[go: up one dir, main page]

WO2012138379A2 - Nanoparticules radioactives sans chélateur multifonctionnelles pour imagerie et thérapie - Google Patents

Nanoparticules radioactives sans chélateur multifonctionnelles pour imagerie et thérapie Download PDF

Info

Publication number
WO2012138379A2
WO2012138379A2 PCT/US2011/056928 US2011056928W WO2012138379A2 WO 2012138379 A2 WO2012138379 A2 WO 2012138379A2 US 2011056928 W US2011056928 W US 2011056928W WO 2012138379 A2 WO2012138379 A2 WO 2012138379A2
Authority
WO
WIPO (PCT)
Prior art keywords
nanoparticle
cus
cancer
nps
copper
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2011/056928
Other languages
English (en)
Other versions
WO2012138379A3 (fr
Inventor
Chun Li
Min Zhou
Rui Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Texas System
University of Texas at Austin
Original Assignee
University of Texas System
University of Texas at Austin
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Texas System, University of Texas at Austin filed Critical University of Texas System
Publication of WO2012138379A2 publication Critical patent/WO2012138379A2/fr
Publication of WO2012138379A3 publication Critical patent/WO2012138379A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
    • 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
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
    • A61K51/1251—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles micro- or nanospheres, micro- or nanobeads, micro- or nanocapsules

