KR102264231B1 - Biopolymers and metal-organic frameworks conjugated complexes and uses thereof - Google Patents

Abstract

It relates to a complex in which a biopolymer and a metal-organic framework are combined, a pharmaceutical composition, and a method for preventing or treating cancer in an individual, and according to an aspect, the metal-organic framework and a pharmaceutical composition comprising the same, the target It has a high targeting ability to cells, so it can be effectively delivered to a target cell, and not only chemotherapy but also photodynamic therapy can be used, so it can be usefully used as a target therapeutic agent. In addition, according to the method of treating cancer according to another aspect, it is possible to effectively treat cancer.

Description

Biopolymers and metal-organic frameworks combined complexes and uses thereof {Biopolymers and metal-organic frameworks conjugated complexes and uses thereof}

It relates to a complex in which a biopolymer and a metal-organic framework are combined, a pharmaceutical composition, and a method for preventing or treating cancer in a subject.

Metal-organic frameworks (MOFs) are crystalline organic-inorganic hybrid polymers in which metal ions or metal ion clusters are coordinated with organic ligands. MOFs, also called porous coordination polymers (PCPs), have regular pore structures and high specific surface areas, and can be synthesized into various structures through the selection of ligands and metal ions. In general, by controlling the size of the organic ligand, the size of the pores can be controlled from several Å to nanometers, and the surface properties of the pores can be controlled by selecting an appropriate metal ion or introducing a functional group to the organic ligand. In particular, unsaturated metal sites formed inside the structure during dehydration or desolvation act as adsorption sites for gas molecules or guest molecules. Based on these characteristics, it is being actively studied for the development of fuel gas adsorption and storage materials, catalysts, sensors, synthetic media, drug delivery media, proton conductors, and the like. However, despite many developments, its introduction into industry outside the research field is still stagnant due to low thermal, chemical, and mechanical stability. To solve this problem, zeolitic imidazolate frameworks (ZIFs) or covalent organic frameworks (COFs) are being developed. is being raised

Therefore, as a new strategy to improve the characteristics of MOFs and give them new functions, research is underway to create composites by fusion with various materials.

Accordingly, the present inventors provide a complex in which a biopolymer is bound to the surface of MOFs having a cell targeting function.

One aspect is to provide a metal-organic framework (MOFs) having a porous three-dimensional structure in which biopolymers are bonded to a surface and metal ions are bonded between organic molecules.

Another aspect is to provide a pharmaceutical composition for preventing or treating cancer comprising an anticancer agent, a metal-organic framework (MOFs) having a biopolymer bonded to the surface thereof, as an active ingredient.

Another aspect is to provide a method of treating cancer in a subject, comprising administering to the subject in an amount effective to prevent or treat cancer, the pharmaceutical composition described above.

One aspect provides a metal-organic framework (MOFs) having a porous three-dimensional structure in which biopolymers are bonded to a surface and metal ions are bonded between organic molecules.

In the present invention, the biopolymer may be characterized in that it is biodegradable and has biocompatibility.

The term “biodegradable” can mean that the block copolymer can be chemically degraded in the body to form non-toxic compounds. The rate of degradation may be the same as or different from the rate of drug release. And "biocompatibility" may mean a property of interacting with the human body without undesirable subsequent effects.

As used herein, the term “metal-organic framework (MOFs)” refers to an organic/inorganic hybrid material having a 1-, 2- or 3-dimensional structure in which metal ions or ion clusters are coordinated with organic molecules and are porous. can

The metal ion may be a pure metal or an electrolytic metal, and examples of the pure metal or electrolytic metal include, but are not limited to, magnesium (Mg), calcium (Ca), manganese (Mn), iron (Fe), copper (Cu), zinc (Zn). ), gallium (Ga), germanium (Ge), selenium (Se), strontium (Sr), zirconium (Zr), molybdenum (Mo), silver (Ag), or platinum (Pt) may be included.

The organic molecule and the metal ion may be bound by a coordination bond.

In one embodiment, the biopolymer may be a stimulus-sensitive polymer.

In one embodiment, the biopolymer may interact with a receptor expressed on the cell surface.

In one embodiment, the cell may be a cancer cell.

As used herein, the term "stimulus-sensitive polymer" may refer to a polymer that continuously or discontinuously changes physical properties in response to an external stimulus. External stimuli may include chemical or biochemical stimuli by pH, ions and metabolites, and physical stimuli by temperature, light, electric fields, solvents, and interactions between cells.

Examples of receptors expressed on the cancer cell surface include, but are not limited to, CD44, CD133, CD166, CD19, CD20, CD21, CD22, CD45, BCMA, MART-1, MAGE-A3, glycoprotein 100 (gp100), NY-ESO -1, HER2 (ErbB2), IGF2B3, EGFRvIII, kallikrein 4, KIF20A, Lengsin, Meloe, MUC-1, MUC5AC, MUC-16, B7-H3, B7-H6, CD70, CEA, CSPG4, EphA2, EpCAM, EGFR family, FAP, FRa, glupican-3, GD2, GD3, HLA-A1+MAGE1, IL-11Rα, IL-23Rα2, Lewis-Y, mesothelin, NKG2D ligand, PSMA, ROR1, survivin, TAG72 or VEGFR2 may be included.

In one embodiment, the polymer may be one capable of releasing a supported drug by being absorbed into the cell by endocytosis and decomposed by an enzyme.

As used herein, the term “endocytosis” may refer to a method of transporting substances by enclosing an extracellular material with a cell membrane to form a vesicle and drawing it into the cell.

In one embodiment, the biopolymer is hyaluronic acid (Hyaluronic acid, HA), pullulan (pullulan), curdlan (curdlan), pectin (pectin), heparin (Heparin), chitosan (chitosan), methyl cellulose (methyl) cellulose), poly(vinyl alcohol), dextran, starch, agarose, poly-L-lysine, polyaspartic acid, and derivatives thereof from the group consisting of It may include any one or more selected.

In one embodiment, the metal-organic framework is MIL-88A, MIL-88Bt, MIL-89, MIL-127, MIL-101, MIL-100, MIL-53, MOF-74, UiO-66, UiO -67, ZIF-8, ZIFs, HKUST-1, M ₂ (dobpdc), NU-1000, PCN-222, PCN-224, and may include any one selected from the group consisting of derivatives thereof.

In one embodiment, the organic molecule may be a photosensitizer capable of generating singlet oxygen.

As used herein, the term “photosensitizer” may be a material that is activated by light to perform a photochemical reaction. It can be used to generate triplet excited states in organic molecules used in photocatalysis, photodynamic therapy, etc. Mainly in cancer treatment, it can be used to kill cells by generating singlet oxygen by irradiation with light after being injected into the human body.

As used herein, the term "singlet oxygen" may be oxygen in a ^{state in which electrons are transferred to only one of the two π *} orbitals in the oxygen molecule, and may be highly reactive because it is in an excited state.

In one embodiment, the metal-organic framework may be one in which a drug is supported.

In one embodiment, the drug may be an anticancer agent.

