AU2021101355A4 - Nanocarriers for treatment of breast cancer - Google Patents
Nanocarriers for treatment of breast cancer Download PDFInfo
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Abstract
NANOCARRIERS FOR TREATMENT OF BREAST CANCER
Aspects of the present disclosure relate to nanocarriers for treatment of breast cancer. Breast
cancer is cancer that forms in the cells of the breasts. The breast cancer occurs when some
5 breast cells begin to grow abnormally. These cells divide more rapidly than healthy cells do
and continue to accumulate, forming a lump or mass. The present invention provides a
nanocarrier which is having having an interior and an exterior. The nanocarrier is also
comprising of at least one conjugate, wherein each conjugate includes a polyethylene glycol
(PEG) polymer. Each conjugate can also includes two amphiphilic compounds. The
10 nanocarriers are such that each conjugate self-assembles in an aqueous solvent present to
form the required nanocarrier. The hydrophobic pocket is formed in the interior of the
nanocarrier due to the orientation of the hydrophobic face of each amphiphilic compound
which is towards each other.
(FIG. 1 will be the reference figure)
15
- 19-
A B
H Ho
HO
H0 HO 21 nm
HO CH, CH80 H
CH, CH 1
H
For covalent loading probes -=:* NH
NH
HN 0 OH
NH
C OH H
OH
HH,.
FIG. 1shows (A) chemical structure and (B) particle size ofPEG3000-CA8.
5
10
- 20-
Description
A B H Ho HO H0 HO 21 nm HO CH, CH80H
CH, CH 1 H
For covalent loading probes -=:* NH
NH HN 0 OH
FIG. 1shows (A) chemical structure and (B) particle size ofPEG3000-CA8.
COMPLETE SPECIFICATION AUSTRALIAN GoVERNEMNT
1. TITLE OF THE INVENTION
2. APPLICANTS (S) NAME NATIONALITY ADDRESS
kshok Kumar IN Room.No-306, Department of Computer Science, AIM & ACT Building, Banasthali Vidyapith, Banasthali, Rajasthan-304022, India.
iaruna Sharma IN Room.No-303, Department of Computer Science, AIM & ACT Building, Banasthali Vidyapith, Banasthali, Rajasthan-304022, India.
)r. Apeksha Saraf IN School of Pharmacy, Devi Ahilya Vishwavidyalaya, Takshashila Campus, Khandwa Road, (Ring Road), Indore 452001, India
)r. Mayank Sharma IN SVKM's NMIMS School of Pharmacy and Technology Management, Mukesh Patel Technology Park, National Highway 3, Village Babulde, Shirpur -425405 (Maharashtra)
rof. Saurabh IN Room.No-207, Department of Computer Science, AIM
Mukherjee & ACT Building, Banasthali Vidyapith, Banasthali, Rajasthan-304022, India. 3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed
[0001] The present disclosure relates to drug delivery and in particular to the nanocarriers for treatment of breast cancer.
[0001] The Paclitaxel (Taxol@) is a standard and effective chemotherapeutic agent for many cancer types, e.g. ovarian cancer, breast cancer, small cell lung cancer, and non-small cell lung cancer. Because paclitaxel is very insoluble in water, formulation of this drug requires Cremophor EL which causes significant side effects such as allergic reactions. Patients receiving Paclitaxel (PTX) require premedication with histamine blockers and steroid.
[0002] Abraxane@ is a newer formulation of paclitaxel that has less of these side effects and it is among the first nanotherapeutic agents approved by the FDA. It consists of human serum albumin nanoparticles (~130 nm) loaded with paclitaxel. However, because of its relatively large size, it is unlikely that Abraxane can penetrate deep into the tumor mass. In addition, these relatively large nanoparticles have a propensity to be trapped in the liver and the reticuloendothelial system (RES). Doxil or liposomal doxorubicin, another nanotherapeutic drug, has similar dimensions as Abraxane but is coated by polyethylene glycol (PEG). Compared to the parent doxorubicin free drug, Doxil has less cardiotoxicity. Similar to Abraxane, it is doubtful that Doxil can penetrate deep into the tumor mass.