Definitions

  • the present invention relates generally to the field of diagnosis and therapy, especially for cancer patients. More particularly, it concerns radiolabeled nanoparticles with a plurality of diagnostic and therapeutic functions.
  • Radioisotopes have been introduced to various nanoparticles (NPs), including quantum dots (Schipper et al., 2007; Cai et al., 2007), gold NPs (Lu et al., 2010; Melancon et al., 2008; Zhang et al., 2009), carbon nanomaterials (McDevitt et al., 2007; Liu et al., 2007), and polymeric NPs (Pressly et al., 2007; Schluep et al., 2009; Yang et al., 2007; Yang et al., 2009), through radionuclide labeling to allow noninvasive in vivo nuclear imaging of NPs' pharmacokinetics, tissue distribution, and clearance.
  • PET has been used to investigate the pharmacokinetics and biodistribution of 64 Cu-labeled NPs (Lu et al., 2010; Schluep et al., 2009).
  • the radioisotopes are linked to NPs through chelators such as diethylene triamine pentaacetic acid or 1, 4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid to form stable complexes.
  • the radiometal-chelator complexes may be detached from the surface of the NPs, or the radiometal ions may be displaced in vivo from the radiometal-chelator complexes owing to transchelation in the presence of high plasma protein concentrations, which again could lead to in vivo data not accurately reflecting the pharmacokinetics and biodistribution of NPs (Bass et al, 2000). [0006] Therefore, there is a continued need in the medical arts for developing chelator-free radiolabeling techniques with independent analytical tools.
  • Nanotechnology is an applied science that creates and studies molecules or aggregates that have an overall size in the 1-1000 nm range ( ⁇ 1 ⁇ ).
  • nanoparticles have been used in biomedical studies investigating new and improved diagnosis and therapy agents.
  • Oncology is one of the disciplines that has benefited most from nanotechnology.
  • Radioisotopes linked to nanoparticles through a chelating agent have been investigated in non-invasive nuclear imaging.
  • chelator-based radio-labeling techniques have problems in several aspects as described above, particularly, chelated radioisotopes in in vivo administered radiolabeled nanoparticles are inherently prone to displacement by serum proteins with metal-binding activity, reducing the available radioactivity available for tumor uptake.
  • aspects of the present invention overcome a major deficiency in the art by providing a novel inorganic nanoparticle, wherein the nanoparticle comprises a metal radioisotope as an integral component of the nanoparticle.
  • One advantage of the nanoparticle is to obviate conjugation of radioisotopes to the nanoparticle by a chelating agent, and thus the issues associated with chelate instability, as such stability is the primary reason for accumulation of high radioactivity in non-target organs.
  • the nanoparticle has small size, strong absorption in near infrared absorption and integration of radioisotope into the nanoparticle, making it ideally suited for a plethora of functions in diagnosis and therapy.
  • the nanoparticle can be used for the "see and treat” strategy in which nuclear imaging is used to noninvasive ly monitor nanoparticles' in vivo distribution and near-infrared light is applied to tumor sites where accumulation of nanoparticles in the tumor is confirmed.
  • the use of such nanoparticles for administering both radiotherapy and photothermal ablation therapy for tumor has a synergistic effect than either treatment alone.
  • Nanoparticles of the embodiments may have any transition metal as an integral component, such as the core of nanoparticles. Transition metals in the nanoparticles are virtually insoluble in aqueous solutions due to partially covalent character of the crystal lattice.
  • Non-limiting examples of transition metals in the nanoparticles include one or more of zinc, molybdenum, cadmium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, yttrium, zirconium, niobium, technetium, ruthenium, rhodium, palladium, silver, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, rutherfordium, dubnium, seaborgium, rohrium, hassium, meitnerium, darmstadtium, roentgenium, and copernicium.
  • the nanoparticle is a copper nanoparticle.
  • Nanoparticles may be made from metal chalcogenides, such as metal oxides or metal sulfides. These chalcogenides all have an element from Group VI of the periodic table, including oxides, sulfides, selenides, and tellurides, and compounds of polonium.
  • metal sulfide nanoparticles such as copper sulfide nanoparticles can be formulated by varying the molar ratio of metal to sulfide during
  • a [metal (e.g., Cu )] to [S " ] ratio of between about 1 and about 2, such as about 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.6, 1.9 or 2.0 can be used.
  • the absorbance peak of the resulting nanoparticles can be increased in wavelength.
  • the nanoparticle can be made radioactive by utilizing radioactive starting material or by external activation (such as exposure to neutrons) after the nanoparticles are synthesized.
  • the nanoparticle can have one metal composition throughout the particle (impurities may be present but not desired).
  • the nanoparticle can have more than one metal compositions.
  • the metal integral to the nanoparticle may be a mixture of a metal radioisotope (e.g. , a copper radioisotope) and a stable metal isotope (e.g., a stable
  • the metal radioisotope and stable metal isotope may be of the same metal type or different metal type.
  • the metal radioisotope or stable isotope may be, for example, a radioisotope or a stable isotope of gold, silver, copper, iron, zinc, or any other transition metal.
  • the radioisotope is a gamma emitter, a positron emitter or a beta-emitter.
  • the radioisotope can be Cu-64, In-I l l , Tc-99m, Ga- 67, Ga-68, Y-90, Lu-177 or a mixture thereof.
  • the radioisotope may be a copper radioisotope.
  • the copper radioisotope is Cu-64, Cu-67, Cu-62, Cu-63, Cu-61 , or any other copper radioisotopes.
  • the radioisotopes may be chosen which are alpha, beta, or gamma emitters.
  • the nanoparticle may further comprise a surface stabilizer and/or targeting agent.
  • surface stabilizer include citrate, polyacetylene glycol, cysteine, folic acid, polypropylene glycol, copolymers of polyethylene glycol and polypropylene glycol, polylysine, polyvinyl alcohol, human serum albumin, bovine serum albumin, hyaluranic acid, polyethyleimine (PEI), polyvinylprrolidone (PVP) or any chemical compound that passivates the surface of nanoparticle and protects the nanoparticle from further growth.
  • the polyacetylene glycol is polyethylene glycol (PEG).
  • the polyethylene glycol may have a molecular weight ranging from 500- 20,000 dalton, or more particularly, from 1000-5000 dalton.
  • the PEG may have at least, at most or about 100, 200, 300, 400, 500, 600, 700,800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10,000, 20,000, 30,000, 40,000, 50,000 dalton, or any range derivable therefrom.
  • the surface stabilizer can also act as a targeting agent (e.g., hyaluranic acid and folic acid can be used to target particular classes of tumor cells).
  • the surface stabilizer may be virtually composed of a monomolecular layer.
  • the surface property of nanoparticles, particularly property of the surface stabilizer layer, could determine the solubility, chemical reactivity, biodistribution, or pharmacokinetic properties of nanoparticles. Very small size, uniformity of particles, and critical role of the surface distinguishes nanoparticles from both colloidal and molecular systems.
  • nanoparticle may be used to describe objects of from 1 to 300 nm in diameter represented by vesicles, polymers or colloids. These species are used for drug delivery and for diagnostic purposes.
  • the nanoparticle may have a particle diameter of less than 1000 nm, about 10 nm to about 500 nm, about 10 to 200 nm, about 20 to about 200 nm, about 20 to about 100 nm, about 20 to about 30 nm, or any range derivable therein.
  • the particle diameter may be a mean or an average diameter.
  • nanoparticles in certain aspects of the present embodiments includes particles that have a diameter of at least, about, or at most, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, or 150 nm, or any intermediate ranges.
  • Photothermal ablation (PTA) therapy has been used in minimally invasive treatments for cancer.
  • Nanoparticles with optical properties such as infrared absorption may be used as photothermal coupling agents for PTA therapy to convert optical energy to thermal energy, enabling optical energy into tumors for thermal ablation.
  • the nanoparticle has a near-infrared absorption.
  • the nanoparticle has a maximum absorption at about, at least or at most 700, 750, 800, 850, 900, 950, 980, 1000, 1064, 1100 nm or any intermediate range.
  • the nanoparticle may be coupled with a tumor targeting moiety, a targeting ligand, a therapeutic, an imaging agent, a peptide, an antibody, a nucleic acid, a small molecule, or a polymer.
  • the targeting ligand may be a CD44 targeting ligand, such as hyaluronic acid (HA), for selective targeting of nanoparticles to CD44 positive tumor cells.
  • the targeting ligand may bind to folate receptors, such as a targeting ligand comprising folic acid (FA).
  • FA folic acid
  • NPs comprising FA can be used to target head and neck tumors or ovarian tumors.
  • the nanoparticle may be formulated in a pharmaceutically acceptable nanoparticle composition.
  • the nanoparticle formulation can be a liquid formulation or a solid formulation, such as a powder.
  • the composition may be dehydrated or lyophilized for long term storage with improved stability.
  • the composition may be present in a substantially aqueous solution.
  • the composition may be rehydrated or re-suspended in a solution or liquid from the previously lyophilized composition.
  • the composition used in the methods may be previously dehydrated, lyophilized or in some other aspects, an aqueous solution or liquid formulation of previously lyophilized or dehydrated composition, an effective amount of which are administered to the subject.
  • the present invention also provides, in certain aspects, previously lyophilized or dried composition after being stored at 4 degree for at least 1 week, for at least 3 weeks, for up to 4 weeks, or any period derivable therein, for treating the disease with retained activity after resuspension or rehydration.
  • Application of nanoparticles having integral radioisotopes may significantly improve the detection limit of cancer, increase effectiveness of radiotherapy and photothermal ablation therapy, and reduce the overall side effects.
  • a method of treating an angiogenic or a malignant tissue in a subject may comprise administering to a subject or an angiogenic or a malignant tissue in a subject an effective amount of such inorganic nanoparticles.
  • the nanoparticle has a metal radioisotope as an integral component of the nanoparticle.
  • the method may be further defined as a radiotherapy or brachytherapy due to the radiotherapeutic effect of the integrated radioactive isotope in the nanoparticle, such as Cu-64 or Cu-67.
  • the nanoparticle may enter an angiogenic or a malignant tissue in the subject.
  • the nanoparticle can be a metal chalcogenide comprising a metal radioisotope as an integral component.
  • the metal radioisotope comprises copper radioisotope.
  • the method may comprise imaging the nanoparticles in the subject after a period of time that is sufficient for the nanoparticles to enter an angiogenic or a malignant tissue.
  • the imaging method may be any optical or nuclear imaging method, such as positron emission tomography (PET), single photon emission computed tomography (SPECT), or photoacoustic tomography.
  • PET imaging can be used in conjunction with photoacoustic imaging (e.g., for lymph node mapping).
  • the imaging may further comprise imaging of lymph nodes in the subject.
  • [ 64 Cu]CuS NP can be used for lymph node imaging with PET/CT and/or photoacoustic imaging.
  • This application can be potentially used in noninvasive detection of lymph node metastasis.
  • the ability to detect lymph nodes metastasis is extremely important in cancer staging, determining prognosis, and monitoring treatment outcome.
  • the method may further comprise administering a photothermal ablation therapy to the tissue having the nanoparticles.
  • the photothermal ablation therapy may comprise administering to the tissue a near-infrared light, for example, from a near-infrared laser at about 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20 W/cm , or any intermediate range for about 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 minutes or any intermediate range.
  • the near-infrared light may have a wavelength of about 700, 750, 800, 850, 900, 950, 980, 1000, 1064, 1 100 nm or any intermediate range.
  • a photothermal ablation therapy comprises use of a laser having a wavelength of about 900 nm to 1 100 nm (e.g., about 980 nm or 1064 nm).
  • a laser for use in the methods of the embodiments can be a continuous wave laser or a pulsed laser (e.g., a nanosecond, microsecond or millisecond pulsed laser).
  • the subject may be any animal, like a mammal.
  • the subject may be a human or a mouse.
  • the subject may have cancer.
  • the cancer may include melanoma, leukemia, ovarian cancer, colon cancer, prostate cancer, lung cancer, liver cancer, pancreatic cancer, bladder cancer, cervical cancer, breast cancer, gastric cancer, colon cancer, head and neck cancer, esophagus cancer, synovium cancer, brain cancer, bronchus cancer or any known cancer.
  • the nanoparticle or nanoparticle formulation may be administered at a dose of at least, at most or about lxlO 4 , lxlO 5 , lxlO 6 , lxlO 7 , lxlO 8 , lxlO 9 , lxlO 10 , lxlO 11 , lxlO 12 , lxlO 13 , 2xl0 14 , 3xl0 14 , 4xl0 14 , 5xl0 14 , 8xl0 14 , lxlO 15 , lxlO 16 ,
  • the nanoparticle or nanoparticle formulation administered to the subject may have a radioactivity of at least, at most or about 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 250, 300, 350, 400 ⁇ per kg body weight or per tumor.
  • the nanoparticle administered may have a radioactivity of at least, about or at most 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 35, 30, 35, 40, 45, 50 mCi (or any range derivable therein) per subject.
  • the nanoparticle or nanoparticle formulation may be administered about 500 mg/m (body