The anticancer agent is abarelix [abarelix (Plenaxis depot ^® )]; aldesleukin (Prokine ^® ); Aldesleukin (Proleukin ^® ); Alemtuzumab (Campath ^® ); alitretinoin (Panretin ^® ); allopurinol [allopurinol (Zyloprim ^® )]; altretamine (Hexalen ^® ); amifostine [amifostine (Ethyol ^® )]; anastrozole (Arimidex ^® ); arsenic trioxide (Trisenox ^® ); Asparaginase better the [asparaginase (Elspar ^®)]; Azacytidine [azacitidine (Vidaza ^®)]; bevacuzimab (Avastin ^® ); bexarotene capsules (Targretin ^® ); bexarotene gel (Targretin ^® ); Bleomycin [bleomycin (Blenoxane ^®)]; bortezomib (Velcade ^® ); busulfan intravenous (Busulfex ^® ); oral busulfan [busulfan oral (Myleran ^® )]; calusterone (Methosarb ^® ); capecitabine [capecitabine (Xeloda ^® )]; carboplatin [carboplatin (Paraplatin ^® )]; carmustine (BCNU ^® , BiCNU ^® ); carmustine (Gliadel ^® ); Carmustine and Polypeprosan 20 Implant (Gliadel Wafer ^® ); celecoxib (Celebrex ^® ); cetuximab (Erbitux ^® ); chlorambucil [chloambucil (Leukeran ^® )]; Cisplatin [cisplatin (Platinol ^®)]; cladribine (Leustatin ^® ) 2-CdA ^® ; clofarabine (Clolar ^® ); cyclophosphamide (Cytoxan ^® , Neosar ^® )]; cyclophosphamide (Cytoxan Injection ^® )]; cyclophosphamide (Cytoxan Tablet ^® ); cytarabine (Cytosar-U ^® ); cytarabine liposomal (DepoCyt ^® ); dacarbazine (DTIC-Dome ^® ); Shut actinomycin (dactinomycin), liquid actinomycin ^{D [actinomycinD (Cosmegen ®)]} ; Darbepoetin alfa (Aranesp ^® ); daunorubicin liposomal (Danuoxome ^® ); Daunorubicin (daunorubicin), daunomycin [daunomycin (Daunorubicin ^®)]; daunorubicin, daunomycin [daunomycin (Cerubidine ^® )]; Denileukin diftitox (Ontak ^® ); dexrazoxane (Zinecard ^® ); docetaxel (Taxotere ^® ); Doxorubicin ^{[doxorubicin (Adriamycin PFS ®)]} ; Doxorubicin ^{[doxorubicin (Adriamycin ®, Rubex ®} )]; doxorubicin (Adriamycin PFS Injection ^® )]; doxorubicin liposomal (Doxil ^® ); dromostanolone propionate (dromostanolone ^® ); dromostanolone propionate (masterone injection ^® ); Elliott's B Solution (Elliott's B Solution ^® ); epirubicin (Ellence ^® ); Epoetin alfa (epogen ^® ); erlotinib (Tarceva ^® ); estramustine (Emcyt ^® ); Etoposide phosphate ^{[etoposide phosphate (Etopophos ®)]} ; etoposide, VP-16 (Vepesid ^® ); exemestane (Aromasin ^® ); Filgrastim (Neupogen ^® ); Floc repair Dean ^{[floxuridine (intraarterial) (FUDR ®} )]; fludarabine (Fludara ^® ); Fluorouracil [Fluorouracil, 5-FU (Adrucil ^® )]; fluvestrant (Faslodex ^® ); gefitinib (Iressa ^® ); gemcitabine [gemcitabine (Gemzar ^® )]; gemtuzumab ozogamicin (Mylotarg ^® ); goserelin acetate (Zoladex Implant ^® ); goserelin acetate (Zoladex ^® ); histrelin acetate [histrelin acetate (Histrelin implant ^® )]; hydroxyurea [hydroxyurea (Hydrea ^® )]; Ivry Tomorrow Thank tiuk cetane ^{[Ibritumomab Tiuxetan (Zevalin ®)]} ; idarubicin (Idamycin ^® ); ifosfamide [ifosfamide (IFEX ^® )]; imatinib mesylate (Gleevec ^® ); Interferon alpha -2a [interferon alfa-2a (Roferon A ®)]; Interferon alfa -2b [Interferon alfa-2b (Intron A ®)]; irinotecan [irinotecan (Camptosar ^® )]; lenalidomide (Revlimid ^® ); letrozole (Femara ^® ); leucovorin [leucovorin (Wellcovorin ^® , Leucovorin ^® )]; Leuprolide Acetate (Eligard ^® ); levamisole (Ergamisol ^® ); lomustine-CCNU (CeeBU ^® ); mechlorethamine, nitrogen mustard (Mustargen ^® ); megestrol acetate (Megace ^® ); melphalan, L-PAM (Alkeran ^® ); mercaptopurine [mercaptopurine, 6-MP (purinethol ^® )]; mesna (Mesnex ^® ); mesna (Mesnex tabs ^® ); methotrexate [methotraxate (methotraxate ^® )]; methoxsalen (Uvadex ^® ); Mitomycin ^{C [mitomycin C (Mutamycin ®)} ]; mitotane (Lysodren ^® ); mitoxantrone (Novantrone ^® ); nandrolone phenpropionate (Durabolin-50 ^® ); nelarabine (Arranon ^® ); Nofetumomab (Verluma ^® ); Oprelvekin (Neumega ^® ); Oxaliplatin [oxaliplatin (Eloxatin ^®)]; Paclitaxel [paclitaxel (Paxene ^®)]; Paclitaxel [paclitaxel (Taxol ^®)]; paclitaxel protein-bound particles (Abraxane ^® ); palipermin [palifermin (Kepivance ^® )]; pamidronate (Aredia ^® ); peg ademas [pegademase (Adagen (Pegademase Bovine) ^® )]; peg aspartate gaahje [pegaspargase (Oncaspar ^®)]; peg filgrastim [Pegfilgrastim (Neulasta ^® )]; pemetrexed disodium (Alimta ^® ); pentostatin (Nipent ^® ); pipobroman (Vercyte ^® ); plicamycin [plicamycin], mithramycin (Mithracin ^® ); porfimer sodium (Photofrin ^® ); procarbazine (Matulane ^® ); quinacrine (Atabrine ^® ); Rasburicase (Elitek ^® ); Rituximab [Rituximab (Rituxan ^®)]; sargramostim (Leukine ^® ); Sargramostim (Prokine ^® )]; sorafenib (Nexavar ^® ); streptozocin (Zanosar ^® ); sunitinib maleate (Sutent ^® ); Talc [talc (Sclerosol ^®)]; tamoxifen (Nolvadex ^® ); temozolomide (Temodar ^® ); teniposide [teniposide, VM-26 (Vumon ^® )]; testolactone (Teslac ^® ); thioguanine [thioguanine, 6-TG (thioguanine ^® )]; thiotepa (thioplex ^® ); topotecan (Hycamtin ^® ); toremifene (Fareston ^® ); Tositumomab (Bexxar ^® ); tositumomab/I-131 tositumomab (Bexxar ^® ); Trastuzumab (Herceptin ^® ); Tretinoin ^{[tretinoin, ATRA (Vesanoid ®)} ]; Uracil Mustard (Uracil Mustard Capsules ^® ); valrubicin (Valstar ^® ); vinblastine (Velban ^® ); vincristine (Oncovin ^® ); vinorelbine (Navelbine ^® ); zoledronate (Zometa ^® ), pharmaceutically acceptable salts thereof, mixtures thereof, and the like.