[0003] Breast cancer occurs when the cells in the breast area of the female starts growing abnormally. These cells start to divide abnormally overtime. These cells are capable of dividing more rapidly than the healthy cells in the breast which results in the formation of lump.
[0004] Although both of these nanotherapeutics show a good clinical toxicity profile, their antitumor effects are only slightly better than the original pharmaceutical preparations. Amphiphilic block copolymers can form nanometer micelles and have been applied to the development of drug delivery systems. Amphiphilic block copolymers can form nanometer (<100nm) hydrophobic micelles, and have been applied to the development of drug delivery systems. However, most of these micelles are non-biodegradable and easily captured by RES. In addition, these micelles are often composed of linear hydrophobic polymers, which form a loose core in an aqueous environment, leading to instability and low drug-carrying capacity. There is a need to develop smaller (20-80 nm) shells and biocompatible micelles as effective nanocarriers for in vivo delivery of anticancer drugs.
[0005] Recently, we have developed several new nanocarriers for PTX or other hydrophobic drugs. These new nanocarriers containing PEG and oligocholic acid can self assemble under aqueous conditions to form a core-shell (cholane-PEG) structure, which can carry PTX inside a hydrophobic interior. These amphiphilic drug-loaded nanoparticles are expected to be therapeutic themselves and have an improved clinical toxicity profile. More importantly, when modified with ligands targeting cancer cell surfaces and / or tumor vascular ligands, these nanocarriers can deliver toxic therapeutic agents to the tumor site. The final size of the nanocarrier (10 to 100 nm) can be adjusted by using a variety of different cholane-PEG formulations or a combination thereof. The nanocarrier and its components, PEG and cholic acid are all non-toxic and completely biocompatible.
[0006] Due to its inertness and biocompatibility, PEG has been widely used in various biomedical applications. There are many FDA-approved PEG-modified protein drugs, such as PEGylated asparagine. PEGylation not only improves the pharmacokinetic properties, but also reduces the immunogenicity of protein drugs. Upon PEGylation, small molecule or peptide drugs show increased circulation time and delayed metabolism. PEG grafted to the surface of nanoparticles reduces the extravasation of these particles into normal tissues and the reticuloendothelial system (RES) in vivo. In in vivo imaging studies, PEG modification has been shown to reduce the aggregation and toxicity of inorganic material. Bile acid is a natural surfactant biosynthesized in the liver of mammals, which acts as an emulsifier in fat digestion. Bile acid is the main component of bile acid, and it has a surface amphiphilic structure: a rigid steroid skeleton with four hydrophobic groups on one surface of the skeleton and a hydrophobic methyl group on the other surface. Bile salts form cigar-shaped micelles in water, and their synthetic oligomers form single-molecule micelles with hydrophobic pockets in water, which can thermally isolate hydrophobic molecules. However, the application of oligocholic acid in drug delivery is limited due to its poor solubility and low drug loading capacity. We previously prepared a star cholic acid-PEG compound with four PEG chains grafted to a monocholic acid core. This compound can form spherical micelles in aqueous solution and can be used as a carrier in drug delivery. However, due to the predominance of hydrophilic PEG components, the critical micelle concentration (cmc) of this compound is higher than that of monocholane units, and the micelles produced under aqueous conditions are relatively large ((diameter> 200nm ).
[00071 Surprisingly, the present invention meets this and other needs by providing a much smaller and more stable nanocarrier with a core-shell structure prepared from cholane on PEG.
[0002] It is an object of the present disclosure which provides nanocarrier for efficient drug delivery for breast cancer.