  • the nanoparticle or nanoparticle formulation may be administered intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intratracheally, intravitreally, intravaginally, intrarectally, intratumorally, intramuscularly, intraperitoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, intrathecally, locally, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, via a catheter, or via a lavage.
  • the composition may be administered by injection or infusion.
  • the nanoparticle or nanoparticle formulation may be administered in combination with at least an additional agent such as a radiotherapeutic agent, a hormonal therapy agent, an immunotherapeutic agent, a chemotherapeutic agent, a cryotherapeutic agent and/or a gene therapy agent.
  • an additional agent such as a radiotherapeutic agent, a hormonal therapy agent, an immunotherapeutic agent, a chemotherapeutic agent, a cryotherapeutic agent and/or a gene therapy agent.
  • a method of preparing such a nanoparticle may comprise providing a mixture comprising a copper radioisotope, a stable copper salt and a non-copper chalcogenide.
  • the mixture may be incubated at a reaction condition having a temperature of at least, about or at most 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130°C, or any intermediate ranges.
  • the reaction condition may have a pH of at least, about or at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or any intermediate ranges.
  • the reaction condition may last at least, at most or 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, 25, 30, 35, 40, 50, 60, 80, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1440, 1500, 1600 minutes or any intermediate ranges.
  • the mixture may be aqueous or may be non-aqueous.
  • the mixture may further comprise a source of a surface stabilizer for the nanoparticle, such as citrate or PEG.
  • the ratio of copper radioisotope and a stable copper salt may be about, at least or at most 1, 10 "1 , 10 "2 , 10 “3 , 10 “4 , 10 “5 , 10 “6 , 10 “7 , 10 “8 , 10 “9 or any range derivable therein.
  • the mixture may further comprise an adjuvant such as a tumor targeting moiety, a targeting ligand, a therapeutic, a peptide, an antibody, a nucleic acid, a small molecule, or a polymer.
  • the reaction condition may be also suitable for coupling the nanoparticle with any adjuvant.
  • a method of preparing a nanoparticle coated with a homing ligand comprising providing a composition comprising a copper radioisotope, a stable copper salt and a non-copper chalcogenide at the ratio specified above.
  • the reaction may be carried out under the reaction conditions (temperature, pH, solvent, and time) specified in the foregoing paragraph.
  • the mixture may further comprise a source of a surface stabilizer for the nanoparticle, such as citrate or PEG in the presence of the homing ligands.
  • nanoparticle may be coated with homing ligands after nanoparticles are formed using standard bioconjugation chemistry, click chemistry, and other methods of introducing homing ligands.
  • compositions comprising admixing the nanoparticle into a pharmaceutically acceptable nanoparticle formulation.
  • the method may further comprise homogenization and/or sonication for homogenous dispersion.
  • the method may further comprise dehydrating or lyophilizating the formulation.
  • the method may further comprise rehydrating or resuspending in a solution or liquid.
  • Embodiments discussed in the context of methods and/or compositions of the invention may be employed with respect to any other method or composition described herein. Thus, an embodiment pertaining to one method or composition may be applied to other methods and compositions of the invention as well.
  • FIGS. 1A-B Characterization of CuS NPs.
  • FIG. 1A TEM image of Cit- CuS NPs. Inset: particle size distribution.
  • FIG. 2C Biodistribution of PVP-and PEG-coated CuSNPs at 24 h after iv injection in mice bearing subcutaneous U87. PVP - polyvinylpyrrolidone .
  • FIG. 3 Micro -PET/CT images of nude mice-bearing s.c. U87 glioma xenografts acquired at 1 , 6, and 24 h after i.v. injection of PEG-[ 64 Cu]-CuS NPs. Yellow arrow: tumor; orange arrow: bladder; Red arrow: standard.
  • FIGS. 4A-B PEG-CuS NPs acted as an efficient photothermal coupling agent.
  • FIG. 4A Temperature elevation over a period of 9 min of exposure to NIR light (808 nm, 16 W/cm") at various PEG-CuS NP concentrations. Water was used as control.
  • FIG. 4B Temperature change ( ⁇ ) over a period of 9 min as a function of PEG-CuS NP concentration expressed as CuS molecular units.
  • FIGS. 5A-C PEG-CuS NPs induced photothermal destruction of U87 tumors in vivo.
  • FIG. 5A Photographs of tumor-bearing mice before and at 24 h after NIR laser irradiation (12 W/cm at 808 nm for 5 min).
  • FIG. 5B Representative microphotograph of tumors removed at 24 h after NIR laser treatment. The tissues were cryosectioned into 5 ⁇ slices and stained with H&E. Bar, top, 200 ⁇ ; Bar, bottle, 20 ⁇ .
  • NPs CuS nanoparticles; NIR, near-infrared laser; T, tumor.
  • FIG. 6 Nuclear magnetic resonance (NMR) study of Cit-CuS NPs and PEG- CuS NPs.
  • NMR Nuclear magnetic resonance
  • FIG. 7 X-ray diffraction pattern (XRD) of CuS NPs. All diffraction peaks can be indexed as covellite-phase copper sulfide with lattice parameters similar to those of Joint Committee on Powder Diffraction Standards card 79-2321. The relatively broad diffraction peaks reflect the small size of copper sulfide crystals. No obvious impurity peaks were detected, indicating the acquirement of covellite CuS with high quality.
  • FIG. 8 Hydrodynamic size of CuS NPs by DLS.
  • the particle size of Cit-CuS NPs and PEG-CuS NPs are 11.7 nm and 31.6 nm, respectively.
  • FIG. 9 High resolution transmission electron microscope (HRTEM) image of PEG-CuS NPs.
  • FIG. 10 Stability of Cit-CuS NPs and PEG-CuS NPs in different buffer solutions at 37°C for 7 days: photograph. Solutions were as follows: 1, water; 2, citrate solution (0.4 mM); 3, acetate buffer solution (100 mM); 4, NaCl solution(100 mM); 5, 4-(2- hydroxyethyl)-l-piperazineethanesulfonic acid buffer (HEPES); 6, Phosphate buffered saline (PBS); 7, bovine serum albumin solution (BSA) (50 mM); 8, PBS containing 10% fetal bovine serum (FBS); and 9, 100% FBS.
  • FIG. 11 Radiolabeling efficiency and stability of radioactive CuS NPs. Representative radio-ITLC chromatogram of [ 64 Cu]-CuS NP solution in PBS and fetal bovine serum (FBS) at 37°C at 24 h.
  • FIG. 12 Instant thin layer chromatography (ITLC) of PEG-[ 64 Cu]-CuS NPs from urine 24 h after i.v. injection. ITLC revealed that PEG-[ 64 Cu]-CuS NPs was cleared from the renal system in the form of CuS NPs, indicating that a fraction of smaller CuS NPs were capable of clearance by the kidney in vivo.
  • ITLC Instant thin layer chromatography
  • FIG. 13 Cell viability after NIR laser irradiation. Fluorescence photomicrographs of U87 cells after PTA therapy in vitro. U87 cells were treated with PEG- CuS NPs for 2 h followed by NIR laser (808 nm) irradiation. Treatments with combined PEG-CuS NPs at 500 ⁇ and NIR laser at power density greater than 16 W/cm caused significant depletion of viable tumor cells. No apparent damage to cells was observed when cells were treated with PEG-CuS NPs alone or NIR laser alone. Viable cells were stained green with calcein AM. Bar, 20 ⁇ .
  • FIG. 14 Cytotoxicity of CuS nanoparticles. Cell viability test show with varying CuS NPs concentration of 0-1 mM at 48 h.
  • FIG. 15A-D A, schematic of the experimental design for antitumor activity study in nude mice bearing s.c. BT474 tumors.
  • B tumor growth curves after treatments with radiotherapy (RT), photothermal therapy (PTT), and combined radio-photothermal therapy (RPTT).
  • C photographs of representative mouse from each treatment group on day 30 after treatment.
  • D Representative microphotograghs of tumors stained with hematoxylin and eosin. Tumors were removed on day 30 after the initiation of treatment. Bars: 200 ⁇ (top panel); 20 ⁇ (bottom panel).
  • FIG. 16 A, body weight changes as a function of time after treatments. B, histology of H&E stained tissues. No noticeable abnormality was observed in heart, liver, spleen, kidney, and lung.
  • FIG. 17 PTA images of chick breast tissues with imbedded CuS NP- containing gels containing, (a) Photograph of the cross section of chicken breast tissue with gelatin objects containing CuS NP (1 mM) and a steel needle, (b) Two dimensional photoacoustic image at the depth of ⁇ 5 cm from laser illuminated surface acquired with 800 nm laser.
  • FIG. 18 MicroPET/CT images of a rat 24 h after subcutanenous injection of the [64Cu]CuS NP in the right front paw. Arrows: lymph nodes.
  • FIG. 19 Photothermal conducting effect of HA-CuS NP. HA-CuS NP showed high photothermal conducting efficiency. HA, hyaluronic acid.
  • FIG. 20 Selective binding of 64 Cu-labeled HA-CuS NP to human breast cancer MDA-MB231 cells that express CD44 receptors.
  • Cells incubated with 64 Cu-labeled HA-CuS NP showed significantly higher uptake in the cancer cells than non-targeted 64Cu- labeled CuS NP, and this uptake could be completely blocked by co-incubation with cold HA.
  • FIG. 21 Selective binding of FITC-labeled HA-CuS NP to CD44-positive HeLa cells. Cells incubated with FITC-labeled HA-CuS NP showed selective uptake in HeLa cells.
  • FIG. 22 Selective photothermal ablation of HeLa cells exposed to HA-CuS
  • NP and near-infrared (NIR) laser 808 nm.
  • NIR near-infrared
  • Cells were treated with EthD-1 for visualization of dead cells (red) and Calcein AM for visualization of viable cells (green).
  • FIG. 23 Physical properties of a CuS nanoparticles with incorporated Ga-68. ITLC results show that the Ga-68 is stably incorporated into CuS NP (FIG. 23A) and does not significantly alter the absorbance properties of the particles (FIG. 23B).
  • FIG. 24 Graph shows the optical absorbance peak of nanoparticles
  • FIG. 25A-B CuS NPs efficiently convert laser energy to heat at 980 nm (A) or 808 nm (B).
  • CuNPs were compared to hollow gold nanospheres (HAuNS), carbon nanotubes (CNTs), graphene and water alone (control). The concentration of all nanoparticles were 100 ⁇ g/ml.
  • FIG. 26 CuS NPs can efficiently and repeatedly convert laser energy to heat. Particles were dispersed at a concentration of 50 mg/L and exposed to pulses of a 3W laser beam (1 cm diameter) having a wave length of 808 nm over the time periods shown.
  • FIG. 27 CuS NPs can efficiently convert pulsed laser energy to heat with superior spatial control.
  • HeLa cells were treated as indicated with no therapy (Cell only); only laser application (Cell + laser) only NPs [CuS NP (2 OD)] or with laser in the presence of CuS NPs. Laser exposures in each case were for 10 seconds with nanosecond pulses using a 17 mJ, 1064 nm laser beam.
  • FIG. 28 Physical properties of FA coated CuS NPs. Particles were assessed for peak absorbance (A); photothermal conduction (B) particle size (C); and stability in a variety of buffers including FBS, NaCl, HEPES, BSA, PBS and water (D). FA, folic acid.
  • FIG. 29 Binding properties of FA coated CuS NPs on KB cells. KB cells were imaged to determine whether FA coated CuS NPs could specifically bind the cells. Cells were imaged to visualize DAPI staining, Cy5.5 staining or both in the presence of PEG- CuS NPs (1 mM), FA-CuS NPs (1 mM) or FA-CuS NPs (1 mM) with excess FA as indicated. FA, folic acid.
  • FIG. 30 FA-CuS NPs selectively target KB cells for photothermal ablation. A 3W, 2 min NIR laser exposure was applied to cells in the presence of FA-CuS NPs (1 mM); PEG-CuS NPs (1 mM); FA-CuS NPs plus blocking FA or without NPs (laser alone), as indicated. FA, folic acid.
  • FIG. 31 FA-CuS NPs selectively target KB tumors in vivo. Biodistribution of FA-coated CuS NPs after injection in mice KB tumors in the presence (Blocking) or absence of excess FA (FA-CuS). Tissue abbreviation are blood (Bl), heart (He), liver (Li), spleen (Sp), kidney (Ki), lung (Lu), stomach (St), intestinal (In), muscle (Mu), bone (Bo), brain (Br) and tumor (Tu). FA, folic acid.
  • FIG. 32 FA-CuS NPs are effective mediators of photothermal ablation in KB tumor tissue. Images show cells from KB tumors that were exposed to laser energy in the absence of NPs (Non-treatment, the presence of PEG-CuS NPs or FA-CuS NPs. FA, folic acid.
  • FIG. 33 PEG-CuS NPs provide an excellent contrast for photoacoustic imaging. PEG-CuS NPs were imaged by photoacoustic tomography with a 1064 nm, 36.5 mJ laser at a depth of 1 cm. The samples in agarose gel were imbedded in chicken breast.
  • the concentrations of PEG-CuS NP were 100 ⁇ (1); 50 ⁇ g/ml (2); 25 ⁇ g/ml (3); 12.5 ⁇ (4); 6.25 ⁇ g/ml (5) andr 3.125 ⁇ g/ml (6). (7) indicates agarose gel alone as a control.
  • FIG. 34 MicroPET/CT image of PEG-[ 64 Cu]CuS NPs and 64 CuCl 2 24 h after intratumoral injection into B474 tumors in mice.
  • a novel class of nanoparticles having radioactive isotope as an integral component such as chelator-free [ 64 Cu]-CuS nanoparticles (NPs) suitable for both PET imaging, radiotherapy and as photothermal coupling agents for photothermal ablation, were synthesized and evaluated.
  • [ 64 Cu]-CuS NPs were simple to make, possessed excellent stability, and allowed robust noninvasive micro-PET imaging.
  • radioactive CuS NPs displayed strong absorption in the near-infrared (NIR) region
  • passive targeting long circulation in the blood and extravasation at tumor vasculature
  • mediated ablation of tumor cells upon exposure to NIR light both in vitro and in vivo after either intratumoral or intravenous injection.
  • PEG-[ 64 Cu]- CuS NPs acted as an efficient radiotracer for pharmacokinetics, biodistribution, and PET imaging
  • PEG-CuS NPs acted as an efficient photothermal coupling agent and photoacoustic contrast agent.
  • PEG-[ 64 Cu]-CuS NPs showed high uptake in U87 human glioblastoma xenografts owing to enhanced permeability and retention effect.
  • Active targeting of such nanoparticles, such as radioactive CuS NPs, to solid tumors by conjugating receptor-specific or tumor-specific targeting moieties onto the NPs' surface may be contemplated in certain aspects. Improved tumor uptake of radioactive nanoparticles could increase the efficacy of photothermal ablation therapy, decrease the energy dose of the laser, and minimize the potential damage to surrounding normal tissues.
  • radiolabeled NPs may also have an application for therapy, like radiotherapy or photothermal ablation therapy.
  • therapy like radiotherapy or photothermal ablation therapy.
  • the combination of small diameter, strong NIR absorption, and integration of a radioisotope as a structural component makes this novel nanopaticle ideally suited for combining its intrinsic nuclear and optical properties in multifunctional molecular imaging and therapy, for example, image-guided photothermal ablation therapy.