Another aspect provides a pharmaceutical composition for preventing or treating cancer comprising an anticancer agent, a metal-organic framework (MOFs) having a biopolymer bonded to the surface thereof, as an active ingredient.

The term “pharmaceutical composition” may refer to a molecule or compound that confers some beneficial effect upon administration to a subject. Advantageous effects include enabling diagnostic decisions; amelioration of a disease, symptom, disorder or condition; reducing or preventing the onset of a disease, symptom, disorder or condition; and responding to a disease, symptom, disorder or condition in general.

The cancer may be lung cancer (eg, non-small cell lung cancer), pancreatic cancer, stomach cancer, liver cancer, colorectal cancer, brain cancer, breast cancer, thyroid cancer, bladder cancer, esophageal cancer, or uterine cancer. In addition, the cancer may be any one or more selected from the group consisting of gastric cancer, breast cancer, lung cancer, liver cancer, esophageal cancer and prostate cancer having resistance to anticancer drugs (eg, multidrug resistance).

The pharmaceutical composition may be administered parenterally during clinical administration and may be used in the form of general pharmaceutical formulations. Parenteral administration may refer to administration via a route other than oral administration, such as rectal, intravenous, peritoneal, muscle, arterial, transdermal, nasal, inhalation, ocular and subcutaneous. When the pharmaceutical composition of the present invention is used as a pharmaceutical, it may further contain one or more active ingredients exhibiting the same or similar function.

The types of pharmaceutically active ingredients capable of delivering the active ingredient into a subject include anticancer agents, contrast agents (dyes), hormones, antihormones, vitamins, calcium agents, inorganic agents, saccharides, organic acid preparations, protein amino acid preparations, detoxifying agents, enzymes Agents, metabolic agents, diabetic combination agents, tissue revitalization agents, chlorophyll agents, pigment agents, tumor agents, tumor agents, radiopharmaceuticals, tissue cell diagnostic agents, tissue cell therapies, antibiotic agents, antiviral agents, combined antibiotics, chemicals Therapeutic agents, vaccines, toxins, toxoids, antitoxins, leptospirin serum, blood products, biological agents, analgesics, immunogenic molecules, antihistamines, allergens, non-specific immunogenic agents, anesthetics, stimulants, psychoneurologic agents, small molecule compounds, nucleic acids aptamers, antisense nucleic acids, oligonucleotides, peptides, siRNAs and microRNAs, and the like.

When formulating the pharmaceutical composition, it is usually prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, Witepsol, macrogol, Tween 61, cacao butter, liulinji, glycerogelatin, etc. may be used.

In addition, the pharmaceutical composition can be used by mixing with various pharmaceutically acceptable carriers such as physiological saline or organic solvents, and carbohydrates such as glucose, sucrose or dextran, ascorbic acid to increase stability or absorption Antioxidants such as (Ascorbic acid) or Glutathione, Chelating agents, low molecular weight proteins or other Stabilizers may be used as pharmaceuticals.

In one embodiment, the anticancer agent is abarelix [abarelix (Plenaxis depot ^® )]; aldesleukin (Prokine ^® ); Aldesleukin (Proleukin ^® ); Alemtuzumab (Campath ^® ); alitretinoin (Panretin ^® ); allopurinol [allopurinol (Zyloprim ^® )]; altretamine (Hexalen ^® ); amifostine [amifostine (Ethyol ^® )]; anastrozole (Arimidex ^® ); arsenic trioxide (Trisenox ^® ); Asparaginase better the [asparaginase (Elspar ^®)]; Azacytidine [azacitidine (Vidaza ^®)]; bevacuzimab (Avastin ^® ); bexarotene capsules (Targretin ^® ); bexarotene gel (Targretin ^® ); Bleomycin [bleomycin (Blenoxane ^®)]; bortezomib (Velcade ^® ); busulfan intravenous (Busulfex ^® ); oral busulfan [busulfan oral (Myleran ^® )]; calusterone (Methosarb ^® ); capecitabine [capecitabine (Xeloda ^® )]; carboplatin [carboplatin (Paraplatin ^® )]; carmustine (BCNU ^® , BiCNU ^® ); carmustine (Gliadel ^® ); Carmustine and Polypeprosan 20 Implant (Gliadel Wafer ^® ); celecoxib (Celebrex ^® ); cetuximab (Erbitux ^® ); chlorambucil [chloambucil (Leukeran ^® )]; Cisplatin [cisplatin (Platinol ^®)]; cladribine (Leustatin ^® ) 2-CdA ^® ; clofarabine (Clolar ^® ); cyclophosphamide (Cytoxan ^® , Neosar ^® )]; cyclophosphamide (Cytoxan Injection ^® )]; cyclophosphamide (Cytoxan Tablet ^® ); cytarabine (Cytosar-U ^® ); cytarabine liposomal (DepoCyt ^® ); dacarbazine (DTIC-Dome ^® ); Shut actinomycin (dactinomycin), liquid actinomycin ^{D [actinomycinD (Cosmegen ®)]} ; Darbepoetin alfa (Aranesp ^® ); daunorubicin liposomal (Danuoxome ^® ); Daunorubicin (daunorubicin), daunomycin [daunomycin (Daunorubicin ^®)]; daunorubicin, daunomycin [daunomycin (Cerubidine ^® )]; Denileukin diftitox (Ontak ^® ); dexrazoxane (Zinecard ^® ); docetaxel (Taxotere ^® ); Doxorubicin ^{[doxorubicin (Adriamycin PFS ®)]} ; Doxorubicin ^{[doxorubicin (Adriamycin ®, Rubex ®} )]; doxorubicin (Adriamycin PFS Injection ^® )]; doxorubicin liposomal (Doxil ^® ); dromostanolone propionate (dromostanolone ^® ); dromostanolone propionate (masterone injection ^® ); Elliott's B Solution (Elliott's B Solution ^® ); epirubicin (Ellence ^® ); Epoetin alfa (epogen ^® ); erlotinib (Tarceva ^® ); estramustine (Emcyt ^® ); Etoposide phosphate ^{[etoposide phosphate (Etopophos ®)]} ; etoposide, VP-16 (Vepesid ^® ); exemestane (Aromasin ^® ); Filgrastim (Neupogen ^® ); Floc repair Dean ^{[floxuridine (intraarterial) (FUDR ®} )]; fludarabine (Fludara ^® ); Fluorouracil [Fluorouracil, 5-FU (Adrucil ^® )]; fluvestrant (Faslodex ^® ); gefitinib (Iressa ^® ); gemcitabine [gemcitabine (Gemzar ^® )]; gemtuzumab ozogamicin (Mylotarg ^® ); goserelin acetate (Zoladex Implant ^® ); goserelin acetate (Zoladex ^® ); histrelin acetate [histrelin acetate (Histrelin implant ^® )]; hydroxyurea [hydroxyurea (Hydrea ^® )]; Ivry Tomorrow Thank tiuk cetane ^{[Ibritumomab Tiuxetan (Zevalin ®)]} ; idarubicin (Idamycin ^® ); ifosfamide [ifosfamide (IFEX ^® )]; imatinib mesylate (Gleevec ^® ); Interferon alpha -2a [interferon alfa-2a (Roferon A ®)]; Interferon alfa -2b [Interferon alfa-2b (Intron A ®)]; irinotecan [irinotecan (Camptosar ^® )]; lenalidomide (Revlimid ^® ); letrozole (Femara ^® ); leucovorin [leucovorin (Wellcovorin ^® , Leucovorin ^® )]; Leuprolide Acetate (Eligard ^® ); levamisole (Ergamisol ^® ); lomustine-CCNU (CeeBU ^® ); mechlorethamine, nitrogen mustard (Mustargen ^® ); megestrol acetate (Megace ^® ); melphalan, L-PAM (Alkeran ^® ); mercaptopurine [mercaptopurine, 6-MP (purinethol ^® )]; mesna (Mesnex ^® ); mesna (Mesnex tabs ^® ); methotrexate [methotraxate (methotraxate ^® )]; methoxsalen (Uvadex ^® ); Mitomycin ^{C [mitomycin C (Mutamycin ®)} ]; mitotane (Lysodren ^® ); mitoxantrone (Novantrone ^® ); nandrolone phenpropionate (Durabolin-50 ^® ); nelarabine (Arranon ^® ); Nofetumomab (Verluma ^® ); Oprelvekin (Neumega ^® ); Oxaliplatin [oxaliplatin (Eloxatin ^®)]; Paclitaxel [paclitaxel (Paxene ^®)]; Paclitaxel [paclitaxel (Taxol ^®)]; paclitaxel protein-bound particles (Abraxane ^® ); palipermin [palifermin (Kepivance ^® )]; pamidronate (Aredia ^® ); peg ademas [pegademase (Adagen (Pegademase Bovine) ^® )]; peg aspartate gaahje [pegaspargase (Oncaspar ^®)]; peg filgrastim [Pegfilgrastim (Neulasta ^® )]; pemetrexed disodium (Alimta ^® ); pentostatin (Nipent ^® ); pipobroman (Vercyte ^® ); plicamycin [plicamycin], mithramycin (Mithracin ^® ); porfimer sodium (Photofrin ^® ); procarbazine (Matulane ^® ); quinacrine (Atabrine ^® ); Rasburicase (Elitek ^® ); Rituximab [Rituximab (Rituxan ^®)]; sargramostim (Leukine ^® ); Sargramostim (Prokine ^® )]; sorafenib (Nexavar ^® ); streptozocin (Zanosar ^® ); sunitinib maleate (Sutent ^® ); Talc [talc (Sclerosol ^®)]; tamoxifen (Nolvadex ^® ); temozolomide (Temodar ^® ); teniposide [teniposide, VM-26 (Vumon ^® )]; testolactone (Teslac ^® ); thioguanine [thioguanine, 6-TG (thioguanine ^® )]; thiotepa (thioplex ^® ); topotecan (Hycamtin ^® ); toremifene (Fareston ^® ); Tositumomab (Bexxar ^® ); tositumomab/I-131 tositumomab (Bexxar ^® ); Trastuzumab (Herceptin ^® ); Tretinoin ^{[tretinoin, ATRA (Vesanoid ®)} ]; Uracil Mustard (Uracil Mustard Capsules ^® ); valrubicin (Valstar ^® ); vinblastine (Velban ^® ); vincristine (Oncovin ^® ); vinorelbine (Navelbine ^® ); and zoledronate [zoledronate (Zometa ^® )] may be selected from the group consisting of.

