, 220Rn, 222Rn, 226Rn, 221Fr, 223Ra, 224Ra, 226Ra, 225Ac, 227Ac, 227Th, 228Th, 229Th, 230Th, 232Th, 231Pa, 23U, 234U, 235U, 236U, 238U, 237Np, 238Pu, 239Pu, 240Pu, 244Pu, 241Am, 244Cm, 245Cm, 248Cm, 249Cf, or 252Cf.
43. The method of claim 42, wherein the radionuclide comprises 177Lu, 32P, 47Sc, 67Cu, 89Sr, 90Y, 105Rh, mAg, 117mSn, 131I, 149Pm, 153Sm, 166Ho, 186Re, 188Re, 211At, 212Pb or 212Bi.
44. The method of claim 43, wherein the radionuclide comprises 177Lu.
45. The method of any one of claims 26-44, wherein the peptide conjugate further comprises a chelating moiety covalently attached to the integrin-binding peptide, wherein the radionuclide is complexed with the chelating moiety.
46. The method of claim 45, wherein the chelating moiety comprises a DOTA moiety.
47. The method of any one of claims 26-44, wherein the radionuclide is covalently attached directly or indirectly to the integrin-binding peptide.
48. The method of any one of claims 26-33, wherein the peptide conjugate has the structure of Formula (I):
Figure imgf000064_0001
(Formula I), wherein 5G is a PEG28-GNGVPNLRGDLQVLGQRVGRT (SEQ ID NO:3) - PEG28-C(O)NH2 peptide.
49. The method of any one of claims 26-47, wherein the therapeutically effective dose of the peptide conjugate comprises a radioactivity between 25 mCi and 200 mCi.
50. The method of any one of claims 26-49, wherein the therapeutically effective amount comprises between 1 mg and 3500 mg of the DNA repair enzyme inhibitor.
51. The method of any one of claims 26-50, wherein the therapeutically effective amount of the DNA repair enzyme inhibitor is administered prior to the therapeutically effective dose of the peptide conjugate.
52. The method of any one of claims 26-50, wherein the therapeutically effective amount of the DNA repair enzyme inhibitor is administered subsequent to the therapeutically effective dose of the peptide conjugate.
53. The method of any one of claims 26-50, wherein the therapeutically effective amount of the DNA repair enzyme inhibitor is administered concurrently with the therapeutically effective dose of the peptide conjugate.
54. The method of any one of claims 26-53, wherein the method further comprises administering one, two or three additional therapeutically effective amounts of the DNA repair enzyme inhibitor.
55. The method of any one of claims 26-54, wherein the method further comprises administering one, two or three additional therapeutically effective doses of the peptide conjugate.
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