  • the radio isotope can be astatine-211, chromium-51, cobalt-57, cobalt-58, copper-67, Eu-152, gallium-67, gallium-68, indium-I l l, iron-59, lutetium-177m, rhenium-186, rhenium-188, selenium-75, strontium-89, technicium- 99m, thorium-227 and/or yttrium-90.
  • the radioisotope may be a copper radioisotope.
  • Non-limiting examples of copper radioisotope include Copper-64, Copper- 70ml, Copper-70m2, Copper-68m, Copper-69m, Copper-71m, Copper-72m, Copper-76m, Copper-52, Copper-53, Copper-54, Copper-55, Copper-56, Copper-57, Copper-58, Copper- 59, Copper-60, Copper-61, Copper-62, Copper-66, Copper-67, Copper-73, Copper-74, Copper-75, Copper-77, Copper-78, Copper-79, and Copper-80.
  • the copper radioisotope may be Copper-64 (with a half-life of about 12.70 hours) or Copper-67 (with a half-life of about 61.83 hours).
  • radioisotope employed will depend on what the nanoparticle is used for.
  • a positron emitter such as Ga-68 can be employed for PET imaging.
  • radioisotope for use in gamma imaging include, but are not limited to IN-11, Tc-99m and Ga-67.
  • a beta emitter such as Y-90 or Lu- 177 may be preferred.
  • the present invention affords compositions and methods involving a nanoparticle formulation comprising a nanoparticle having an integrated radioisotope.
  • the disclosed formulations e.g., stabilized radioactive nanoparticles, are designed to improve the stability as well as the pharmacokinetics of this nanoparticle so that a better in vivo therapeutic activity can be achieved.
  • the nanoparticle formulation may decrease the loss of radioactivity in blood circulation and increase the drug distribution to tumor tissues and uptake by cancer cells and thus enhance anticancer activity.
  • nanoparticle refers to any particles having dimensions in the 1-1,000 nm range.
  • nanoparticles have dimensions in the 2-200 nm range, preferably in the 5-150 nm range, and even more preferably in the 10- 100 nm range.
  • the nanoparticles may be conjugated to a targeting moiety to provide structures with potential application for targeted delivery, controlled release, enhanced cellular uptake and intracellular trafficking in vitro and in vivo.
  • CuS is of great interest for use in catalysis and photovoltaic.
  • Several methods have been developed for the preparation of copper sulfide nanoparticles (Haram et ah, 1996; Xu et ah, 2009; Huang et ah, 2010).
  • Semiconductor CuS NPs are a new class of promising photothermal coupling agents. Thioglycolic acid-stabilized CuS NPs have been synthesized and demonstrated for photothermal destruction of tumor cells in vitro using a NIR laser beam centered at 808 nm.
  • compositions of the present invention may optionally include one or more additional therapeutic agents.
  • the therapeutic agent may be a chemotherapeutic agent.
  • chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duo
  • compositions may be anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen, raloxifene, droloxifene, 4- hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene; aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate, exemestane, formestanie, fadrozole, vorozole, letrozole, and anastrozole; and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (SERMs), including, for
  • the composition of this invention may enable accumulation of nanoparticles to tissues adjacent to or distant from an administration site.
  • the radioactive isotope integral to the nanoparticle may be capable of providing a local or systemic biological, physiological or therapeutic effect.
  • the nanoparticle may act to kill cancer cells, or to control or suppress tumor growth, among other functions.
  • the nanoparticles are administered in an amount effective to provide the desired level of biological, physiological, pharmacological and/or therapeutic effect.
  • the nanoparticle may stimulate or inhibit a biological or physiological activity.
  • the concentration of the nanoparticle should not be so high that the composition has a consistency that inhibits its delivery to the administration site by the desired method.
  • the lower limit of the amount of the nanoparticle may depend on its activity and the period of time desired for treatment.
  • Targeted delivery is achieved by the addition of ligands without compromising the ability of nanoparticles to deliver their loads. It is contemplated that this may enable delivery to specific cells, tissues and organs.
  • the targeting specificity of the ligand-based delivery systems is based on the distribution of the ligand receptors on different cell types. It is preferable that the ligand to be conjugated to the nanoparticles may bind to the receptors that specifically or predominantly express in tumor cells so that the nanoparticle may be preferentially delivered to the tumor cells.
  • specific antibodies such as anti- CD20 (Rituximab) may be conjugated to the nanoparticles to deliver nanoparticles to malignant B-cells such as those of chronic lymphocytic leukemia and B-cell lymphoma.
  • the targeting ligand may either be non-covalently or covalently associated with a nanoparticle, and can be conjugated to the nanoparticles by a variety of methods as discussed herein.
  • proteins or peptides that can be used to target nanoparticles include transferin, lactoferrin, TGF-a, nerve growth factor, albumin, HIV Tat peptide, RGD peptide, and insulin, as well as others (Gupta et al., 2005; Ferrari, 2005).
  • the nanoparticle may be coupled to a tumor targeting moeity.
  • the tumor targeting moiety is an antibody that binds an antigen selected from the group consisting of, a gastrointestinal cancer cell surface antigen, a lung cancer cell surface antigen, a brain tumor cell surface antigen, a glioma cell surface antigen, a breast cancer cell surface antigen, an esophageal cancer cell surface antigen, a common epithelial cancer cell surface antigen, a common sarcoma cell surface antigen, an osteosarcoma cell surface antigen, a fibrosarcoma cell surface antigen, a melanoma cell surface antigen, a gastric cancer cell surface antigen, a pancreatic cancer cell surface antigen, a colorectal cancer cell surface antigen, a urinary bladder cancer cell surface antigen, a prostatic cancer cell surface antigen, a renal cancer cell surface antigen, an ovarian cancer cell surface antigen, a testicular cancer cell
  • the tumor targeting moiety is an antibody or ligand that binds an antigen or a receptor selected from the group consisting of 5 alpha reductase, a- fetoprotein, AM-1, APC, APRIL, BAGE, ⁇ -catenin, Bcl2, bcr-abl (b3a2), CA-125, CASP- 8/FLICE, Cathepsins, CD19, CD20, CD21, CD23, CD22, CD38, CD33, CD35, CD44, CD45, CD46, CD5, CD52, CD55, CD59 (791Tgp72), CDC27, CDK4, CEA, c-myc, Cox-2, DCC, DcR3, E6/E7, EGFR, EMBP, Ena78, FGF8b and FGF8a, FLK-l/KDR, Folic Acid Receptor, G250, GAGE-Family, gastrin 17, GD2/GD3/GM2, Gn
  • Nanoparticles may be used in an imaging or detection method for diagnosis or localization of tumor or angiogenic tissues. Any optical or nuclear imaging method may be contemplated, such as PET, SPECT, CT, or photoacoustic tomography.
  • the integrated radioactive isotope in the nanoparticle may exert a radiotherapy on the tissue incorporating such nanoparticle.
  • a photothermal ablation therapy may be administered to the tissue having the nanoparticle to enhance the therapeutic effect.
  • Nanoparticles may be used in PET.
  • Positron emission tomography PET is a powerful and widely used diagnostic tool that has the advantages of high sensitivity (down to the picomolar level) and ability to provide quantitative imaging analyses of in vivo abnormalities (Scheinin et al., 1999; Eckelman, 2003; Welch et al, 2009).
  • Nanoparticles may also be used in SPET.
  • Single photon emission computed tomography SPECT, or less commonly, SPET
  • SPET is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera. However, it is able to provide true 3D information. This information is typically presented as cross-sectional slices through the patient, but can be freely reformatted or manipulated as required.
  • the SPET basic technique requires injection of a gamma-emitting radioisotope called radionuclide) into the bloodstream of the patient.
  • the radioisotope is integrated into a nanoparticle, which has chemical properties which allow it to be concentrated in ways of medical interest for disease detection.
  • a nanoparticle comprising a marker radioisotope, which is of interest for its radioactive properties, has been attached to a targeting ligand, which is of interest for its chemical binding properties to certain types of tissues.
  • This marriage allows the combination of ligand and radioisotope (the radiopharmaceutical) to be carried and bound to a place of interest in the body, which then (due to the gamma-emission of the isotope) allows the ligand concentration to be seen by a gamma-camera.
  • Nanoparticles may also be used in CT.
  • Computed tomography is a medical imaging method employing tomography created by computer processing. Digital geometry processing is used to generate a three-dimensional image of the inside of an object from a large series of two-dimensional X-ray images taken around a single axis of rotation. CT is used in medicine as a diagnostic tool and as a guide for interventional procedures. Sometimes contrast materials such as intravenous iodinated contrast are used. This is useful to highlight structures such as blood vessels that otherwise would be difficult to delineate from their surroundings. Using contrast material can also help to obtain functional information about tissues.
  • Nanoparticles may also be used in photoacoustic tomography.
  • Photoacoustic tomography or photoacoustic computed tomography (PACT) is a materials analysis technique based on the reconstruction of an internal photoacoustic source distribution from measurements acquired by scanning ultrasound detectors over a surface that encloses the source under study.
  • the PA source is produced inside the object by the thermal expansion that results from a small temperature rise, which is caused by the absorption of externally applied radiation of pulsed electromagnetic (EM) waves.
  • EM pulsed electromagnetic
  • OAT optoacoustic tomography
  • TAT thermoacoustic tomography
  • each temporal PA signal measured at various detection positions, provides one-dimensional radial information about the PA source relative to the detector position; 2D surface scans offer other 2D lateral information about the PA source. Combining the temporal and spatial measurements affords sufficient information for a complete reconstruction of a 3D PA source. Because the PA signal received by each ultrasound detector is the integral of the ultrasound waves over the sensing aperture of the detector, the reconstruction algorithms depend on the detector apertures as well as the scanning geometries. Small-aperture detectors are often used to approximate point detectors, which receive PA signals originating from spherical shells, centered at each point detector, with radii determined by the acoustic times of flight.
  • Nanoparticles may also be used in photothermal ablation therapy.
  • Photothermal ablation (PTA) therapy has gained increasing attention in recent years as a minimally invasive alternative to conventional approaches to cancer treatment such as surgery and chemotherapy (Amin et ah, 1993;Nolsoe et ah, 1993; Fiedler et ah, 2001; Vogeland Venugopalan, 2003).
  • NPs with unique optical properties primarily gold nanostructures, such as gold nanoshells (Hirsch et ah, 2003; Loo e ⁇ , 2005), gold nanorods (Dickerson et ah, 2008; Park et ah, 2010), gold nanocages (Chen et ah, 2007; Au et ah, 2008), and hollow gold nanospheres (Lu et ah, 2010; Melancon et al leverage 2008; (Lu et ⁇ , 2009), but also carbon nanotubes (Chakravarty et al., 2008 Burke et al., 2009)— have been investigated as photothermal coupling agents to enhance the efficacy of PTA therapy.
  • gold nanostructures such as gold nanoshells (Hirsch et ah, 2003; Loo e ⁇ , 2005), gold nanorods (Dickerson et ah, 2008; Park et ah, 2010), gold nanocages (Chen e
  • These plasmonic nanomaterials exhibit strong absorption in the near-infrared (NIR) region (wavelength 700-1100 nm) and offer an opportunity to convert optical energy to thermal energy, enabling deposition of otherwise benign optical energy into tumors for thermal ablation of tumor cells.
  • NIR near-infrared
  • the particles of the present invention will generally be beneficial to prepare the particles as a pharmaceutical composition appropriate for the intended application.
  • This may entail preparing a pharmaceutical composition that is essentially free of pyrogens, as well as any other impurities that could be harmful to humans or animals.
  • One may also employ appropriate buffers to render the complex stable and allow for uptake by target cells.
  • phrases "pharmaceutical or pharmacologically acceptable” refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as a human, as appropriate.
  • an animal such as a human
  • preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biological Standards.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives ⁇ e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art.
  • solvents dispersion media, coatings, surfactants, antioxidants, preservatives ⁇ e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art.
  • a pharmaceutically acceptable carrier is preferably formulated for administration to a human, although in certain embodiments it may be desirable to use a pharmaceutically acceptable carrier that is formulated for administration to a non-human animal but which would not be acceptable ⁇ e.g. , due to governmental regulations) for administration to a human. Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • the actual dosage amount of a composition of the present invention administered to a patient or subject can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.
  • compositions may comprise, for example, at least about 0.1% of an active compound, such as the nanoparticle or the integrated metal radioisotope.
  • the active compound may comprise between about 1% to about 75% of the weight of the unit, or between about 5% to about 50%, for example, and any range derivable therein.
  • a dose may also comprise from about 1 microgram/kg/body weight, about 50 microgram/kg/body weight, about 100 microgram kg/body weight, about 500 microgram/kg/body weight, about 1 milligram/kg/body weight, about 5 milligram/kg/body weight, about 10 milligram/kg/body weight, about 30 milligram/kg/body weight, about 40 milligram/kg/body weight, about 50 milligram/kg/body weight, about 100 milligram/kg/body weight, or more per administration, and any range derivable therein.
