WO2005107813A1 - Delivery system for bioactive agents on the basis of a polymeric drug carrier comprising an amphiphilic block polymer and a polylacticacid derivative - Google Patents
Delivery system for bioactive agents on the basis of a polymeric drug carrier comprising an amphiphilic block polymer and a polylacticacid derivative Download PDFInfo
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- WO2005107813A1 WO2005107813A1 PCT/KR2005/001330 KR2005001330W WO2005107813A1 WO 2005107813 A1 WO2005107813 A1 WO 2005107813A1 KR 2005001330 W KR2005001330 W KR 2005001330W WO 2005107813 A1 WO2005107813 A1 WO 2005107813A1
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- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/91—Polymers modified by chemical after-treatment
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
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- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/91—Polymers modified by chemical after-treatment
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- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
- C08L67/04—Polyesters derived from hydroxycarboxylic acids, e.g. lactones
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
- C08G2261/10—Definition of the polymer structure
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- C08G2261/126—Copolymers block
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- C08L101/00—Compositions of unspecified macromolecular compounds
- C08L101/02—Compositions of unspecified macromolecular compounds characterised by the presence of specified groups, e.g. terminal or pendant functional groups
- C08L101/06—Compositions of unspecified macromolecular compounds characterised by the presence of specified groups, e.g. terminal or pendant functional groups containing oxygen atoms
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- C08L53/00—Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
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- C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
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- C08L87/00—Compositions of unspecified macromolecular compounds, obtained otherwise than by polymerisation reactions only involving unsaturated carbon-to-carbon bonds
- C08L87/005—Block or graft polymers not provided for in groups C08L1/00 - C08L85/04
Definitions
- This present invention relates to a delivery system and a method for the intracellular delivery of bioactive agents using polymeric drug carriers. More particularly, it relates to a method for the intracellular delivery of bioactive agents using polymeric drug carriers formed from (a) an amphiphilic block copolymer which is comprised of a hydrophilic block and a hydrophobic block, wherein said hydrophobic block has a terminal hydroxyl group that is substituted with a tocopherol or cholesterol group, and (b) a polylactic acid derivative having at least one terminal carboxyl group at the end of the polymer.
- an appropriate amount of the administered drug should enter the target cells in a body.
- an appropriate concentration of the drug should be maintained for a desired time period in the target tissue; furthermore, the drug should enter the target cells in the tissue.
- a high drug concentration in a tissue can be achieved by a formulation exhibiting a long blood circulation time. Therefore, great effort has been made to develop drug delivery systems by the use of nanoparticulate drug carriers, including liposome and polymeric micelles, having long circulation times. Many approaches have been suggested for enhancing the intracellular uptake of bioactive agents.
- Liposomes have also been described for use in the intracellular delivery of bioactive agents such as ohgonucleotides (Feigner, et al., U.S. Pat. No. 5,264,618 (1993); Eppstein, et al., U.S. Pat. No. 4,897,355 (1990); and Wang, et al., Proc. Nat. Acad. Sci. 84: 7851-7855 (1987); U.S. Pat. No. 5,759,519 (1998)).
- the use of liposomes as drug carriers is limited due to such problems as low entrapment efficiency, drug instability, rapid drug leakage, and poor storage stability.
- Small molecular surfactant micelles are easily dissociated when they are diluted with body fluids after being administered into the body; so it is difficult for them to perform their role as drug carriers.
- efforts have been made for the preparation, characterization and pharmaceutical application of polymeric micelles. These were well reviewed by V. Torchilin in Journal of Controlled Release 73(2001) pp.137- 172.
- Polymeric micelles are characterized by a core-shell structure in aqueous media which results from the amphiphilic block copolymers having hydrophobic (core) and hydrophilic (shell) segments. A poorly water soluble drug is entrapped within the hydrophobic core of the micelle.
- the hydrophobic B(inner micelle core block) comprises a biodegradable polymer such as poly-DL-lactide, poly- ⁇ -caprolactone or poly( ⁇ -benzyl-L- aspartate) and that the hydrophilic A (outer micelle shell block) be a polymer which is capable of interacting with plasma proteins and cell membranes, such as polyethylene glycol(PEG).
- Polymeric micelles provide attractive characteristics in that they can avoid uptake of the drug by the reticuloendothelial system (RES) or the mononuclear phagocyte system (MPS) in vivo, and hence, they can circulate in the blood for a long period of time.
- This advantage comes from the structure of a micelle.