[0003] In one embodiment, the present invention provides a nanocarrier having an interior and an exterior for treating breast cancer, the nanocarrier comprising at least one conjugate, wherein each conjugate comprises a polyethylene glycol (PEG) polymer. Each conjugate also contains at least two amphiphilic compounds, which have a hydrophilic side and a hydrophobic side. In addition, each conjugate contains an oligomer, wherein at least two of the amphiphilic compounds are covalently linked to an oligomer covalently linked to the PEG. Each conjugate of the nanocarrier self-assembles in an aqueous solvent to form a nanocarrier so that a hydrophobic pocket is formed inside the nanocarrier due to the orientation of the hydrophobic faces of each amphiphilic compound relative to each other, wherein each conjugate The PEG in the self-assembly outside the nanocarrier.
[00041 In a second embodiment, the present invention provides a method of treating disease by administering a therapeutically effective amount of the nanocarrier of the present invention to a subject in need of treatment.
[0005] In a third embodiment, the present invention provides an imaging method comprising administering a therapeutically effective amount of the nanocarrier of the present invention to a subject to be imaged, wherein the nanocarrier further comprises an imaging agent.
[0006] FIG. 1 shows (A) chemical structure and (B) particle size of PEG3000-CA8.
[00071 FIG. 2 shows the amount of PTX loaded in PEG3000-CA8 at different PTX concentrations using several methods. Separately, for the evaporation method, the concentration of the polymer (PEG3000-CA8) is maintained at 20 mg / mL, and for the dialysis method and the dissolution method, it is maintained at 10 mg / mL.
[00081 FIG. 3 shows a synthetic scheme for preparing the terminal dendrimer of the present invention.
[0009] FIG. 4 shows the intra-abdominal distribution of PEG5000-CA8 nanoparticles. Figure 38A shows in vivo NIRF imaging of mice with SKOV-3 tumors intraperitoneally at different time points after intraperitoneal injection of DiD-PTX-NP. Figure 38B shows the localization of DiD-PTX-NP on the tumor. The mice may be sacrificed 72 hours after injection to expose the abdominal cavity and scanned with a Kodak imaging workstation.
[0010] FIG. 5 show the synthesis of the members of the branched polymer series 1 (P-1). DETAILED DESCRIPTION
[0011] In an embodiment of the present disclosure, the present invention provides a nanocarrier having a hydrophobic interior and a hydrophilic exterior, which allows the nanocarrier to deliver drugs with low water solubility. The nanocarrier is formed by aggregation of the conjugate into micelles. The conjugates of the present invention can take a variety of structures, including linear, branched and terminal dendrimers. The hydrophobic core of the nanocarrier can be provided by cholic acid, which has a hydrophobic surface and a hydrophilic surface. Generally, some cholic acid groups are used to separate drugs in nanocarriers. The hydrophilicity of the nanocarriers is provided by polyethylene glycol polymer chains, which encapsulate the nanocarriers and form micelles by aggregation of the conjugate. Cholic acid and PEG are linked by oligomers that can contain multiple acid repeat units. Generally, the oligomer contains diaminocarboxylic acid: lysine. The nanocarrier of the present invention can be functionalized by optical probes, radionuclides and metal chelates, and hydrophobic drugs.
[0012] In yet another aspect of the present invention, FIG. 1 shows (A) chemical structure and (B) particle size of PEG3000-CA8.
[00131 In yet another aspect of the present invention, FIG. 2 shows the amount of PTX loaded in PEG3000-CA8 at different PTX concentrations using several methods. Separately, for the evaporation method, the concentration of the polymer (PEG3000-CA8) is maintained at 20 mg / mL, and for the dialysis method and the dissolution method, it is maintained at 10 mg / mL.
[0014] In yet another aspect of the present invention, FIG. 3 shows a synthetic scheme for preparing the terminal dendrimer of the present invention.
[0015] In yet another aspect of the present invention, FIG. 4 shows the intra-abdominal distribution of PEG5000-CA8 nanoparticles. Figure 38A shows in vivo NIRF imaging of mice with SKOV-3 tumors intraperitoneally at different time points after intraperitoneal injection of DiD-PTX-NP. Figure 38B shows the localization of DiD-PTX-NP on the tumor. The mice can be sacrificed 72 hours after injection to expose the abdominal cavity and scanned with a Kodak imaging workstation.