  • a range of about 5 microgram kg/body weight to about 5 milligram/kg/body weight, about 50 microgram kg/body weight to about 50 milligram/kg/body weight, etc., can be administered.
  • a nanoparticle may be administered in a dose of 1, 2, 3, 4, 5, 6, 7, 8, 9,
  • Solutions of therapeutic compositions can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions also can be prepared in glycerol, liquid polyethylene glycols, mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • compositions of the present invention are advantageously administered in the form of injectable compositions either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection may also be prepared. These preparations also may be emulsified.
  • a typical composition for such purpose comprises a pharmaceutically acceptable carrier.
  • the composition may contain 10 mg, 25 mg, 50 mg or up to about 100 mg of human serum albumin per milliliter of phosphate buffered saline.
  • Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like.
  • non-aqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oil and injectable organic esters such as ethyloleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, saline solutions, parenteral vehicles such as sodium chloride, Ringer's dextrose, etc.
  • Intravenous vehicles include fluid and nutrient replenishers.
  • Preservatives include antimicrobial agents, anti-oxidants, chelating agents and inert gases. The pH and exact concentration of the various components the pharmaceutical composition are adjusted according to well known parameters.
  • Oral formulations include such typical excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like.
  • the compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders.
  • the therapeutic compositions of the present invention may include classic pharmaceutical preparations. Administration of therapeutic compositions according to the present invention may be via any common route so long as the target tissue is available via that route. This includes oral, nasal, buccal, rectal, vaginal, topical, or aerosol.
  • an effective amount of the therapeutic composition is determined based on the intended goal.
  • unit dose or “dosage” refers to physically discrete units suitable for use in a subject, each unit containing a predetermined-quantity of the therapeutic composition calculated to produce the desired responses discussed above in association with its administration, i.e., the appropriate route and treatment regimen.
  • the quantity to be administered both according to number of treatments and unit dose, depends on the protection or effect desired.
  • Precise amounts of the therapeutic composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment (e.g., alleviation of symptoms versus cure) and the potency, stability and toxicity of the particular therapeutic substance.
  • compositions comprising a nanoparticle formulation may be formulated in a topical formulation or an enteral formulation, and preferably, a parenteral formulation.
  • the compositions may be administered to a subject by injection or infusion for a systematic delivery.
  • Routes of administration can broadly be divided into: topical (local effect, substance is applied directly where its action is desired); enteral (desired effect is systemic (non-local), substance is given via the digestive tract); parenteral (desired effect is systemic, substance is given by routes other than the digestive tract).
  • topical local effect, substance is applied directly where its action is desired
  • enteral desired effect is systemic (non-local), substance is given via the digestive tract
  • parenteral desired effect is systemic, substance is given by routes other than the digestive tract.
  • the U.S. Food and Drug Administration recognizes 111 distinct routes of administration. The following is a brief list of some routes of administration.
  • Topical form of administration includes epicutaneous (application onto the skin), e.g. allergy testing, typical local anesthesia; inhalational, e.g. asthma medications; enema, e.g. contrast media for imaging of the bowel; eye drops (onto the conjunctiva), e.g. antibiotics for conjunctivitis; ear drops - such as antibiotics and corticosteroids for otitis externa; intranasal route (into the nose), e.g. decongestant nasal sprays; vaginal, e.g. topical estrogens, antibacterials.
  • Enteral form of administration involves any part of the gastrointestinal tract: by mouth (orally), many drugs as tablets, capsules, or drops; by gastric feeding tube, duodenal feeding tube, or gastrostomy, many drugs and enteral nutrition; rectally, various drugs in suppository or enema form;
  • Parenteral form of administration by injection or infusion involves intravenous (into a vein), intraarterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), subcutaneous (under the skin), intraosseous infusion (into the bone marrow) - in effect, an indirect intravenous access because the bone marrow drains directly into the venous system; intradermal (into the skin itself), intrathecal (into the spinal canal), intraperitoneal (infusion or injection into the peritoneum), intravesical infusion (infusion into the urinary bladder).
  • Other parenteral administration include transdermal (diffusion through the intact skin), sublingual, i.e.
  • nitroglycerine absorbed through cheek near gumline
  • vaginal suppositories inhalational
  • epidural i.e., peridural
  • injection or infusion into the epidural space intravitreal.
  • Injection encompasses intravenous (IV), intramuscular (IM), and subcutaneous (sub-Q).
  • IV intravenous
  • IM intramuscular
  • sub-Q subcutaneous
  • drugs are most often given intravenously. This is the most reliable route, as in acutely ill patients the absorption of substances from the tissues and from the digestive tract can often be unpredictable due to altered blood flow or bowel motility.
  • a therapeutically effective amount of the pharmaceutical composition comprising a nanoparticle formulated in a pharmaceutically acceptable nanoparticle formulation may be used to treat a diseases and/or condition in a subject.
  • Treatment refers to administration or application of a therapeutic agent to a subject or performance of a procedure or modality on a subject for the purpose of obtaining a therapeutic benefit of a disease or health-related condition.
  • a treatment may include administration of a parenteral pharmaceutical composition comprising a nanoparticle formulated in a pharmaceutically acceptable nanoparticle formulation.
  • a "subject” refers to either a human or non-human, such as primates, mammals, and vertebrates. In particular embodiments, the subject is a human.
  • therapeutic benefit refers to anything that promotes or enhances the well-being of the subject with respect to the medical treatment of this condition. This includes, but is not limited to, a reduction in the frequency or severity of the signs or symptoms of a disease.
  • treatment of cancer may involve a reduction in the size of a tumor, a reduction in the invasiveness of a tumor, reduction in the growth rate of the cancer, or prevention of metastasis. Treatment of cancer may also refer to prolonging survival of a subject with cancer.
  • a "disease” or “health-related condition” can be any pathological condition of a body part, an organ, or a system resulting from any cause, such as infection, genetic defect, and/or environmental stress.
  • a "hyperproliferative disease” includes diseases and conditions that are associated with any sort of abnormal cell growth or abnormal growth regulation, specifically a cancer.
  • the methods include identifying a patient in need of treatment.
  • a patient may be identified, for example, based on taking a patient history, based on findings on clinical examination, based on health screenings, or by self-referral.
  • the present invention can find application in the treatment of any disease for which delivery of a therapeutic nanoparticle to a cell or tissue of a subject is believed to be of therapeutic benefit.
  • diseases include hyperproliferative diseases and quiescent malignant diseases.
  • the disease is a hyperproliferative disease, such as cancer of solid tissues or blood cells.
  • Quiescent malignant diseases that can be treated by the nanoparticles include, for example, chronic lymphocytic leukemia.
  • a nanoparticle formulated in a pharmaceutically acceptable nanoparticle formulation may be administered to treat a hyperproliferative disease.
  • the hyperproliferative disease may be cancer, leiomyomas, adenomas, lipomas, hemangiomas, fibromas, pre-neoplastic lesions (such as adenomatous hyperplasia and prostatic intraepithelial neoplasia), carcinoma in situ, oral hairy leukoplakia, or psoriasis.
  • the cancer may be a solid tumor, metastatic cancer, or non-metastatic cancer.
  • the cancer may originate in the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, duodenum, small intestine, large intestine, colon, rectum, anus, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus.
  • the cancer is ovarian cancer.
  • the cancer may be a chemo-resistant cancer.
  • the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma;
  • compositions and methods of the present invention involve a nanoparticle formulation-based composition as set forth herein with a second or additional therapy.
  • Such therapy can be applied in the treatment of any disease for which treatment with the nanoparticle formulation is contemplated.
  • the disease may be a hyperproliferative disease, such as cancer.
  • the methods and compositions including combination therapies enhance the therapeutic or protective effect, and/or increase the therapeutic effect of another anti-cancer or anti-hyperproliferative therapy.
  • Therapeutic and prophylactic methods and compositions can be provided in a combined amount effective to achieve the desired effect, such as the killing of a cancer cell and/or the inhibition of cellular hyperproliferation.
  • This process may involve contacting the cells with a therapeutic nucleic acid, such as an inhibitor of gene expression, and a second therapy.
  • a tissue, tumor, or cell can be contacted with one or more compositions or pharmacological formulation(s) including one or more of the agents (i.e., inhibitor of gene expression or an anti-cancer agent), or by contacting the tissue, tumor, and/or cell with two or more distinct compositions or formulations, wherein one composition provides 1) an inhibitor of gene expression; 2) an anti-cancer agent, or 3) both an inhibitor of gene expression and an anti-cancer agent.
  • a combination therapy can be used in conjunction with a chemotherapy, radiotherapy, surgical therapy, or immunotherapy.
  • a therapeutic nanoparticle formulation-containing composition set forth herein may be administered before, during, after or in various combinations relative to an anti-cancer treatment.
  • the administrations may be in intervals ranging from concurrently to minutes to days to weeks.
  • the nanoparticle formulation-containing composition is provided to a patient separately from an additional anti-cancer agent, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the two agents would still be able to exert an advantageously combined effect on the patient.
  • the patient may be given one or multiple administrations of the agent(s). Moreover, after a course of treatment, it is contemplated that there is a period of time at which no anti-cancer treatment is administered. This time period may last 1, 2, 3, 4, 5, 6, 7 days, and/or 1, 2, 3, 4, 5 weeks, and/or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more, depending on the condition of the patient, such as their prognosis, strength, health, etc.
  • Administration of any compound or therapy of the present invention to a patient may follow general protocols for the administration of such compounds, taking into account the toxicity, if any, of the agents. Therefore, in some embodiments there is a step of monitoring toxicity that is attributable to combination therapy. It is expected that the treatment cycles would be repeated as necessary. It also is contemplated that various standard therapies, as well as radiation and surgical intervention, may be applied in combination with the described therapy.
  • a standard therapy may include chemotherapy, radiotherapy, immunotherapy, surgical therapy or gene therapy and may be employed in combination with the inhibitor of gene expression therapy, anticancer therapy, or both the therapeutic nucleic acid and the anti-cancer therapy, as described herein.
  • chemotherapeutic agents may be used in accordance with certain aspects of the present invention.
  • the term “chemotherapy” refers to the use of drugs to treat cancer.
  • a “chemotherapeutic agent” is used to connote a compound or composition that is administered in the treatment of cancer. These agents or drugs are categorized by their mode of activity within a cell, for example, whether and at what stage they affect the cell cycle. Alternatively, an agent may be characterized based on its ability to directly cross-link DNA, to intercalate into DNA, or to induce chromosomal and mitotic aberrations by affecting nucleic acid synthesis.
  • chemotherapeutic agents fall into the following categories: alkylating agents, antimetabolites, antitumor antibiotics, mitotic inhibitors, and nitrosoureas. Examples of these agents have been previously set forth.
  • a therapeutic agent for combination with nanoparticles in cancer treatment may also be a compound that specifically targets a specific molecule in a cancer cell or on the cancer cell surface.
  • target-specific therapeutic agents include, for example, Imatinib (Gleevec), rituximab, cetuximab (erbitux), and herceptin (trastuzumab).
  • DNA damaging factors include what are commonly known as ⁇ -rays, X-rays, and/or the directed delivery of radioisotopes to tumor cells.
  • Other forms of DNA damaging factors are also contemplated such as microwaves, proton beam irradiation (U.S. Patents 5,760,395 and 4,870,287) and UV-irradiation. It is most likely that all of these factors affect a broad range of damage on DNA, on the precursors of DNA, on the replication and repair of DNA, and on the assembly and maintenance of chromosomes.
  • Dosage ranges for X-rays range from daily doses of 50 to 200 roentgens for prolonged periods of time (3 to 4 wk), to single doses of 2000 to 6000 roentgens.
  • Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells.