Another aspect provides a method of treating cancer in a subject, comprising administering the pharmaceutical composition to the subject in an amount effective to prevent or treat cancer.

The subject may be a mammal. The mammal may be a human, a dog, a cat, a cow, a goat, or a pig.

The administration may be administered through any general route as long as it can reach the target tissue. For example, eye drop administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, transdermal patch administration, oral administration, intranasal administration, intrapulmonary administration, rectal administration, etc. may be administered, Specifically, it may be administered as desired through the route of eye drop administration.

As used herein, “treatment” or “treating” or “alleviating” or “ameliorating” are used interchangeably. These terms refer to methods of obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or prophylactic benefit. By therapeutic benefit is meant any therapeutically significant amelioration or effect on one or more diseases, conditions or symptoms under treatment. For prophylactic benefit, the composition may be administered to a subject at risk of developing a particular disease, condition, or condition, or to a subject who reports one or more physiological symptoms of a disease, even though the disease, condition or symptom is not yet present.

The term “effective amount” or “therapeutically effective amount” refers to an amount of an agent sufficient to produce a beneficial or desired result. A therapeutically effective amount may vary depending on one or more of the subject and condition being treated, the weight and age of the subject, the severity of the condition, the mode of administration, and the like, which can be readily determined by one of ordinary skill in the art. The term also applies to the capacity to provide an image for detection by any of the imaging methods described herein. The particular dosage may vary depending on one or more of the particular agent selected, the dosing regimen that follows, whether it is administered in combination with other compounds, the timing of administration, the tissue being imaged, and the body delivery system that delivers it.

Any of the terms or elements mentioned in the pharmaceutical compositions and methods of treating cancer, such as those mentioned in the description of the claimed metal-organic framework, are the same as those mentioned in the description of the claimed metal-organic framework. is understood to be

According to a metal-organic framework according to an aspect and a pharmaceutical composition comprising the same, it can be effectively delivered to a target cell due to high targeting ability to target cells, and can be used not only chemotherapy but also photodynamic therapy, so that a targeted therapeutic agent There is an effect that can be usefully used as According to the method of treating cancer according to another aspect, it is possible to effectively treat cancer.

Figure 1 is a schematic diagram of the process of producing a metal-organic framework coupled with HA, and the process of cell death by combining chemotherapy and photodynamic therapy.
2 is an observation of the shape of PCN-224:
Fig. 2a is the result of observation by TEM; and FIG. 2b is a result of observation by SEM.
3 is a result of analyzing the PXRD pattern to confirm the crystallinity of PCN-224 and HA-Dox-PCN.
4 is a result of analyzing the nitrogen adsorption results to confirm the pore size of PCN-224.
5 is a result of confirming the particle size of PCN-224 and HA-Dox-PCN by DLS technology:
Figure 5a is the result of analyzing the DLS results to compare the particle size of PCN-224 and HA-Dox-PCN; and Figure 5b is a result of analyzing the DLS results for 0, 1, 2, 24 and 48 hours to confirm the colloidal stability of HA-Dox-PCN.
6 is a result of measuring the surface of PCN-224 and HA-Dox-PCN by zeta potential to confirm that HA is bound to the PCN-224 surface.
7 is a result of analyzing the binding relationship between HA and PCN-224:
Figure 7a is a result of carbazole assay (carbazole assay) at 0, 2, 20 and 200 mM NaCl concentration to confirm that the HA binding on the surface of PCN-224 is stable; and FIG. 7b is a result of fluorescence titration analysis to confirm the binding between HA and PCN-224.
8 is a result confirming the physical adsorption of PCN-224 and HA:
Figure 8a is the result of confirming the interaction of PCN-224, HA and water through molecular dynamics simulation; Figure 8b is the result of analyzing the DET calculation to confirm the coordination bond between the HA and Zr6 node; FIG. 8c is a result of schematically showing states at each stage in the graph of FIG. 8b as an atomic model.
9 is a result of measurement with a Shimadzu RFPC 5430 spectrophotometer to analyze the emission profile of Dox from HA-Dox-PCN.
10 is a result of analyzing the absorbance of ABDA to confirm the generation of singlet oxygen of PCN-224 and HA-Dox-PCN.
11 is a result of analyzing cell viability to compare the therapeutic effects of PCN-224 and HA-Dox-PCN:
Figure 11a is the result of analyzing the cell viability in Hek 293T cells; 11B is a result of analyzing the cell viability in MDA-MB-231 cells.
12 is a photograph of cells confirming the cytoplasmic uptake pathway to confirm the intracellular penetration mechanism of HA-Dox-PCN.
13 is a photograph of cells analyzing the cellular uptake ability of HA-Dox-PCN.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not to be construed as being limited by these examples.