[00161 In yet another aspect of the present invention, FIG. 5 show the synthesis of the members of the branched polymer series 1 (P-1).
[00171 In an aspect of the present invention, the present invention provides micelle forming nanocarriers, where each individual nanocarrier is a micelle having a hydrophobic interior and a hydrophilic exterior. The hydrophobic region of the nanocarrier can isolate hydrophobic drugs. Nanocarriers are formed by aggregation of conjugates with hydrophobic regions (formed by amphiphilic compounds) and hydrophilic regions (such as polyethylene glycol (PEG) polymers). The size of PEG is sufficient to encapsulate the hydrophobic region of the conjugate, so that the conjugate is soluble in water and self-assembles to form nanocarrier micelles, which facilitates the administration of hydrophobic drugs or imaging agents to the subject.
[0018] In some embodiments, the present invention provides nanocarriers capable of separating hydrophobic drugs. The nanocarrier of the present invention has an interior and an exterior, the nanocarrier comprises at least one conjugate, wherein each conjugate comprises a polyethylene glycol (PEG) polymer. Each conjugate also contains at least two amphiphilic compounds with hydrophilic and hydrophobic faces. In addition, each conjugate comprises an oligomer, wherein at least two of the amphiphilic compounds are covalently linked to an oligomer covalently linked to PEG. The nanocarrier allows each conjugate to self-assemble in an aqueous solvent to form a nanocarrier so that a hydrophobic pocket is formed inside the nanocarrier due to the orientation of the hydrophobic faces of each amphiphilic compound relative to each other, and The PEG self-assembles outside the nanocarrier.
[0019] In another aspect of the present invention, the conjugates of the invention also contain at least two identical or different amphiphilic compounds. Amphiphilic compounds that can be used in the conjugates of the invention are those that have both hydrophilic and hydrophobic faces. In addition, each amphiphilic compound is connected to a monomer unit which itself is connected to another monomer unit and / or PEG polymer. In some embodiments, the amphiphilic compounds can each independently be cholic acid, allocholic acid, pythonic acid, avian cholic acid, deoxycholic acid, or chenodeoxycholic acid. Those skilled in the art will appreciate that other amphiphilic compounds can also be used in the present invention.
[0020] In yet another aspect of the present invention, the conjugate of the present invention also includes multiple monomer units. In some embodiments, the multiple monomer units are linked together to form an oligomer. The oligomer is covalently linked to
PEG and to the amphiphilic compound. The oligomer may adopt any of some structures, such as a linear structure, a branched structure, or a terminal dendritic structure.
[0021] In yet another aspect of the present invention, the nanocarrier contains a hydrophobic drug or imaging agent, so that the hydrophobic drug or imaging agent is isolated in the hydrophobic pocket of the nanocarrier. The hydrophobic drug can be any drug that repels water, as described herein. The hydrophobic drug and imaging agent can be isolated in the hydrophobic pocket of the nanocarrier or covalently linked to the conjugate. Imaging agents include paramagnetic substances, optical probes, and radionuclides. Paramagnetic substances include iron particles, such as iron nanoparticles isolated in the hydrophobic pocket of the nanocarrier.
[0022] In some other embodiments, the monomer unit that can be used in the conjugate of the present invention may be diaminocarboxylic acid, dihydroxycarboxylic acid, or hydroxyaminocarboxylic acid. In other embodiments, the diaminocarboxylic acid is an amino acid. Examples of the diaminocarboxylic acid group of the present invention include, but are not limited to 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 2,5 diaminovaleric acid (ornithine), 2,6- Diaminocaproic acid (lysine), (2-aminoethyl) -cysteine, 3-amino-2-aminomethylpropionic acid, 3-amino-2-aminomethyl-2-methylpropane Acid, 4 amino-2- (2-aminoethyl) butyric acid and 5-amino-2- (3-aminopropyl) valeric acid. Examples of the dihydroxycarboxylic acid group of the present invention include but are not limited to glyceric acid, 2,4-dihydroxybutyric acid, 2,2-bis (hydroxymethyl) propionic acid, 2,2-bis (hydroxymethyl) butyric acid Acid, serine and threonine. Examples of hydroxyaminocarboxylic acids include but are not limited to serine and homoserine.