  • the terms "contacted" and "exposed,” when applied to a cell, are used herein to describe the process by which a therapeutic composition and a chemotherapeutic or radiotherapeutic agent are delivered to a target cell or are placed in direct juxtaposition with the target cell. To achieve cell killing, for example, both agents are delivered to a cell in a combined amount effective to kill the cell or prevent it from dividing.
  • immunotherapeutics In the context of cancer treatment, immunotherapeutics, generally, rely on the use of immune effector cells and molecules to target and destroy cancer cells.
  • Trastuzumab (HerceptinTM) is such an example.
  • the immune effector may be, for example, an antibody specific for some marker on the surface of a tumor cell.
  • the antibody alone may serve as an effector of therapy or it may recruit other cells to actually affect cell killing.
  • the antibody also may be conjugated to a drug or toxin (chemotherapeutic, radionuclide, ricin A chain, cholera toxin, pertussis toxin, etc) and serve merely as a targeting agent.
  • the effector may be a lymphocyte carrying a surface molecule that interacts, either directly or indirectly, with a tumor cell target.
  • Various effector cells include cytotoxic T cells and NK cells. The combination of therapeutic modalities, i.e., direct cytotoxic activity and inhibition or reduction of ErbB2 would provide therapeutic benefit in the treatment of ErbB2 overexpressing cancers.
  • the tumor cell must bear some marker that is amenable to targeting, i.e., is not present on the majority of other cells.
  • Common tumor markers include carcinoembryonic antigen, prostate specific antigen, urinary tumor associated antigen, fetal antigen, tyrosinase (p97), gp68, TAG-72, HMFG, Sialyl Lewis Antigen, MucA, MucB, PLAP, estrogen receptor, laminin receptor, erb B and pi 55.
  • Immune stimulating molecules also exist including: cytokines such as IL-2, IL-4, IL-12, GM-CSF, gamma-IFN, chemokines such as MIP-1, MCP-1, IL-8 and growth factors such as FLT3 ligand.
  • cytokines such as IL-2, IL-4, IL-12, GM-CSF, gamma-IFN
  • chemokines such as MIP-1, MCP-1, IL-8 and growth factors such as FLT3 ligand.
  • Combining immune stimulating molecules, either as proteins or using gene delivery in combination with a tumor suppressor has been shown to enhance anti-tumor effects (Ju et al, 2000).
  • antibodies against any of these compounds can be used to target the anti-cancer agents discussed herein.
  • immunotherapies currently under investigation or in use are immune adjuvants, e.g., Mycobacterium bovis, Plasmodium falciparum, dinitrochlorobenzene and aromatic compounds (U.S. Patents 5,801,005 and 5,739,169; Hui and Hashimoto, 1998; Christodoulides et al, 1998); cytokine therapy, e.g., interferons ⁇ , ⁇ and ⁇ ; IL-1, GM-CSF and TNF (Bukowski et al, 1998; Davidson et al, 1998; Hellstrand et al, 1998); gene therapy, e.g., TNF, IL-1, IL-2, p53 (Qin et al, 1998; Austin- Ward and Villaseca, 1998; U.S.
  • immune adjuvants e.g., Mycobacterium bovis, Plasmodium falciparum, dinitrochlorobenzene and aromatic compounds
  • cytokine therapy e.g.,
  • an antigenic peptide, polypeptide or protein, or an autologous or allogenic tumor cell composition or "vaccine” is administered, generally with a distinct bacterial adjuvant (Ravindranath and Morton, 1991; Morton et al, 1992; Mitchell et al, 1990; Mitchell et al, 1993).
  • adoptive immunotherapy the patient's circulating lymphocytes, or tumor infiltrated lymphocytes, are isolated in vitro, activated by lymphokines such as IL-2 or transduced with genes for tumor necrosis, and readministered (Rosenberg et al, 1988; 1989).
  • Curative surgery is a cancer treatment that may be used in conjunction with other therapies, such as the treatment of the present invention, chemotherapy, radiotherapy, hormonal therapy, gene therapy, immunotherapy and/or alternative therapies.
  • Curative surgery includes resection in which all or part of cancerous tissue is physically removed, excised, and/or destroyed.
  • Tumor resection refers to physical removal of at least part of a tumor.
  • treatment by surgery includes laser surgery, cryosurgery, electrosurgery, and microscopically controlled surgery (Mohs' surgery). It is further contemplated that the present invention may be used in conjunction with removal of superficial cancers, precancers, or incidental amounts of normal tissue.
  • a cavity may be formed in the body.
  • Treatment may be accomplished by perfusion, direct injection or local application of the area with an additional anti-cancer therapy.
  • Such treatment may be repeated, for example, every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, 4, and 5 weeks or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.
  • These treatments may be of varying dosages as well.
  • agents may be used in combination with certain aspects of the present invention to improve the therapeutic efficacy of treatment.
  • additional agents include immunomodulatory agents, agents that affect the upregulation of cell surface receptors and GAP junctions, cytostatic and differentiation agents, inhibitors of cell adhesion, agents that increase the sensitivity of the hyperproliferative cells to apoptotic inducers, or other biological agents.
  • Immunomodulatory agents include tumor necrosis factor; interferon alpha, beta, and gamma; IL-2 and other cytokines; F42K and other cytokine analogs; or MIP- 1, MIP-lbeta, MCP-1, RANTES, and other chemokines. It is further contemplated that the upregulation of cell surface receptors or their ligands such as Fas / Fas ligand, DR4 or DR5 / TRAIL (Apo-2 ligand) would potentiate the apoptotic inducing abilities of the present invention by establishment of an autocrine or paracrine effect on hyperproliferative cells. Increasing intercellular signaling by elevating the number of GAP junctions would increase the anti-hyperproliferative effects on the neighboring hyperproliferative cell population.
  • hyperthermia is a procedure in which a patient's tissue is exposed to high temperatures (up to 106°F).
  • External or internal heating devices may be involved in the application of local, regional, or whole-body hyperthermia.
  • Local hyperthermia involves the application of heat to a small area, such as a tumor. Heat may be generated externally with high-frequency waves targeting a tumor from a device outside the body. Internal heat may involve a sterile probe , including thin, heated wires or hollow tubes filled with warm water, implanted microwave antennae, or radiofrequency electrodes.
  • a patient's organ or a limb is heated for regional therapy, which is accomplished using devices that produce high energy, such as magnets.
  • some of the patient's blood may be removed and heated before being perfused into an area that may be internally heated.
  • Whole -body heating may also be implemented in cases where cancer has spread throughout the body. Warm-water blankets, hot wax, inductive coils, and thermal chambers may be used for this purpose.
  • Hormonal therapy may also be used in conjunction with certain aspects of the present invention or in combination with any other cancer therapy previously described.
  • the use of hormones may be employed in the treatment of certain cancers such as breast, prostate, ovarian, or cervical cancer to lower the level or block the effects of certain hormones such as testosterone or estrogen. This treatment is often used in combination with at least one other cancer therapy as a treatment option or to reduce the risk of metastases. VIII. Examples
  • Citrate-coated CuS NPs (Cit-CuS NPs) were readily synthesized in aqueous solution by reacting CuCl 2 and Na 2 S in the presence of sodium citrate at 90°C for 15 min. PEG coating was introduced by incubating Cit-CuS NPs with SH-PEG (molecular mass, 5,000 Da) at room temperature overnight.
  • FIG. 1A is a representative transmission electron microscopy image of the CuS NPs.
  • the optical spectra of Cit-CuS NPs and PEG-CuS NPs are shown in FIG. IB. Both types of NPs displayed a blue-shifted band gap absorption compared to bulk CuS materials (peak >1100 nm) (Zhao et al., 2009), confirming the effect of quantum size confinement.
  • the hydrodynamic sizes of the CuS NPs were determined from dynamic light scatting study (FIG 8).
  • CuS NPs which had a TEM diameter of 11 nm showed DLS size of 11.7 nm and 31.6 nm before and after PEG coating, respectively.
  • the increased diameter of PEG- coated NPs in aqueous solution is probably due to the PEG layer that is invisible in TEM measurement.
  • These CuS NPs were significantly larger than previously reported thioglycolic acid-stabilized CuS NPs, which had an average diameter of 3 nm and displayed peak absorbance at 900 nm.
  • the high-resolution TEM (FIG 9) reveals the fringes of hexagonal CuS (102) planes with a lattice spacing of about 0.3 nm. These results are in agreement with the lattice spacing of the ⁇ 102 ⁇ plane (0.305 nm) of hexagonal CuS nanostructures described in previous reports (Wu et ⁇ , 2006; Xu et ah, 2006).
  • the maximum absorption of the 11 -nm Cit-CuS NPs and PEG-CuS NPs, 930 nm is 30 nm red-shifted compared to the absorption of the 3-nm CuS NPs previously reported but is 50 nm blue-shifted compared to the absorption of the 15-nm CuS NPs previously reported by Zhao et al. (2009), who studied the composition dependence of plasmonic resonance spectra of Cu 2 - x S. Future studies are needed to identify and clarify the effect of size on the NIR plasmonic resonance spectra for CuS NPs.
  • Cit-CuS NPs and PEG-CuS NPs were investigated by incubating these NPs in various media, including water, 0.4 mM citrate solution, 100 mM acetate buffer solution, 100 mM NaCl solution, 4-(2-hydroxyethyl)-l- piperazineethanesulfonic acid buffer (HEPES), phosphate -buffered saline (PBS), 50 mM bovine serum albumin solution, PBS containing 10% fetal bovine serum (FBS), and 100% FBS at 37°C for up to 7 days. No precipitates were observed and no obvious change of hydrodynamic particle sizes were found for either type of NP in these solutions (FIG.
  • [00163] [ 64 Cu]-CuS NPs were prepared using the same procedures used for the preparation of plain CuS NPs except that for the synthesis of PEG-[ 64 Cu]-CuS NPs, the PEG coating was introduced directly during the course of CuS NP synthesis instead of after CuS NP formation through PEG/citrate substitution. This is necessary to shorten the time of synthesis for [ 64 Cu]-CuS NPs.
  • the preparation of the 3-nm CuS described in a previously reported procedure requires more than 24 h for the reaction to complete at room temperature, which is not suitable for Cu labeling because the decay half- life of Cu is only 12.7 h.
  • Cit-[ 64 Cu]-CuS NPs lost 12.7% and 15.3% of radioactivity, respectively.
  • negligible amount of radioactivity was lost from PEG-[ 64 Cu]-CuS NPs.
  • MDA MB231 cells human brain U87 tumor cells, human embryonic kidney 293 cells (HEK293 cells) are shown in FIG. 13.
  • CuS has no cytotoxic effect on the cells at concentration up to 100 ⁇ after 48 hours of incubation.
  • Copper(II) chloride (CuCl 2 ), sodium sulfide (Na 2 S-9H 2 0), sodium citrate, and methoxy-PEG-thiol (SH-PEG; molecular weight, 5,000) were purchased from Sigma-Aldrich (St. Louis, MO). Isoflurane was obtained from Baxter (Deerfield, IL). 64 CuCl 2 was obtained from Wisconsin University at Madison (Madison, WI). PD-10 columns were purchased from Amersham-Pharmacia Biotech (Piscataway, NJ). All the chemicals and solvents were at least ACS grade and were used without further purification.
  • Deionized water (18 ⁇ ) was obtained from a Milli-Q synthesis system (Millipore, Billerica, MA). Human U87 glioblastoma cells were obtained from American Type Culture Collection (Manassas, VA). RPMI-1640 culture medium and calcein AM were obtained from Sigma- Aldrich.
  • the UV-Vis spectroscopy of CuS NPs was recorded on a Beckman Coulter DU-800 UV-VIS spectrometer (Brea, CA) with a 1.0-cm optical path length quartz cuvette.
  • the identity and crystallinity, crystalline structure, size, and shape of the NPs were observed by X-ray diffraction and a high-resolution transmission electron microscope (200 kV, JEOL, Japan).
  • Cit-[ 64 Cu]-CuS NPs and PEG-[ 64 Cu]-CuS NPs are shown in FIG 2B.
  • Cit-[ 64 Cu]-CuS NPs displayed significantly higher uptake than did PEG-[ 64 Cu]-CuS NPs in the liver and the spleen, both are RES enriched tissues.
  • PEG-[ 64 Cu]-CuS NPs were less likely being captured by RES cells, and therefore, displayed higher levels in the heart, kidney, lung, stomach, intestine, and bone.
  • FIG 3 shows representative whole-body micro-PET/CT images of a mouse acquired at 1, 6, and 24 h after i.v. injection of PEG-[ 64 Cu]-CuS NPs. Consistent with the biodistribution analysis, PET/CT images revealed high uptake of PEG-[ 64 Cu]-CuS NPs in the liver and the spleen.
  • PEG-[ 64 Cu]-CuS NPs gradually accumulated in the tumor between 1 h and 24 h, permitting remarkably clear visualization of the tumor at 24 h after injection.
  • Quantitative analysis showed that the average tumor-to-muscle ratios at 1 h, 6 h, and 24 h after NP injection were 2.74: 1, 6.14: 1, and 6.55: 1, respectively, indicating that PEG-[ 64 Cu]-CuS NPs were deposited in and retained in the tumor over the 24-h period.
  • mice were intravenously injected with radioactive CuS NPs (4 x 10 11 particles, 50 ⁇ / ⁇ ⁇ in 0.2 mL), and blood samples (10 ⁇ ) were collected from the tail vein at predetermined time points.
  • the blood pharmacokinetic parameters of the radiotracer were analyzed with a two-compartmental model using WinNonlin 5.0.1 software (Pharsight Corporation, Palo Alto, CA). The animals were euthanized by C0 2 exposure at the end of the study.
  • mice were killed by C0 2 overexposure 24 h after injection. Blood, heart, liver, spleen, kidney, lung, stomach, intestine, muscle, bone, brain, and tumor tissues were removed and weighed, and radioactivity was measured with a Packard Cobra gamma counter (Ramsey, MN). Uptakes of 64 Cu-labeled CuS NPs in various organs were expressed as percentage of injected dose per gram of tissue (%ID/g).
  • the micro-PET and CT images were generated separately and then fused using Inveon Research Workplace (Siemens Preclinical Solution, Knoxville, TN).
  • ROI region of interest
  • a circular region of interest was drawn on the muscle of the opposite leg of the mouse on CT images, and copied to the PET images.
  • the mean signal intensities of the tumor and muscle in the ROIs were recorded.
  • the tumor-to-muscle ratio was calculated by dividing signal intensity of the tumor by that of the muscle.