experimental material

All chemicals and reagents were purchased from Sigma-Aldrich, TCI and Alfa Aesar (Korea) and used without further purification unless otherwise specified. Sodium hyaluronate was purchased from Acros Organic (Belgium). Doxorubicin hydrochloride was purchased from Ontario Chemicals Inc, Canada. Deionized (DI) water was produced on a Millipore Milli-Q system (18.2 MΩ cm).

Example 1. Preparation of a metal-organic framework having a polymer bound to the surface and capable of supporting a drug

1. Preparation of PCN-224 nanoMOFs

In the present invention, it was attempted to prepare a drug delivery system with improved targeting ability by binding a polymer to the surface of a metal-organic framework for use as a drug delivery agent. To this end, metal-organic frameworks (MOFs) were first prepared.

Specifically, 90nm PCN-224 nanoMOFs were synthesized under solvothermal conditions. Meso-Tetra (4-carboxyphenyl) porphyrin (Meso-Tetra (4-carboxyphenyl) porphyrin (TCPP)) (100mg, 0.13mmol), ZrOCl ₂ 8H ₂ O (300mg, 0.93mmol), Benzoic acid (Benzoic acid) ( 2.8 g, 23 mmol) and DMF (100 mL) were combined in a 250 mL round bottom flask. The mixture was heated to 90° C. for 5 hours with stirring at 300 rpm and then cooled to room temperature. The product was collected by centrifugation at 15000 rpm for 30 minutes and washed with fresh DMF and acetone to finally obtain PCN-224. The synthesized PCN-224 sample was characterized by powder X-ray diffraction (PXRD) (FIG. 3). 3 is a result of analyzing the PXRD pattern to confirm the crystallinity of PCN-224 and HA-Dox-PCN.

2. Preparation of Dox-PCN nanoMOFs

About 4 mg of PCN-224 prepared in Section 1 above was dispersed in 8 mg of Dox, dissolved in 1 mL of DMSO, and stirred at room temperature for 24 hours. PCN-224 containing Dox was then collected by centrifugation and dried under high vacuum. Then, the dried sample was redispersed in deionized water (DI) to finally obtain Dox-PCN.

3. HA-Dox-PCN Manufacturing

The PCN containing about 1 mg of Dox prepared in Section 2 was dispersed in 20 ml of deionized water (DI) containing 2 mg of hyaluronic acid (HA), and stirred at room temperature for 24 hours. Then, HA-coated Dox-PCN was collected by centrifugation and redispersed in deionized water (DI) to finally obtain HA-Dox-PCN.

Experimental Example 1. Characterization of PCN-224 and HA-Dox-PCN

The characteristics of PCN-224 and HA-Dox-PCN prepared in Section 1 or Section 3 of Example 1 were analyzed.

First, the shape of PCN-224 was observed with a transmission electron microscope (TEM) and a scanning electron microscope (SEM). As a result, a spherical shape with a size of about 90 nm was observed as shown in FIGS. 2A and 2B. Figure 2a is the result of observation with TEM, Figure 2b is the result of observation with SEM.

The crystallinity of PCN-224 and HA-Dox-PCN was confirmed by powder X-ray diffraction (PXRD). It was confirmed that the PXRD pattern was consistent with the PCN-224 simulation, which means that the crystallinity was maintained even after HA coating, and the MOF structure remained in the synthesis process (FIG. 3). 3 is a result of analyzing the PXRD pattern to confirm the crystallinity of PCN-224 and HA-Dox-PCN.

The surface area area and pore size distribution of PCN-224 were confirmed through Brunauer-Emmett-Teller (BET) and non-local density functional theory (NLDFT) analysis.

Specifically, 90nm-PCN-224 samples were thoroughly washed 3 times with DMF and 2 times with acetone before the gas adsorption measurement. After discarding the acetone, the sample was dried under vacuum for 3 hours. Then, the dried powder was activated in ASAP 2020 at 85 °C for 30 minutes and at 120 °C for 5 hours for nitrogen adsorption measurement.

As a result, it was confirmed that it had a large BET surface area of 2296(8) m ² /g and a three-dimensional channel with a pore size of 1.8 nm measured by a nitrogen adsorption study at 77K (Fig. 4). 4 is a result of analyzing the nitrogen adsorption results to confirm the pore size of PCN-224.

Through this, it was confirmed that the high surface area and porosity of PCN-224 allows for a large amount of drug loading as a drug carrier.

The particle sizes of PCN-224 and HA-Dox-PCN were confirmed using dynamic light scattering (DLS) technology. As a result, compared with the size of PCN-224, ~164 ± 20 nm, it was confirmed that the size of HA-Dox-PCN was increased to ~250 ± 20 nm (Fig. 5a). Figure 5a is a result of analyzing the DLS results to compare the particle size of PCN-224 and HA-Dox-PCN. In addition, in order to confirm the colloidal stability of HA-Dox-PCN, the particle size change was measured by DLS technique by varying the time in the medium. As a result, it was confirmed that there was no significant difference in the particle size of HA-Dox-PCN for 48 hours, confirming the high colloidal stability of HA-Dox-PCN (FIG. 5b). Figure 5b is a result of analyzing the DLS results for 0, 1, 2, 24 and 48 hours to confirm the colloidal stability of HA-Dox-PCN.

In addition, the surface of PCN-224 and HA-Dox-PCN in aqueous solution was measured as a zeta potential (zeta potential). As a result, it was confirmed that the surface charge was changed from the positive potential (+27 mV) of PCN-224 to the negative potential (-34 mV) of HA-Dox-PCN ( FIG. 6 ). These size and surface charge changes indicate that HA was successfully bound to the PCN-224 surface. 6 is a result of measuring the surface of PCN-224 and HA-Dox-PCN by zeta potential to confirm that HA is bound to the PCN-224 surface.

Experimental Example 2. Binding analysis between HA and PCN-224

An experiment was performed to analyze the binding relationship between HA and PCN-224.