[0023] In another embodiment, more than one type of monomer unit is used in the conjugate of the present invention to provide an acid copolymer. For example, the acid copolymer may have diaminocarboxylic acid alternating with hydroxyaminocarboxylic acid or dihydroxycarboxylic acid.
[0024] In other embodiments, at least one monomer unit is optionally linked to an optical probe, radionuclide, metal chelate, or drug. The drug may be a variety of hydrophilic or hydrophobic drugs, and is not limited to hydrophobic drugs isolated inside the nanocarrier of the present invention.
[0025] In yet another aspect of the present invention, Drugs that can be isolated within the nanocarrier or linked to the conjugate of the invention include, but are not limited to: cytostatic agents, cytotoxic agents (such as but not limited to DNA interacting agents (such as cisplatin or doxorubicin)); Taxanes (e.g. taxotere, taxol); topoisomerase II inhibitors (e.g. etoposide); topoisomerase I inhibitors (e.g. irinotecan (or CPT-11 ), Camptostar or topotecan); tubulin interacting agents (such as paclitaxel, docetaxel or epothilones); hormone drugs (such as tamoxifen) Fen); thymidylate synthase inhibitors (eg 5-fluorouracil); antimetabolites (eg methotrexate); alkylating agents (eg temozolomide (TEMODARTM from Schering-Plough Corporation, Kenilworth, NJ)), cyclophosphine Amide); aromatase combination; ara-C, doxorubicin, cytoxan, and gemcitabine. Other drugs that can be used in the nanocarriers of the present invention include but are not limited to uracil nitrogen mustard, nitrogen mustard, ifosfamide (Ifosfamide), melphalan, chlorambucil, piperidine Triethyleneimine triazine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, azuridine, cytarabine, 6-mercapto Purine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin (Sanofi-Synthelabo, France's ELOXATINTM), penastatin (Pentostatine), vinblastine , Vincristine, vindesine, bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, idarubicin, miramycin, deoxygenation Typomycin, mitomycin-C, L-asparaginase, teniposide (Teniposide), 17a ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromethandone propionate Ketones, testosterone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorestrin, hydroxyprogesterone, amlutide, estramustine, Medroxyprogesterone acetate, Leuprolide, Flutamide, Toremifene, Goserelin, Cisplatin, Carboplatin, Hydroxyurea, Acridine, Procarbazine , Tuotan, mitoxantrone, levamisole, navelbine (Navelbene), anastrozole (anastrazole), letrozole, Capecitabine, Reloxafine, Droloxafine, or hexamethylmelamine. Other drugs which can be useful in the present invention include radionuclides such as following: 67Cu, 90Y, 1231,
1251, 1311, 177Lu, 188Re, 186Re, and 211At. In some other embodiments, the radionuclide can play a therapeutic role as a drug and imaging agent.
[0026] In yet another aspect of the present invention, the hydrophobic drugs that can be used in the nanocarrier of the present invention include any drugs with low water solubility. In some embodiments, the hydrophobic drug is paclitaxel, doxorubicin, etoposide, irinotecan, SN-38, camptothecin, cyclosporin A, podophyllotoxin, carmustine, amphotericin Amycin, ixabepilone, pratopyrone (Epothilones), rapamycin and platinum drugs. In other embodiments, the drug may be paclitaxel, SN38, camptothecin, etoposide, or doxorubicin. Prodrug forms can also be used in the present invention.