  • NPs smaller than 20 nm having NIR absorption there have been few reports on NPs smaller than 20 nm having NIR absorption.
  • the smallest gold nanostructures reported to date as having plasmon NIR absorption were -40 nm in diameter (Melancon et ah, 2008; Lu et ah, 2009). Because the pharmacokinetics and biodistribution pattern of NPs are strongly affected by their size (Zhang et ah, 2009; Yang et ah, 2009), it is highly desirable that novel nanostructures having diameter less than 20 nm with NIR absorption be identified and evaluated.
  • CuS NPs which are much smaller than gold nanostructures, may have a better chance of reaching their targets and being cleared from the body through the renal system (Zhang et ah, 2009; Choi et ah, 2007; Burns et al, 2009).
  • FIG 4A shows the temperature change of an aqueous solution containing PEG-CuS NPs as a function of exposure time.
  • the new 11 -nm CuS NPs displayed higher photothermal conversion efficiency.
  • the temperature of an aqueous solution of 3-nm CuS NPs increased 12.7°C over a period of 5 min at an output power of 24 W/cm and a concentration of 770 ⁇ CuS units ( ⁇ 4.8xl0 16 particles/mL).
  • NPs human U87 glioblastoma cells were incubated with PEG-CuS NPs for 2 h. The cells were then irradiated with NIR laser centered at 808 nm. The cell viability after exposure to NIR laser was probed using calcein AM dye, which reports ubiquitous intracellular esterase activity. Twenty-four hours after laser treatment, cells treated with PEG-CuS NPs at a concentration of 500 ⁇ CuS plus NIR laser (16 W/cm 2 for 5 min, 40 W/cm 2" for 2 mm, or 40 W/cm for 5 min) had substantially reduced cell density (FIG. 13). No apparent change in cell viability was observed when cells were treated with CuS NPs alone at 100 ⁇ or 500
  • mice bearing subcutaneous U87 tumors the skin of the mice at the tumor site turned greenish after both i.t. and i.v. injection of PEG-CuS NPs owing to the deposition of the NPs in the tumor (FIG 5A).
  • the skin at the tumor sites in both mice that received i.t. injection and mice that received i.v. injection of PEG-CuS NPs turned brownish or dark red, indicating tissue burn caused by local photothermal effect.
  • there was no noticeable change in the skin of mice treated with PEG-CuS NPs alone, saline plus NIR irradiation, or NIR laser alone (FIG 5A).
  • NPs administered by either i.t. or i.v. injection followed by laser treatment caused significantly greater necrotic response than did PEG-CuS NPs without laser, saline plus laser, or saline only (FIG 5B).
  • PEG-CuS NPs plus laser common features of thermonecrosis, such as loss of nucleus, cell shrinkage, and coagulation, were found in the tumor tissues.
  • mice treated with i.t. injection of PEG-CuS NPs plus laser almost all of the tumor tissue was necrotized, exhibiting pyknosis, karyolysis, cytoplasmic acidophilia, and degradation and corruption of the extracellular matrix of the tumor.
  • the laser was a continuous- wave GCSLX-05-1600m-l fiber-coupled diode laser with a center wavelength of 808 ⁇ 10 nm. It was powered by a DH 1715A-5 dual-regulated power supply (15PLUS laser, Diomed, Andover, MA). A 5-m, 600- ⁇ core BioTex LCM-001 optical fiber (BioTex Inc., Houston, TX) was used to transfer laser power from the laser unit to the target. This fiber had a lens mounting at the output that allowed the laser spot size to be changed by changing the distance from the output to the target.
  • the output power was independently calibrated using a handheld model 840-C optical power meter (Newport Corporation, Irvine, CA) and was found to be 1 W for a spot diameter of 3.5 mm ( ⁇ 8 W/cm ) and a 2-amp supply current.
  • the end of the optical fiber was attached to a retort stand using a movable clamp and positioned directly above the sample cell.
  • NIR laser light (808 nm) was delivered through a quartz cuvette containing the CuS NPs (100 ⁇ ).
  • a thermocouple was inserted into the solution perpendicular to the path of the laser light. The temperature was measured over 10 min. Water was used as a control.
  • mice in groups B and C were injected intravenously with PEG-CuS NPs (200 ⁇ , 8 mM/mouse).
  • Mice in group D were injected intravenously with saline.
  • Mice in group E did not receive any treatment.
  • the tumors in mice from groups A, B, and D were irradiated with NIR laser at 12 W/cm for 5 min.
  • the mice were killed 24 h after laser treatment, and tumors were removed, snap frozen, and cryosectioned into 1000 ⁇ .
  • the slides were stained with hematoxylin-eosin.
  • the slices were examined under a Zeiss Axio Observer.Zl fluorescence microscope.
  • the images were taken using a Zeiss AxioCam MRc5 color camera, and the extent of tumor necrosis, expressed as a percentage of the entire tumor area, was analyzed with Zeiss Axio Vision software (version 4.6.3).
  • Photoacoustic tomography is a developing biomedical imaging modality that is based on the acoustical detection of the optical absorption of laser light by biomolecules.
  • the semiconductor copper sulfide nanoparticles CuS NP, -11 nm in diameter
  • HAuNS hollow gold nanoshells
  • the nanoparticles were dispersed with 10% polyacryl amide gelatin and used as an imaging object inside fresh chicken breast tissues.
  • Near-infrared laser pulses 800-1064 nm were used to induce photoacoustic signals.
  • PAT images were acquired with a prototype PAT device.
  • Objects containing a concentration of 1 mM of CuS NP and HAuNS could be clearly visualized at ⁇ 5 cm depth from the laser illuminating surface. Imaging resolution and sensitivity were estimated to be -800 ⁇ and ⁇ 6 nmol, respectively, at this depth. Significantly, PAT imaging of gels containing CuS NP at 7 cm was attainable under optimal data acquisition conditions.
  • Both CuS NP nanoparticles were capable of transmitting and detecting photoacoustic signals (FIG. 17). It is feasible to obtain deeply penetrating PAT images with high ultrasonic spatial imaging resolution in the presence of appropriate contrast agents.
  • [00191] [ 64 Cu]CuS NP was used for lymph node imaging with PET/CT. This technique can be potentially used in noninvasive detection of lymph node metastasis. The ability to detect lymph nodes metastasis is extremely important in cancer staging, determining prognosis, and monitoring treatment outcome.
  • the lymphoscintigraphy could guide metastasis lymph node(LN) detection during the surgery; guide the accuracy resection of sentinel nodes for biopsy; and provide accuracy information to oncologist on guiding postoperation chemoradiotherapy of individual patient.
  • MicroPET/CT images of a rat 24 h after subcutanenous injection of the [ 64 Cu]CuS NP in the right front paw were shown for lymph nodes as indicated by arrow.
  • CD44 The cell surface receptor CD44 is found on many cancer cells, and has been implicated in various processes such as inflammation and tumor metastasis. CD44 is a major receptor for the hyaluronic acid (HA).
  • HA hyaluronic acid
  • HA is mixed with CuCl 2 (or a mixture of CuCl 2 and 64 CuCl 2 ) in aqueous solution. Then Na 2 S solution was added into the above solution at room temperature. The reaction solution was stirred at 90°C for a few minutes. CuS NP coated with HA was isolated by ultracentrifugation. The resulting HA-coated CuS NP (HA-CuS NP) were evaluated with regard to their photothermal conducting effect (FIG. 19), binding to CD44(+) tumor cells (FIGS. 20-21), and selective photothermal ablation of tumor cells (FIG. 22).
  • [00194] CuS nanoparticles were synthesized essentially as described or the synthesis of [ 64 Cu]CuS NP, however, the positron emitter 68 Ga was incorporated into the particles in place of 64 Cu. Briefly, 100 ⁇ (2 mCi) of 68 GaCl 2 was mixed with 1000 ⁇ of CuCl 2 containing sodium citrate (0.2 g/L). Then, 10 ⁇ , of sodium sulfide solution (100 mM) was added to the CuCl 2 solution under stirring. The mixture was then heated to 90°C for 15 min until a dark green solution was obtained. The reaction mixture was transferred to ice-cold water to give Cit-[ 68 Ga]-CuS NPs.
  • Cit-[ 68 Ga]-CuS NPs The same procedure used for Cit-[ 68 Ga]-CuS NPs was used for the preparation of PEG-[ 68 Ga]-CuS NPs. As shown in FIG. 23 68 Ga was incorporated into CuS nanoparticles with high efficiency without affecting the optical properties of [ 68 Ga]CuS NP (see, FIG. 23B).
  • CuS NPs were produced as detailed above, but in this case coated with folic acid (FA). The physical properties of the particles were then assessed using previously described techniques.
  • the FA coated NPs showed a peak absorbance in a range that would be useful for photothermal therapy (FIG. 28A) and indeed exhibited excellent photothermal conduction properties (FIG. 28B).
  • the CuS NPS with FA coating also maintained a small average particle size of approximately 12 nm as assessed by TEM (FIG. 28C) and showed similar stability in a variety of buffers (FIG. 28D).
  • FA coated NPs were found to specifically bind to KB cells (see FIG.
  • FA-CuS NPs are also able to selectively target KB tumors in vivo and tumor accumulation of FA-CuS NPs (Tu) was partially inhibited by excess FA (FIG. 31).
  • the targeted FA-CuS NPs were far more effective (relative to untargeted PEG-CuS NPs) at killing tumor cells by photothermal ablation (FIG. 32).
  • Example 11 Radio-photothermal therapy and imaging with PEG-[ Cu]CuS NP
  • PEG-[ 64 Cu]CuS NPs were synthesized essentially as described above.
  • CuCl 2 (10 jxL, 4000 ⁇ Ci) was added to 190 ⁇ . of CuCl 2 solution (4 mM) containing PEG-SH (0.2 g/L), after which 8 ⁇ , of sodium sulfide solution (100 mM) was added to the CuCl 2 solution with stirring. The mixture was then heated to 90 °C for 15 min until a dark- green solution was obtained. The reaction mixture was transferred to ice-cold water to give PEG-[ 64 Cu]CuS NP.
  • the non-radioactive analogue NPs, PEG-CuS NP were synthesized using the similar protocols for synthesizing radioactive nanop articles. A general procedure for the synthesis of CuS NP in water is described as follows.
  • the synthesis was completed with 20 min. Transmission electron microscopy image of the PEG-CuS NP confirmed approximately uniform size distribution of the NPs with an average diameter of 11 nm.
  • the optical spectra of PEG-CuS NP showed a strong absorption band in near-infrared region (peak at approximately 930 nm) as previously demonstrated (see, FIG. IB).
  • This important feature of CuS NP is their NIR light-induced thermal effect, which could be used for photothermal therapy.
  • the temperature change of an aqueous solution containing PEG-CuS NP as a function of exposure time was also determined.
  • the radiolabeling efficiency and stability of labeled NP were also analyzed using instant thin-layer chromatography (ITLC).
  • ITLC strips were developed with PBS (pH 7.4) containing 4 mM ethylenediammetetraacetic acid and quantified using an IAR-2000 TLC imaging scanner (Bioscan, Washington, DC).
  • PBS pH 7.4
  • IAR-2000 TLC imaging scanner Bioscan, Washington, DC
  • the PEG-[ 64 Cu]CuS NP were suspended in PBS or mouse serum and incubated at 37 °C for 24 h. Free 64 Cu 2+ ions moved to the solvent front, and the NP remained at the original spot. The radioactivity at the original spot was recorded as a percentage of the total radioactivity of the ITLC strip. Results showed that >99% of the radioactivity was associated with PEG-[ 64 Cu]CuS NP at the end of synthesis, indicating that the radio-labeling efficiency approached >99%.
  • mice For the in vivo studies twenty four nu/nu mice ( - 6 weeks old) were bought from Charles River Laboratories (Wilmington, MA). All experiments were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee of the University of Texas, MD Anderson Cancer Center.
  • NIR laser 808nm
  • FIG. 15A shows experimental design for in vivo anticancer effects of various treatments with CuS NP in s.c. BT-474 breast cancer model.
  • FIG. 15B shows tumor growth curves. Compared to untreated control group, significant growth delay was achieved with PEG-[ 64 Cu]CuS NP alone (RT), PEG-CuS NP-plus NIR laser (PTT), and PEG- [ 64 Cu]CuS NP-plus-NIR laser (RPTT) treatment groups. The mean tumor volumes of untreated control mice reached 998 ⁇ 354 mm by day 30. In animals treated with radiotherapy alone, photothermal therapy alone, and combined radio-photothermal therapies,
  • the mean tumor volumes were 392 ⁇ 96 mm , 264 ⁇ 345 mm , and 75 ⁇ 105 mm , respectively.
  • tumor mass is localized in the subcutaneous tissue, with an overlying epidermis. At higher magnification, the tumor demonstrates a solid growth pattern with a vague nesting formation. No unequivocal intracellular mucin or glands are present.
  • the tumor is a high- grade breast carcinoma with metaplastic features. Tumor cells display marked pleomorphism, with enlarged nuclei and prominent nucleoli. Atypical mitotic figures are seen readily. However, for the radiotherapy group, tumor mass shows marked degenerative and necrotic changes. Approximately 40% of tumor cells are viable.
  • the tumor displays an array of treatment effects characterized by clear cell/ballooning degeneration and coagulative tumor necrosis. Histological examinations of tumor tissues also confirmed the successful destruction of tumor cells by the photothermal effect of PEG-CuS NP. According to the hematoxylin and eosin (H&E) staining results, common features of thermonecrosis such as loss of nucleus, cell shrinkages, and coagulation were found from the tumor tissues treated with PEG-CuS NP + NIR. Tumor mass is shrunken, with a small focus of tumor nests that occupy ⁇ 10% of the nodule.
  • H&E hematoxylin and eosin
  • the nodule mainly consists of fibroblasts, histocytes, and lymphoplasmocytes, which surround a small focus of tumor nests. Tumor cells reveal degenerative changes and single-cell necrosis. All features are consistent with therapeutic effect.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Nanotechnology (AREA)
  • Dispersion Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne des procédés et des compositions pour améliorer le potentiel thérapeutique et le potentiel d'imagerie de nanoparticules radioactives. Dans certains aspects, elle concerne par exemple des procédés pour préparer une composition contenant une nanoparticule présentant un radio-isotope métallique intégré et ses utilisations. L'invention concerne également une telle composition.
PCT/US2011/056928 2010-10-19 2011-10-19 Nanoparticules radioactives sans chélateur multifonctionnelles pour imagerie et thérapie Ceased WO2012138379A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US39465410P 2010-10-19 2010-10-19
US61/394,654 2010-10-19