First, when HA was coated on PCN-224, it was confirmed by carbazole assay whether HA was stable depending on the NaCl concentration. As a result, it was confirmed that it was very stable even at a high salt concentration (2M) (FIG. 7a). 7a is a result of carbazole assay at 0, 2, 20 and 200 mM NaCl concentrations to confirm that the HA coating on the PCN-224 surface is stable. These results suggest that the coating of HA can occur by coordination bonding together with the electrostatic interaction in FIG. 6 .

Fluorescence titration was performed to further study the binding between HA and PCN-224. Specifically, to prepare FITC-HA, an amine functional group was first modified with fluorescein isothiocyanate (FITC). FITC (5 mg, 12 μmol) and ethylenediamine (1 μL, 18 μmol) were dissolved in 2 mL of DMSO. Then, the mixture was stirred at room temperature for 12 hours, and then the solvent and ethylenediamine were removed with a freeze dryer. Then, for the synthesis of FITC-HA, hyaluronic acid (HA) (20 mg) was dissolved in 10 mL of deionized water, and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1-Ethyl -3-(3-dimethylaminopropyl) carbodiimide, EDC) (15mg, 97μmol) and N-hydroxysuccinimide (NHS) (11mg, 96μmol) were added to the HA solution, and the mixture was stirred at room temperature for 4 hours. did. Then, amine-modified FITC (2.2 mg, 5 μmol) was added to the mixed solution, stirred at room temperature for 24 hours, and the mixture was purified by dialysis using a 2.5K dialysis bag for 1 week. After dialysis, the solution was removed with a freeze dryer.

As a result, when the binding constants of FITC-modified high molecular weight HA (1,500 ~ 2,200 kDa) and low molecular weight HA (8 ~ 15 kDa) were compared, the fluorescence of FITC-modified HA (FITC-HA) showed that PCN-224 nanoparticles When added, it was confirmed that the energy transfer from FITC to the porphyrin framework was significantly reduced. The normalized fluorescence intensity of FITC-HA at 520 nm is plotted against the ratio of nanoparticles to polymer (Fig. 7b). 7b is a result of fluorescence titration analysis to confirm the binding between HA and PCN-224.

In addition, the binding constant (Ks) between HA and PCN-224 was analyzed. Specifically, 1 mL HA-FITC solution (2.5 nM) was placed in a vial, and different amounts of PCN-224 (8.55 nM) and deionized water were added to the HA-FITC solution to adjust the volume of the mixture solution to 3 mL. The emission spectrum of the sample was recorded at 470 nm. After measurement, the normalized fluorescence intensity corrected for each control at 520 nm was plotted against the concentration of PCN-224. The coupling constant (Ks) was obtained through Nonlinear least-squares curve-fitting analysis. As a result, it was confirmed that the Ks of the high molecular weight HA-FITC bound to PCN-224 was 2.9 x 10 ¹¹ M ^-1 , and the low molecular weight HA-FITC was ^{significantly reduced to 3.19 x 10 7} M ^-1 (Fig. 7b). These results suggest that the carboxylate group of HA affects the binding force.

We observed the physical adsorption of HA on the surface of PCN-224 through molecular dynamics simulations.

As a result, as shown in FIG. 8a in the hydrated state, it was confirmed that the terminal hydroxyl group of the Zr6 node interacted with water molecules, contributing to the stable positioning of the HA coating layer near the surface. Through this, it can be seen that the coordination bond between HA and PCN-224 is induced by a strong hydrogen bonding force. Figure 8a is the result of confirming the interaction of PCN-224, HA and water through molecular dynamics simulation.

To confirm the coordination bond between the HA and Zr6 nodes, the thermodynamic mechanism was calculated through density functional theory (DFT) calculations ( FIGS. 8b and 8c ). FIG. 8b is a result of analyzing the DET calculation to confirm the coordination bond between the HA and Zr6 nodes, and FIG. 8c is the result of schematicizing the state at each stage in the graph of FIG. 8b as an atomic model. Considering the molecular arrangement observed in the hydrated state in MD simulations, HA monomers and water molecules were placed near the terminal -OH group of the Zr6 cluster. To make a coordination bond between HA and PCN-224, we determined that the reaction would occur in a structure interconnected by hydrogen bonding interactions, i.e., water molecules, the carboxylic acids of HA, and the terminal -OH groups of the Zr6 cluster. In the initial reaction, a hydrogen atom was transferred from the carboxylic acid of HA to the terminal -OH group of the Zr6 node stabilized by an adjacent water molecule. The residual carboxylate was then coordinated to open the Zr site with an activation energy (Ea) of 4.16 kcal/mol and a heat of reaction (ΔE) of -6.63 kcal/mol. From IM1 to FS, the resulting water molecule was easily separated from the Zr atom and at the same time the carboxylate was coordinated to the Zr atom with an Ea of 9.42 kcal/mol and a mole of -13.25 kcal/ΔE. Considering this relatively low Ea, it was found that if the HA polymer was located close to the Zr6 metal node of PCN-224, the polymer would make a new coordination bond with PCN-224 even at room temperature.

Experimental Example 3. Drug release analysis

Experiments were performed to analyze the drug release profile of HA-Dox-PCN.

We first monitored the degradation of HA by HAdase in aqueous solution by observing the change in surface charge. As shown in FIG. 6 , the surface charge of HA-PCN was changed from -34 mV to + 4 mV after incubation with HAdase. This indicates that the coated HA of PCN-224 was degraded by HAdase.

HAdase-induced drug release was investigated by measuring the release of Dox from HA-Dox-PCN. Specifically, the release rate of HA-Dox-PCN was analyzed with a Shimadzu RFPC 5430 spectrophotometer. After HA-Dox-PCN was dispersed in phosphate-buffered saline (pH 7.4), Dox fluorescence intensity was measured at a wavelength of 480 nm. To determine the induced drug release profile, HAdase was added to the HA-Dox-PCN solution for 4 h and the release profile was analyzed using fluorescence.

As shown in FIG. 9 , when HAdase was added to the HA-Dox-PCN aqueous suspension after 3 hours of incubation, the Dox fluorescence intensity gradually increased, which caused drug release by HAdase decomposing the HA attached to the PCN-224 surface. means to induce. Through this, it was confirmed that there was no unwanted drug release by stable encapsulation of Dox in HA-Dox-PCN. This means that HA effectively blocks the PCN-224 pore entrance before degradation by HAdase. 9 is a result of measurement with a Shimadzu RFPC 5430 spectrophotometer to analyze the emission profile of Dox from HA-Dox-PCN.

Experimental Example 4. Singlet oxygen generation analysis

Since the (4-carboxyphenyl) porphyrin photosensitizer constituting PCN-224 can generate singlet oxygen using light, an experiment was performed to confirm this.

Specifically, a Newport IQE-200 solar simulator (Irvine, CA, USA) was used as a light source, and the power density for light was 40 mW/cm2. To measure the generated singlet oxygen, 9,10-anthracenediyl bis(methylene)malonic acid (ABDA) and nanoparticles (PCN-224) (100 μM and 20 μM) were mixed in distilled water. prepared. The absorbance of ABDA is weakened after the reaction of PCN-224 with singlet oxygen, and the degree of absorbance change before and after light irradiation means the absolute amount of singlet oxygen production. Absorbance was measured every 2 minutes after irradiation.