- the hydrophilic portions of an amphiphilic block copolymer form the outer shell and are exposed to body fluid, and hence, effectively protect the micelles from interactions with the cell membranes and plasma proteins in the blood [V. Torchilin et al., Advanced Drug Delivery Reviews 16(1995) pp.141-155].
- the present invention provides a method for the targeted intracellular delivery of bioactive agents using a polymeric micelle or nanoparticle drug carrier.
- 0.01 to 10 equivalents of a di- or tri-valent metal ion is bound to 1 equivalent of the carboxyl terminal group of said polylactic acid derivative.
- It is another object of the present invention to a delivery system for the intracellular delivery of bioactive agents comprising bioactive agents and a polymeric drug carrier with said bioactive agents entrapped therein in the aqueous solution
- the polymeric drug carrier is prepared by a polymeric composition comprising (a) an amphiphilic block copolymer consisting of a hydrophilic block and a hydrophobic block in which said hydrophobic block has a terminal hydroxyl group that is substituted with a tocopherol orcholesterol group and (b) a polylactic acid derivative having at least one carboxyl group at the end of the polymer; and wherein said bioactive agents entrapped in the polymeric drug carrier are allowed to be delivered into a cell in a greater quantity when the drug carrier contact with said cell.
- It is another object of the present invention to a composition for the intracellular delivery of bioactive agents comprising bioactive agents and a polymeric drug carrier with said bioactive agents entrapped therein in the aqueous solution
- the polymeric drug carrier is prepared by a polymeric composition comprising (a) an amphiphilic block copolymer consisting of a hydrophilic block and a hydrophobic block in which said hydrophobic block has a terminal hydroxyl group that is substituted with a tocopherol orcholesterol group and (b) a polylactic acid derivative having at least one carboxyl group at the end of the polymer; and wherein said bioactive agents entrapped in the polymeric drug carrier are allowed to be delivered into a cell in a greater quantity when the drug carrier contact with said cell.
- the present invention relates to polymeric drug carriers which can deliver a bioactive agent into a targeted cell.
- Fig. 1 is a schematic diagram of the cellular internalization of a bioactive agent from the body fluid after administration of the composition of the present invention.
- Fig. 2A shows the number of cells in which the drug is internalized after treatment of doxorubicin-sensitive cells(MES-SA) with the drug compositions.
- Fig. 2B shows the number of cells in which the drag is internalized after treatment of doxorubicin-resistant cells(MES-S A/Dx-5) with the drug compositions.
- Fig. 3A shows the fluorescence intensity detected by FACS after treatment of doxorubicin-sensitive cells(MES-SA) with the drug compositions.
- Fig. 1 shows the number of cells in which the drug is internalized after treatment of doxorubicin-sensitive cells(MES-SA) with the drug compositions.
- Fig. 2B shows the number of cells in which the drag is internalized after treatment of doxorubicin-resistant cells(MES-S A/Dx-5) with the drug compositions.
- FIG. 3B shows the fluorescence intensity detected by FACS after treatment of doxorubicin-resistant cells(MES-SA/Dx-5) with the drug compositions.
- Fig. 4A shows confocal microscopic images obtained 2 hours after treatment of doxorubicin-sensitive cells(MES-SA) with the doxorubicin-containing composition (composition 1, right side) and a conventional solution formulation(left side).
- Fig. 4B shows confocal microscopic images obtained 8 hours after treatment of doxorubicin-sensitive cells(MES-SA) with the doxorubicin-containing composition (composition 1) and a conventional solution formulation.
- FIG. 4C shows confocal microscopic images obtained 2 hours after treatment of doxorubicin-resistant cells(MES-SA/Dx-5) with the doxorubicin-containing composition (composition 1) and a conventional solution formulation.
- Fig. 4D shows confocal microscopic images obtained 8 hours after treatment of doxorubicin-resistant cells(MES-SA/Dx-5) with the doxorubicin-containing composition (composition 1) and a conventional solution formulation.
- Fig. 4E shows confocal microscopic images obtained 2 hours after treatment of epirabicin-sensitive cells(MCF-7) with the epirubicin-containing composition (composition 6) and conventional solution formulation.
- FIG. 4F shows confocal microscopic images obtained 8 hours after treatment of epirabicin-sensitive cells(MCF-7) with the epirubicin-containing composition (composition 6) and a conventional solution formulation.
- Fig. 4G shows confocal microscopic images obtained 2 hours after treatment of epirubicin-resistant cells(MCF-7/ADR) with the epirubicin-containing composition (composition 6) and a conventional solution formulation.