Publications (2)

Publication Number Publication Date
WO2012138379A2 true WO2012138379A2 (fr) 2012-10-11
WO2012138379A3 WO2012138379A3 (fr) 2013-02-07

Family

ID=46969742

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/056928 Ceased WO2012138379A2 (fr) 2010-10-19 2011-10-19 Nanoparticules radioactives sans chélateur multifonctionnelles pour imagerie et thérapie

Country Status (1)

Country Link
WO (1) WO2012138379A2 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8975413B2 (en) 2012-07-02 2015-03-10 Korea Atomic Energy Research Institute Method of preparing radioisotope nanostructure with ligand-metal framework and application
CN104548140A (zh) * 2014-12-25 2015-04-29 中国科学院上海硅酸盐研究所 新型铜基磁共振/光声/近红外热成像三模式成像纳米造影剂及其制备方法
CN105079807A (zh) * 2015-09-23 2015-11-25 北京化工大学 一种近红外光热响应的抗癌药物纳米胶囊及其制备方法
CN106315663A (zh) * 2015-06-17 2017-01-11 中国科学院苏州纳米技术与纳米仿生研究所 超小金属硫族化合物纳米晶、其亲生物合成方法及应用
WO2017019659A1 (fr) * 2015-07-28 2017-02-02 Gerald Lee Wolf Effet abscopal du théragnostic par uspio et immunothérapie pour le traitement du cancer
CN108210924A (zh) * 2018-03-09 2018-06-29 北京科技大学 一种基于硫化铜的热消融作用介导的经皮给药的方法
CN109250747A (zh) * 2018-10-01 2019-01-22 嘉兴德扬生物科技有限公司 一种支化聚乙烯亚胺介导的纳米硫化铜的制备方法
CN110482590A (zh) * 2019-08-06 2019-11-22 河南师范大学 一种片状纳米硫化铜的合成方法及其在制备光热抗癌药物中的应用
CN110755618A (zh) * 2019-12-08 2020-02-07 广西师范大学 一种透明质酸-铜(ii)复合纳米粒子及其制备方法
CN113209046A (zh) * 2021-05-08 2021-08-06 中国人民解放军陆军军医大学 一种CoSe@BSA纳米粒子药物组合物及其制备方法和应用
CN114367673A (zh) * 2022-01-25 2022-04-19 南京邮电大学 二维超薄PdRu纳米片及其制备方法和应用
CN115364248A (zh) * 2022-08-16 2022-11-22 天津医科大学总医院 一种131I-BSA@CuS纳米颗粒及其制备方法和应用
CN116999411A (zh) * 2023-06-21 2023-11-07 浙江大学 一种双响应型铜死亡纳米颗粒材料及其制备方法和应用
CN117756064A (zh) * 2022-09-16 2024-03-26 上海交通大学医学院附属第九人民医院 一种铜铁硫硒纳米粒子及其制备方法和用途

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070189965A1 (en) * 2004-06-17 2007-08-16 Kuperus John H Copper-complex isonitrile positron emission tomography (pet) imaging agent and method
WO2006017179A1 (fr) * 2004-07-09 2006-02-16 Robert Sabin Compositions pour le traitement de maladies mammaliennes et leurs procédés d’utilisation
KR100604976B1 (ko) * 2004-09-03 2006-07-28 학교법인연세대학교 다작용기 리간드로 안정화된 수용성 나노입자

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8975413B2 (en) 2012-07-02 2015-03-10 Korea Atomic Energy Research Institute Method of preparing radioisotope nanostructure with ligand-metal framework and application
CN104548140A (zh) * 2014-12-25 2015-04-29 中国科学院上海硅酸盐研究所 新型铜基磁共振/光声/近红外热成像三模式成像纳米造影剂及其制备方法
CN106315663A (zh) * 2015-06-17 2017-01-11 中国科学院苏州纳米技术与纳米仿生研究所 超小金属硫族化合物纳米晶、其亲生物合成方法及应用
WO2017019659A1 (fr) * 2015-07-28 2017-02-02 Gerald Lee Wolf Effet abscopal du théragnostic par uspio et immunothérapie pour le traitement du cancer
CN105079807A (zh) * 2015-09-23 2015-11-25 北京化工大学 一种近红外光热响应的抗癌药物纳米胶囊及其制备方法
CN105079807B (zh) * 2015-09-23 2018-03-30 北京化工大学 一种近红外光热响应的抗癌药物纳米胶囊及其制备方法
CN108210924A (zh) * 2018-03-09 2018-06-29 北京科技大学 一种基于硫化铜的热消融作用介导的经皮给药的方法
CN109250747A (zh) * 2018-10-01 2019-01-22 嘉兴德扬生物科技有限公司 一种支化聚乙烯亚胺介导的纳米硫化铜的制备方法
CN110482590A (zh) * 2019-08-06 2019-11-22 河南师范大学 一种片状纳米硫化铜的合成方法及其在制备光热抗癌药物中的应用
CN110755618A (zh) * 2019-12-08 2020-02-07 广西师范大学 一种透明质酸-铜(ii)复合纳米粒子及其制备方法
CN110755618B (zh) * 2019-12-08 2021-08-10 广西师范大学 一种透明质酸-铜(ii)复合纳米粒子及其制备方法
CN113209046A (zh) * 2021-05-08 2021-08-06 中国人民解放军陆军军医大学 一种CoSe@BSA纳米粒子药物组合物及其制备方法和应用
CN113209046B (zh) * 2021-05-08 2022-09-09 中国人民解放军陆军军医大学 一种CoSe@BSA纳米粒子药物组合物及其制备方法和应用
CN114367673A (zh) * 2022-01-25 2022-04-19 南京邮电大学 二维超薄PdRu纳米片及其制备方法和应用
CN114367673B (zh) * 2022-01-25 2024-02-27 南京邮电大学 二维超薄PdRu纳米片及其制备方法和应用
CN115364248A (zh) * 2022-08-16 2022-11-22 天津医科大学总医院 一种131I-BSA@CuS纳米颗粒及其制备方法和应用
CN117756064A (zh) * 2022-09-16 2024-03-26 上海交通大学医学院附属第九人民医院 一种铜铁硫硒纳米粒子及其制备方法和用途
CN116999411A (zh) * 2023-06-21 2023-11-07 浙江大学 一种双响应型铜死亡纳米颗粒材料及其制备方法和应用

Also Published As

Publication number Publication date
WO2012138379A3 (fr) 2013-02-07

Similar Documents

Publication Publication Date Title
WO2012138379A2 (fr) Nanoparticules radioactives sans chélateur multifonctionnelles pour imagerie et thérapie
Li et al. Gram-scale synthesis of highly biocompatible and intravenous injectable hafnium oxide nanocrystal with enhanced radiotherapy efficacy for cancer theranostic
Juengpanich et al. Pre-activated nanoparticles with persistent luminescence for deep tumor photodynamic therapy in gallbladder cancer
Mao et al. Ultrasmall biocompatible Bi2Se3 nanodots for multimodal imaging-guided synergistic radiophotothermal therapy against cancer
Zeng et al. Carbon dots as a trackable drug delivery carrier for localized cancer therapy in vivo
Wang et al. Janus gold triangle-mesoporous silica nanoplatforms for hypoxia-activated radio-chemo-photothermal therapy of liver cancer
Yu et al. Tumor microenvironment-triggered fabrication of gold nanomachines for tumor-specific photoacoustic imaging and photothermal therapy
Geng et al. Combining anti-PD-1 antibodies with Mn2+-drug coordinated multifunctional nanoparticles for enhanced cancer therapy
Lu et al. Photothermally activatable PDA immune nanomedicine combined with PD-L1 checkpoint blockade for antimetastatic cancer photoimmunotherapy
Cherukuri et al. Targeted hyperthermia using metal nanoparticles
Cheng et al. Gold nanosphere gated mesoporous silica nanoparticle responsive to near-infrared light and redox potential as a theranostic platform for cancer therapy
Li et al. Hyaluronic acid–methotrexate conjugates coated magnetic polydopamine nanoparticles for multimodal imaging-guided multistage targeted chemo-photothermal therapy
Liu et al. Molybdenum disulfide-based hyaluronic acid-guided multifunctional theranostic nanoplatform for magnetic resonance imaging and synergetic chemo-photothermal therapy
Li et al. Octopod PtCu nanoframe for dual-modal imaging-guided synergistic photothermal radiotherapy
You et al. Graphene oxide-based nanocarriers for cancer imaging and drug delivery
Hou et al. Remodeling the tumor microenvironment with core–shell nanosensitizer featuring dual-modal imaging and multimodal therapy for breast cancer
Wu et al. Remotely controlled drug release based on iron oxide nanoparticles for specific therapy of cancer
Hao et al. Multifunctional biodegradable Prussian blue analogue for synergetic photothermal/photodynamic/chemodynamic therapy and intrinsic tumor metastasis inhibition
Sherlock et al. Multifunctional FeCo-graphitic carbon nanocrystals for combined imaging, drug delivery and tumor-specific photothermal therapy in mice
Sawant et al. Cancer research and therapy: Where are we today
US20230390394A1 (en) Bismuth-Gadolinium Nanoparticles
Tang et al. A logic-gated modular nanovesicle enables programmable drug release for on-demand chemotherapy
CN111956801A (zh) 光控释放co和阿霉素的纳米药物系统及其制备和应用
Tsai et al. Photothermal, targeting, theranostic near-infrared nanoagent with SN38 against colorectal cancer for chemothermal therapy
WO2020055455A1 (fr) Nanoparticules ciblées pour le diagnostic, la détection, et le traitement du cancer

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11863007

Country of ref document: EP

Kind code of ref document: A2