As a result, as shown in FIG. 10 , it was confirmed that the ABDA absorbance was consistently decreased by increasing the illumination time. This means that the present invention can be used as a therapeutic agent using photodynamic therapy as well as chemotherapy. 10 is a result of analyzing the absorbance of ABDA to confirm the generation of singlet oxygen of PCN-224 and HA-Dox-PCN.

Experimental Example 5. Cell viability analysis

Cell viability was measured to compare the therapeutic effects of PCN-224 and HA-Dox-PCN.

Specifically, the human breast cancer cell line MDA-MB-231 (CD44 positive), and non-cancerous fibroblast HeK293T (CD44 negative) cells were treated with 10% fetal bovine serum (FBS), 100 μg/ml ⁻¹ streptomycin and 100 U/mL ^{-1 In} a medium containing penicillin (using RPMI 1640 and DMEM medium, respectively), the culture was performed at 37°C and 5% CO2. Cells (5 × 10 ³ cells/well) were then cultured in sterile 96-well Nunc (Thermo Scientific Inc.) plates for 24 h, and different concentrations of PCN-224, HA-Dox-PCN (1.0, 2.0, 3.0 , 4.0 and 5.0 μg/ml) and incubated in the dark for 12 h. Thereafter, the medium was replaced with a fresh medium and the cells were irradiated for 30 minutes in ^{sunlight (100 mW/cm −2 ) using a solar simulator.} Cells were further incubated for 12 h before cytotoxicity was confirmed using Alamar blue dye assay according to the manufacturer's protocol (DAL 1025, Invitrogen).

As a result, only PCN-224 was toxic to CD44-negative cells under light irradiation (FIG. 11a). In addition, HA-Dox-PCN showed increased toxicity when irradiated with light in CD44 positive cells (Fig. 11b). These results suggest that HA promotes selective cancer cell uptake and that the combined chemo-photodynamic therapy increases the cancer treatment effect under light irradiation. FIG. 11a is a result of analyzing cell viability in Hek 293T cells, and FIG. 11b is a result of analyzing cell viability in MDA-MB-231 cells.

Experimental Example 6. Endocytosis pathway analysis

To confirm the intracellular penetration mechanism of HA-Dox-PCN, a cytoplasmic uptake pathway experiment was performed.

An experiment was performed to confirm the entry into the cell of HA-Dox-PCN mediated by endocytosis.

Specifically, MDA-MB231 cells were seeded on a cover glass with 4 wells (Lab Tek II, Thermo Scientific Inc.), and sucrose (clathrin-mediated inclusion, 400 nM), Inhibitors including methyl-beta cytodextrin (caveolae-mediated inclusion) and amilorin (macropinocytosis) were pretreated in serum-free DMEM for 1 hour, respectively. It was replaced with fresh medium. After that, it was added to the HA-Dox-PCN medium and cultured for 1 hour, and the cells were analyzed with a confocal microscope (Olympus FV1000) connected to a _{CO 2 incubator.}

As a result, it was confirmed that the intracellular uptake of HA-Dox-PCN is related to clathrin-mediated endocytosis ( FIG. 12 ). 12 is a photograph of cells confirming the cytoplasmic uptake pathway to confirm the intracellular penetration mechanism of HA-Dox-PCN.

Experimental Example 7. Cell uptake analysis

An experiment was performed to analyze the cellular uptake capacity of HA-Dox-PCN.

Specifically, the cellular uptake of HA-Dox-PCN nanoparticles in HeK293T (CD44 negative cells), MDA-MB-231 (CD44 positive cells) and SCC-7 (CD44 positive cells) cells was examined by live confocal microscopy images (live). confocal microscope images) (Olympus FV 1000 series). ^{Cells were seeded at a density of 2 x 10 5} cells/well in a two-well cover glass (Lab Tek II, Thermo Scientific.), incubated for 24 hours, and then HA with Dox to a final concentration of 10 µg/mL -Dox-PCN was treated at different time points and analyzed with a confocal microscope.

As a result, MDA-MB231 and SCC-7 cells exhibited higher Dox intensity compared to Hek 293T cells (FIG. 13). These results suggest that HA-Dox-PCN nanoparticles can be selectively absorbed by the CD44 receptor expressing cancer cells. 13 is a photograph of cells analyzing the cellular uptake ability of HA-Dox-PCN.

Claims (13)