[0027] In some embodiments, the conjugate has Formula I:
R2 R2 I I A-X't-t X-YT-X-R'
Where A is a polyethylene glycol (PEG) polymer of 1-100 kDa, where A is optionally attached to the binding ligand L. Each X is a monomer unit. X'is a monomer unit optionally linked to an optical probe, radionuclide, metal chelate or drug. Y is each a spacer monomer unit. RI is each H, an optical probe, a radionuclide, a metal chelate, a hydrophobic drug, or a polyethylene glycol of 1-100 kDa optionally connected with an optical probe, a radionuclide, a metal chelate, or a drug Alcohol (PEG) polymer. R2 is each independently a cholic acid or a monomer unit substituted with two cholic acid groups, wherein each cholic acid group is optionally substituted with 1-3 polyethylene glycol (PEG) polymers. The ethylene glycol polymers are each independently 200-10,000 Da in size. The subscript m is 2-20.
[00281 In other embodiments, the conjugate has Formula Ia:
(Ia) 2 R
L-A--X-tX-Yt--R'
Where A is a 3kDa PEG polymer. The monomer unit of X'is lysine. X is each lysine. Y is
0
0
R2 is each a lysine linked to two cholic acid groups.
[0029] In other embodiments, the conjugate has Formula II:
2 R
Where A is a polyethylene glycol (PEG) polymer of 1-100 kDa, where A is optionally attached to the binding ligand L. Each X is a monomer unit. X'is a monomer unit optionally linked to an optical probe, radionuclide, metal chelate or drug. Y is each a spacer monomer unit. R1 is each independently H, an optical probe, a radionuclide, a metal chelate, a hydrophobic drug, or a 1-100 kDa optionally connected with an optical probe, a radionuclide, a metal chelate, or a hydrophobic drug of polyethylene glycol (PEG) polymer. R2 is each independently a cholic acid or a monomer unit substituted with two cholic acid groups, wherein each cholic acid group is optionally substituted with 1-3 polyethylene glycol (PEG) polymers. The ethylene glycol polymers are each independently 200-10,000 Da in size. The subscripts m and m'are each independently 2-20. The subscript p is 0-10.
[00301 In other embodiment, the conjugate has formula Ila:
(Ila)
Y-X47RI R2
[00311 In other embodiments, each R 2 is cholic acid. In still other embodiments, each R2 is a monomer unit that connects two cholic acid groups.
[00321 In another embodiment, the conjugate has formula Ilb:
(Ilb)
kY-X R1
Where A is a 3kDa PEG polymer. The monomer unit of X'is lysine. X is each lysine. Y is 0
0
R2 is cholic acid. The subscripts m and m'are each 4.
[00331 In some embodiments, the conjugate has Formula I1c:
(IIc) R2
R3
The subscript p is 1-10.
[00341 In other embodiments, the conjugate has formula III:
R2 -X R2 \1/-
/ x-x / \ A -+(X'97n-X /X \R222 \ IR x-x R 2 R1x/ -X \ R2 R2
Where A is a polyethylene glycol (PEG) polymer of 1-100 kDa, where A is optionally attached to the binding ligand L. Each X is a monomer unit. X'is a monomer unit optionally linked to an optical probe, radionuclide, metal chelate or drug. R2 is each cholic acid, wherein each cholic acid group is optionally substituted with 1-3 polyethylene glycol (PEG) polymers, each independently having a size of 200-10,000 Da.
[0035] In other embodiments, the conjugate has Formula II1a: (ilia)
2 R -X \'- /R2 R(22 x-x L-A-X'-X \R2
2 -x R -- X R2
R2
Where A is 5000Da PEG polymer. The monomer unit of X'is lysine. X is each lysine. R2 is cholic acid.
[00361 In yet another aspect of the present invention, the nanocarrier of the present invention can be prepared according to many different methods known to those skilled in the art. The Pharmaceutically acceptable carriers can also be determined in part by the particular composition administered and the particular method used to administer the composition. Therefore, there are various suitable formulations for the pharmaceutical composition of the present invention (see, for example, Remington's Pharmaceuticals, 20th Edition, 2003, see above). Effective formulations include oral and nasal formulations, parenteral formulations, and compositions formulated for delayed release.