- Fig. 4H shows confocal microscopic images obtained 8 hours after treatment of a epirubicin-resistant cells(MCF-7/ADR) with the epirubicin-containing composition (composition 6) and a conventional solution formulation.
- FIG. 5A shows the cell viability after treatment of doxorubicin-sensitive cells(MES-SA) with the drag compositions (0.1 zg/ml).
- Fig. 5B shows the cell viability after treatment of doxorubicin-resistant cells(MES-SA/Dx-5) with the drag compositions (1.0 .g/ml).
- Fig. 6 shows drag concentration in blood plasma with time after intravenous administration of the drug compositions in rats.
- bioactive agent means an organic compound or drug which has a desirable biological activity or function, i.e. a biological effect or pharmacological effect, in vivo.
- bioactive agent consisting of therapeutic agents may alter cellular functions, such as gene function.
- bioactive agents consisting of diagnostic agents such as magnetic resonance imaging (“MRI”) or computerized tomography (“CT”) agents, have the biological function of enhancing the diagnostic images of tissues and/or organs.
- MRI magnetic resonance imaging
- CT computerized tomography
- biodegradable or “biodegradation” is defined as the conversion of materials into less complex intermediates or end products by solubilization hydrolysis, or by the action of biologically formed entities which can be enzymes or other products of the organism.
- biocompatible means materials or the intermediates or end products of materials formed by solubilization hydrolysis, or by the action of biologically formed entities which can be enzymes or other products of the organism and which cause no adverse effects on the organisms.
- Pho ⁇ y(lactide) or “PLA” shall mean a polymer derived from the condensation of lactic acid or by the ring opening polymerization of lactide.
- lactide and lactate are used interchangeably.
- the present invention provides a method for the intracellular delivery of bioactive agents using polymeric drag carriers formed from polymeric compositions comprising an amphiphilic block copolymer which is comprised of a hydrophilic block and a hydrophobic block, wherein said hydrophobic block has a terminal hydroxyl group that is substituted with a tocopherol or cholesterol group, and a polylactic acid derivative having at least one terminal carboxyl group at the end of the polymer.
- the present invention also provides a method for the intracellular delivery of bioactive agents using drag carriers formed from polymeric compositions comprising an amphiphilic block copolymer which comprised of a hydrophilic block and a hydrophobic block, wherein said hydrophobic block has a terminal hydroxyl group that is substituted with a tocopherol succinic acid or cholesterol succinic acid group, a polylactic acid derivative having at least one terminal carboxyl group at the end of the polymer and 0.01 to 10 equivalents of a di- or tri-valent metal ion with respect to 1 equivalent of the carboxyl terminal group of the polylactic acid derivative.
- the present invention further provides a delivery system for the intracellular delivery of bioactive agents comprising bioactive agents and a polymeric drag carrier with said bioactive agents entrapped therein in the aqueous solution
- the polymeric drug carrier is prepared by a polymeric composition comprising (a) an amphiphilic block copolymer consisting of a hydrophilic block and a hydrophobic block in which said hydrophobic block has a terminal hydroxyl group that is substituted with a tocopherol orcholesterol group and (b) a polylactic acid derivative having at least one carboxyl group at the end of the polymer; and wherein said bioactive agents entrapped in the polymeric drug carrier are allowed to be delivered into a cell in a greater quantity when the drag carrier contact with said cell.
- the bioactive agents are allowed to be delivered into a cell in a greater quantity, and preferably, in more efficient manner, than those in absence of the polymeric drag carrier.
- the present invention further provides polymeric drug carriers which can deliver a bioactive agent into targeted cell.
- the present invention provides a method for the intracellular delivery of bio active agents comprising the steps of: a) selecting at least one bioactive agents; b) preparing a polymeric composition comprising an amphiphilic block copolymer comprised of a hydrophilic block and a hydrophobic block wherein said hydrophobic block has a terminal hydroxyl group that is substituted with a tocopherol or cholesterol group, a polylactic acid derivative having at least one carboxyl group at the end of the polymer; c) mixing and dissolving said polymeric composition and said bioactive agents in a solvent and evaporating the solvent; d) adding an aqueous solution to form a polymeric drug carrier with said bioactive agents entrapped therein in the solution; and e) contacting said drag carrier with a cell to facilitate delivery of said bio active agents within said cell.