Metal-organic framework (MOFs) nanoparticles having a porous three-dimensional structure in which biopolymers are bonded to the surface and metal ions are bonded between organic molecules,
the surface is a metal-organic framework surface,
The metal-organic framework is MIL-88A, MIL-88Bt, MIL-89, MIL-127, MIL-101, MIL-100, MIL-53, MOF-74, UiO-66, UiO-67, ZIF-8 , ZIFs, HKUST-1, M2 (dobpdc), NU-1000, PCN-222, and metal-organic framework nanoparticles comprising any one selected from the group consisting of PCN-224. The metal-organic framework nanoparticles of claim 1, wherein the biopolymer is a stimulus-sensitive polymer. The metal-organic framework nanoparticles of claim 2, wherein the biopolymer interacts with a receptor expressed on a cell surface. The metal-organic framework nanoparticle of claim 3, wherein the cell is a cancer cell. delete The method according to claim 1, The biopolymer is hyaluronic acid (Hyaluronic acid, HA), pullulan (pullulan), curdlan (curdlan), pectin (pectin), heparin (Heparin), chitosan (chitosan), methyl cellulose (methyl cellulose) ), polyvinyl alcohol (poly(vinyl alcohol)), dextran (dextran), starch (starch), agarose (agarose), poly-L- lysine and polyaspartic acid containing any one or more selected from the group consisting of wherein the metal-organic framework nanoparticles. delete The metal-organic framework nanoparticles according to claim 1, wherein the organic molecule is a photosensitizer, capable of generating singlet oxygen. The metal-organic framework nanoparticles according to claim 1, wherein the drug is supported thereon. The metal-organic framework nanoparticles of claim 9, wherein the drug is an anticancer agent. As a pharmaceutical composition for the prevention or treatment of cancer comprising a metal-organic framework (MOFs) nanoparticles having a biopolymer bonded to the surface as an active ingredient,
the surface is a metal-organic framework surface,
The metal-organic framework nanoparticles is a pharmaceutical composition for preventing or treating cancer in which an anticancer agent is supported. The method according to claim 11, wherein the anticancer agent is abarelix [abarelix (Plenaxis depot ^® )]; aldesleukin (Prokine ^® ); Aldesleukin (Proleukin ^® ); Alemtuzumab (Campath ^® ); alitretinoin (Panretin ^® ); allopurinol [allopurinol (Zyloprim ^® )]; altretamine (Hexalen ^® ); amifostine [amifostine (Ethyol ^® )]; anastrozole (Arimidex ^® ); arsenic trioxide (Trisenox ^® ); Asparaginase better the [asparaginase (Elspar ^®)]; Azacytidine [azacitidine (Vidaza ^®)]; bevacuzimab (Avastin ^® ); bexarotene capsules (Targretin ^® ); bexarotene gel (Targretin ^® ); Bleomycin [bleomycin (Blenoxane ^®)]; bortezomib (Velcade ^® ); busulfan intravenous (Busulfex ^® ); oral busulfan [busulfan oral (Myleran ^® )]; calusterone (Methosarb ^® ); capecitabine [capecitabine (Xeloda ^® )]; carboplatin [carboplatin (Paraplatin ^® )]; carmustine (BCNU ^® , BiCNU ^® ); carmustine (Gliadel ^® ); Carmustine and Polypeprosan 20 Implant (Gliadel Wafer ^® ); celecoxib (Celebrex ^® ); cetuximab (Erbitux ^® ); chlorambucil [chloambucil (Leukeran ^® )]; Cisplatin [cisplatin (Platinol ^®)]; cladribine (Leustatin ^® ) 2-CdA ^® ; clofarabine (Clolar ^® ); cyclophosphamide (Cytoxan ^® , Neosar ^® )]; cyclophosphamide (Cytoxan Injection ^® )]; cyclophosphamide (Cytoxan Tablet ^® ); cytarabine (Cytosar-U ^® ); cytarabine liposomal (DepoCyt ^® ); dacarbazine (DTIC-Dome ^® ); Shut actinomycin (dactinomycin), liquid actinomycin ^{D [actinomycinD (Cosmegen ®)]} ; Darbepoetin alfa (Aranesp ^® ); daunorubicin liposomal (Danuoxome ^® ); Daunorubicin (daunorubicin), daunomycin [daunomycin (Daunorubicin ^®)]; daunorubicin, daunomycin [daunomycin (Cerubidine ^® )]; Denileukin diftitox (Ontak ^® ); dexrazoxane (Zinecard ^® ); docetaxel (Taxotere ^® ); Doxorubicin ^{[doxorubicin (Adriamycin PFS ®)]} ; Doxorubicin ^{[doxorubicin (Adriamycin ®, Rubex ®} )]; doxorubicin (Adriamycin PFS Injection ^® )]; doxorubicin liposomal (Doxil ^® ); dromostanolone propionate (dromostanolone ^® ); dromostanolone propionate (masterone injection ^® ); Elliott's B Solution (Elliott's B Solution ^® ); epirubicin (Ellence ^® ); Epoetin alfa (epogen ^® ); erlotinib (Tarceva ^® ); estramustine (Emcyt ^® ); Etoposide phosphate ^{[etoposide phosphate (Etopophos ®)]} ; etoposide, VP-16 (Vepesid ^® ); exemestane (Aromasin ^® ); Filgrastim (Neupogen ^® ); Floc repair Dean ^{[floxuridine (intraarterial) (FUDR ®} )]; fludarabine (Fludara ^® ); Fluorouracil [Fluorouracil, 5-FU (Adrucil ^® )]; fluvestrant (Faslodex ^® ); gefitinib (Iressa ^® ); gemcitabine [gemcitabine (Gemzar ^® )]; gemtuzumab ozogamicin (Mylotarg ^® ); goserelin acetate (Zoladex Implant ^® ); goserelin acetate (Zoladex ^® ); histrelin acetate [histrelin acetate (Histrelin implant ^® )]; hydroxyurea [hydroxyurea (Hydrea ^® )]; Ivry Tomorrow Thank tiuk cetane ^{[Ibritumomab Tiuxetan (Zevalin ®)]} ; idarubicin (Idamycin ^® ); ifosfamide [ifosfamide (IFEX ^® )]; imatinib mesylate (Gleevec ^® ); Interferon alpha -2a [interferon alfa-2a (Roferon A ®)]; Interferon alfa -2b [Interferon alfa-2b (Intron A ®)]; irinotecan [irinotecan (Camptosar ^® )]; lenalidomide (Revlimid ^® ); letrozole (Femara ^® ); leucovorin [leucovorin (Wellcovorin ^® , Leucovorin ^® )]; Leuprolide Acetate (Eligard ^® ); levamisole (Ergamisol ^® ); lomustine-CCNU (CeeBU ^® ); mechlorethamine, nitrogen mustard (Mustargen ^® ); megestrol acetate (Megace ^® ); melphalan, L-PAM (Alkeran ^® ); mercaptopurine [mercaptopurine, 6-MP (purinethol ^® )]; mesna (Mesnex ^® ); mesna (Mesnex tabs ^® ); methotrexate [methotraxate (methotraxate ^® )]; methoxsalen (Uvadex ^® ); Mitomycin ^{C [mitomycin C (Mutamycin ®)} ]; mitotane (Lysodren ^® ); mitoxantrone (Novantrone ^® ); nandrolone phenpropionate (Durabolin-50 ^® ); nelarabine (Arranon ^® ); Nofetumomab (Verluma ^® ); Oprelvekin (Neumega ^® ); Oxaliplatin [oxaliplatin (Eloxatin ^®)]; Paclitaxel [paclitaxel (Paxene ^®)]; Paclitaxel [paclitaxel (Taxol ^®)]; paclitaxel protein-bound particles (Abraxane ^® ); palipermin [palifermin (Kepivance ^® )]; pamidronate (Aredia ^® ); peg ademas [pegademase (Adagen (Pegademase Bovine) ^® )]; peg aspartate gaahje [pegaspargase (Oncaspar ^®)]; peg filgrastim [Pegfilgrastim (Neulasta ^® )]; pemetrexed disodium (Alimta ^® ); pentostatin (Nipent ^® ); pipobroman (Vercyte ^® ); plicamycin [plicamycin], mithramycin (Mithracin ^® ); porfimer sodium (Photofrin ^® ); procarbazine (Matulane ^® ); quinacrine (Atabrine ^® ); Rasburicase (Elitek ^® ); Rituximab [Rituximab (Rituxan ^®)]; sargramostim (Leukine ^® ); Sargramostim (Prokine ^® )]; sorafenib (Nexavar ^® ); streptozocin (Zanosar ^® ); sunitinib maleate (Sutent ^® ); Talc [talc (Sclerosol ^®)]; tamoxifen (Nolvadex ^® ); temozolomide (Temodar ^® ); teniposide [teniposide, VM-26 (Vumon ^® )]; testolactone (Teslac ^® ); thioguanine [thioguanine, 6-TG (thioguanine ^® )]; thiotepa (thioplex ^® ); topotecan (Hycamtin ^® ); toremifene (Fareston ^® ); Tositumomab (Bexxar ^® ); tositumomab/I-131 tositumomab (Bexxar ^® ); Trastuzumab (Herceptin ^® ); Tretinoin ^{[tretinoin, ATRA (Vesanoid ®)} ]; Uracil Mustard (Uracil Mustard Capsules ^® ); valrubicin (Valstar ^® ); vinblastine (Velban ^® ); vincristine (Oncovin ^® ); vinorelbine (Navelbine ^® ); And zoledronate [zoledronate (Zometa ^® )] The pharmaceutical composition for preventing or treating cancer selected from the group consisting of. A method of treating cancer in an individual comprising administering to the individual the pharmaceutical composition of claim 11 in an amount effective to prevent or treat cancer,
The method of treating cancer in an individual, wherein the individual is a mammal other than a human.

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