[00371 In yet another aspect of the present invention, Formulations suitable for oral administration may consist of: (a) a liquid solution, such as an effective amount of a compound of the invention suspended in a diluent (such as water, saline, or PEG 400); (b) a capsule, sachet, Depots or tablets, wherein each contains a predetermined amount of the active ingredient as a liquid, solid, granule or gelatin; (c) suspension in a suitable liquid; (d) a suitable emulsion; and ( e) Patch. The above liquid solution may be a sterile solution. The pharmaceutical form may contain one or more of the following substances: lactose, sucrose, mannitol, sorbitol, calcium phosphate, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, stearic acid Magnesium, stearic acid and other excipients,fillers,binders, colorants, diluents, buffers, wetting agents, preservatives, flavoring agents, dyes, disintegrants and pharmaceutical compatible carriers. Lozenge forms may contain active ingredients with a taste (e.g. sucrose), as well as lozenges (pastille) containing active ingredients in an inert matrix (e.g. gelatin and glycerin) or sucrose and gum arabic emulsions, gels, etc. In addition to the ingredients, there are carriers known in the art.
[0038] The pharmaceutical preparation is usually in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be taken into a packaged preparation, the package can contain discrete quantities of preparation, such as packaged tablets, capsules, and powders in bottles or ampoules. In addition, the unit dosage form itself may also be a capsule, tablet, cachet, or lozenge, or it may be any of these packaging forms in a suitable amount. If desired, the composition may also contain other compatible therapeutic agents. Preferred pharmaceutical formulations can deliver sustained release compounds of the invention.
[0039] In yet another aspect of the present invention, the nanocarrier of the present invention can be administered at a desired frequency, including once an hour, once a day, once a week, or once a month. The compound used in the pharmaceutical method of the present invention is administered at a starting dose of about 0.0001 mg / kg to about 1000 mg / kg per day. A daily dose of about 0.01 mg / kg to about 500 mg / kg, or about 0.1 mg /
kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg or about 10 mg / kg to about 50 mg / kg can be used. However, the dosage given can vary depending on the needs of the patient, the severity of the disease being treated, and the compound used. For example, the dosage can be determined empirically considering the type and stage of disease diagnosed in a specific patient. According to the present invention, the dose administered to the patient should be sufficient to effectively achieve a beneficial therapeutic response to the patient over time. The size of the dose can also be determined by the presence and extent of any adverse side effects that accompany the administration of the specific compound in the specific patient. It is within the ability of a practicing physician to determine the appropriate dosage for a particular situation. Generally, treatment is started with a smaller dose, which is lower than the optimal dose of the compound. Thereafter, increase the dosage by a small amount until the best effect under the environment is reached. For simplicity, if necessary, the total daily dose can be divided and administered in batches throughout the day. According to the decision taken by the treating physician, it can be administered daily or every other day. Administration can be regular or continuous over a longer period of time (weeks, months or years), for example by using subcutaneous capsules, medicine bags or depots, or by patches or pumps.
Claims (8)
1. A nanocarrier for treatment of breast cancer having an interior and an exterior, the nanocarrier consisting atleast on conjugate having formula III:
R2 RZ-X W
X / XXR x-X
Wherein
A is a polyethylene glycol (PEG) polymer;
each X is a monomer unit comprising a diaminocarboxylic acid;
X' is a monomer unit selected from the group consisting of a diaminocarboxylic acid, an NH, and an 0, optionally linked to a member selected from the group, wherein the group consists of an optical probe, , a paramagnetic agent, a radionuclide, a drug and a metal chelate; and
each R2 is independently an amphiphilic compound having both a hydrophilic face and a hydrophobic face, wherein each amphiphilic compound is independently selected from the group consisting of cholic acid, deoxycholic acid, and chenodeoxycholic acid;
wherein each conjugate self-assembles in an aqueous solvent to form the nanocarrier such that hydrophobic pocket is formed in the interior of the nanocarrier by the orientation of the hydrophobic face of each amphiphilic compound towards each other, wherein the PEG of each conjugate self-assembles on the exterior of the nanocarrier.