- the bioactive agents of the present invention can be any organic compound or any drag which exerts a desirable biological activity. This includes, but is not limited to, proteins, hormones such as testosterone, estradiol, estrogen, progesterone, triamcinolon acetate, dexamethasone, etc., genes, polypeptides, oligonuleotides, nucleotides, antibodies, drags such as anticancer agents, anti-inflammatory agents, antifungal agents, antibiotics , anesthetics, antihypertensive agents, and agents for the treatment of diabetes, antihyperlipidemic agents, antiviral agents, agents for the treatment of Parkinson's disease, antidementia agents, antiemetics, immunosuppressants, antiulcerative agents, laxatives, antimalarial agents, and diagnostic imaging agents.
- proteins include, but is not limited to, proteins, hormones such as testosterone, estradiol, estrogen, progesterone, triamcinolon acetate, dexamethasone, etc.
- anticancer drags include paclitaxel, epirubicin, dactinomycin, bleomycin, mitomycin, docetaxel, 5-fluorouracil, methotrexate, camptothecin, etoposide, doxorabicin, dausorabicin, idarabicin, ara-C, cyclosporine A, etc., and derivatives thereof.
- the above bioactive agent may be added to the polymeric composition in a weight-by-weight ratio of 0.1 ⁇ 20:80.0-99.9 to be appropriately contained in the core of the micelles formed from the amphiphilic block copolymer and the polylactic acid derivative.
- the amphiphilic block copolymer of the present invention is preferably an A-B type diblock copolymer or B-A-B type triblock copolymer comprising a hydrophilic A block and a hydrophobic B block.
- the amphiphilic block copolymer when placed in an aqueous phase, forms core-shell type polymeric micelles wherein the hydrophobic B block forms the core and the hydrophilic A block forms the shell.
- the hydrophilic A block is a member selected from the group consisting of polyalkylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, polyacryl amide and derivatives thereof.
- the hydrophilic A block is a member selected from the group consisting of monomethoxypolyethylene glycol, monoacetoxypolyethylene glycol, polyethylene glycol, polyethylene-co-propylene glycol, and polyvinyl pynolidone.
- the hydrophilic A block has a number average molecular weight of 500 to 50,000 Daltons. More preferably, the hydrophilic A block has a number average molecular weight of 1,000 to 20,000 Daltons.
- the hydrophobic B block of the amphiphilic block copolymer of the present invention is a highly biocompatible and biodegradable polymer selected from the group consisting of polyesters, polyanhydrides, polyamino acids, polyorthoesters and polyphosphazine. More preferably, the hydrophobic B block is one or more selected from the group consisting of polylactides, polyglycolides, polycaprolactone, polydioxan-2-one, polylactic-co-glycolide, polylactic-co-dioxan-2-one, polylactic-co-caprolactone, and polyglycolic-co-caprolactone.
- the terminal group of the hydrophobic block has a hydroxyl group, and the hydroxyl terminal group of the hydrophobic B block is substituted with a hydrophobic tocopherol or cholesterol group, both having excellent hydrophobicity, with the aim of increasing the hydrophobicity of the hydrophobic B block while maintaimng its molecular weight.
- Tocopherol or cholesterol group is chemically bound to the hydroxyl terminal gourp of the hydrophobic B block using a linkage agent, e.g. a dicarboxylic acid such as succinic acid, malonic acid, glutaric acid, adipic acid.
- Tocopherol and cholesterol are biocompatible and hydrophobic compounds having a ring structure, which can increase the interior hydrophobicity of the polymeric micelles thereby enhancing the physical stability of the polymeric micelles.
- the hydrophobic B block of the amphiphilic block copolymer has a number average molecular weight of 500 to 50,000 Daltons. More preferably, the hydrophobic B block of the amphiphilic block copolymer has a number average molecular weight 1,000 to 20,000 Daltons.
- the ratio of the hydrophilic A block to the hydrophobic B block of the amphiphilic block copolymer of the present invention is preferably within the range of 3 :7 to 8:2 by weight, and more preferably within the range of 4:6 to 7:3.
- 1' is an integer from 4-1150;
- m' is an integer from 1-300;
- n' is an integer from 0-300; and
- X' is an integer from 0-4.
- the block copolymer having the hydrophobic block whose hydroxyl terminal group is substituted with tocopherol or cholesterol can be prepared according to the following methods.
- a suitable linker e.g. a dicarboxylic acid such as succinic acid, malonic acid, glutaric acid or adipic acid, is introduced into the hydroxyl group of tocopherol or cholesterol, and the carboxylated tocopherol or cholesterol is chemically bound to the hydroxyl terminal group of the hydrophobic B block.