2. The nanocarrier for treatment of breast cancer as claimed in claim 1, wherein the nanocarrier comprises a hydrophobic drug or an imaging agent, wherein the hydrophobic drug or imaging agent is sequestered in the hydrophobic pocket of the nanocarrier.
3. The nanocarrier for treatment of breast cancer as claimed in claim 1, wherein the diamino carboxylic acid is an amino acid.
4. The nanocarrier for treatment of breast cancer as claimed in claim 1, wherein each diamino carboxylic acid is independently selected from the group consisting of 2,3 diamino propanoic acid, 2,4-diaminobutanoic acid, 2,5-diaminopentanoic acid (ornithine), 2,6-diaminohexanoic acid (lysine), (2-Aminoethyl)-cysteine, 3-amino-2-aminomethyl propanoic acid, 3-amino-2-aminomethyl-2-methyl propanoic acid, 4-amino-2-(2 aminoethyl) butyric acid and 5-amino-2-(3-aminopropyl) pentanoic acid.
5. The nanocarrier for treatment of breast cancer as claimed in claim 1, wherein at least one of the monomer units is optionally linked to a member selected from the group consisting of an optical probe, a radionuclide, a paramagnetic agent, a metal chelate and a drug.
6. The nanocarrier for treatment of breast cancer as claimed in claim 2, wherein the hydrophobic drug is selected from the group consisting of paclitaxel, SN38, camptothecin, etoposide and doxorubicin.
7. The nanocarrier for treatment of breast cancer as claimed in claim 1, wherein
A is the polyethyleneglycol (PEG) polymer of 1-100 kDa, wherein A is optionally linked to a binding ligand L; and
each R2 is cholic acid, wherein each cholic acid group is optionally substituted with 1-3 polyethyleneglycol (PEG) polymers each independently 200-10,000 Da in size.
8. The nanocarrier for treatment of breast cancer as claimed in claim 7. the conjugate having formula Ma:
R-X \
/ x-x / \ 2 leK x-x / \ R 2-X R2 R2
Wherein
A is a PEG polymer of 5 kDa;
the monomer unit of X' is lysine;
each X is lysine;
and each R2 is cholic acid.
Application no.: Total no. of sheets: 5 16 Mar 2021 2021101355 Applicant name: Page 1 of 5
FIG. 1 shows (A) chemical structure and (B) particle size of PEG3000-CA8.
Application no.: Total no. of sheets: 5 16 Mar 2021 2021101355 Applicant name: Page 2 of 5
FIG. 2 shows the amount of PTX loaded in PEG3000-CA8 at different PTX concentrations using several methods. Separately, for the evaporation method, the concentration of the polymer (PEG3000-CA8) is maintained at 20 mg / mL, and for the dialysis method and the dissolution method, it is maintained at 10 mg / mL.
Application no.: Total no. of sheets: 5 16 Mar 2021 2021101355 Applicant name: Page 3 of 5
FIG. 3 shows a synthetic scheme for preparing the terminal dendrimer of the present invention.
Application no.: Total no. of sheets: 5 16 Mar 2021 2021101355 Applicant name: Page 4 of 5
FIG. 4 shows the intra-abdominal distribution of PEG5000-CA8 nanoparticles. Figure 38A shows in vivo NIRF imaging of mice with SKOV-3 tumors intraperitoneally at different time points after intraperitoneal injection of DiD-PTX-NP. Figure 38B shows the localization of DiD-PTX-NP on the tumor. The mice were sacrificed 72 hours after injection to expose the abdominal cavity and scanned with a Kodak imaging workstation.
Application no.: Total no. of sheets: 5 16 Mar 2021 2021101355 Applicant name: Page 5 of 5
FIG. 5 show the synthesis of the members of the branched polymer series 1 (P-1).
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