- a suitable linker e.g. a dicarboxylic acid such as succinic acid, malonic acid, glutaric acid or adipic acid
- DCC dicyclohexylcarbodiimide
- DMAP 4-dimethylaminopyridine
- the reactant becomes opaque due to dicyclohexylurea (DCU) formed in the reaction between the terminal -OH of mPEG-PLA and -COOH of the hydrophobic compound.
- DCU dicyclohexylurea
- tocopherol (or cholesterol) succinate is reacted with oxalyl chloride, and then, excessive oxalyl chloride is removed under vacuum at room temperature.
- the mPEG-PLA is weighed and added thereto, and the reaction is performed at 100 °C for 12 hours to obtain mPEG-PLA-tocopherol (or cholesterol).
- the synthesized polymer is dissolved in acetonitrile or methylene chloride, precipitated in hexane/diethyl ether, and filtered.
- tocopherol (or cholesterol) malonate, tocopherol (or cholesterol) glutarate, or tocopherol (or cholesterol) adipate, etc. can be used instead of tocopherol (or cholesterol) succinate.
- tocopherol or cholesterol is bound to the end of mPEG-
- PLA by using a dichloride compound as a linkage agent. Specifically, tocopherol or cholesterol is weighed and dehydrated by using a vacuum pump at 50 °C. Excessive linkage agent is added thereto, and the reaction is performed for 12 hours. After the reaction is completed, the excessively added linkage agent is removed under vacuum at 100 °C. Thereto is added weighed mPEG-PLA, and the reaction is performed at 100 °C for 12 hours. The synthesized polymer is dissolved in methylene chloride, and precipitated in hexane/diethyl ether in order to obtain the amphiphilic block copolymer in which tocopherol or cholesterol is bound to PLA via succinic acid diester, i.e.
- the precipitated polymeric product is filtered, and dried under vacuum to obtain the polymer as white particles.
- the linkage agent which can be used in the reaction may be selected from such dichloride compounds as succinyl chloride, oxalyl chloride, malonyl chloride, glutaryl chloride, adipoyl chloride, etc.
- One or more ends of the polylactic acid derivative of the present invention are covalently bound to at least one carboxylic acid or carboxylate salt.
- the other end of the polylactic acid derivative of the present invention may be covalently bound to a functional group selected from the group consisting of hydroxyl, acetoxy, benzoyloxy, decanoyloxy and palmitoyloxy groups.
- the carboxylic acid or carboxylate salts function as a hydrophilic group in an aqueous solution of pH 4 or higher which enables the polylactic acid derivative to form polymeric micelles therein.
- the hydrophilic and hydrophobic components present in the polylactic acid derivative should be balanced in order to form polymeric micelles. Therefore, the number average molecular weight of the polylactic acid derivative of the present invention is preferably within the range of 500 to 2,500 Daltons.
- the molecular weight of the polylactic acid derivative can be adjusted by controlling the reaction temperature, time, and the like, during the preparation process.
- the polylactic acid derivative is preferably represented by the following formula: RO-CHZ-[A] n -[B] m -COOM (I) wherein A is -COO-CHZ-; B is -COO-CHY-, -COO-CH 2 CH 2 CH 2 CH 2 CH 2 - or - COO-CH 2 CH 2 OCH 2 ; R is a hydrogen atom, acetyl, benzoyl, decanoyl, palmitoyl, methyl or ethyl group; Z and Y each are a hydrogen atom, methyl, or phenyl group; M is H, Na, K, or Li; n is an integer from 1 to 30, and m is an integer from 0 to 20.
- One end of the polylactic acid derivative of the present invention is covalently bound to a carboxyl group or an alkali metal salt thereof, preferably, an alkali metal salt thereof.
- the metal ion in the alkali metal salt which forms the polylactic acid derivative is monovalent, e.g. sodium, potassium or lithium.
- the polylactic acid derivative in the metal ion salt form is a solid at room temperature, and is very stable because of its relatively neutral pH.
- the polylactic acid derivative is represented by the following formula: RO-CHZ-[COO-CHX]p-[COO-CHY'] q -COO-CHZ-COOM (II) wherein X is a methyl group; Y' is a hydrogen atom or phenyl group; p is an integer from 0 to 25; q is an integer from 0 to 25, provided that p+q is an integer from 5 to 25; R, Z and M are the same as defined in Formula (I).
- polylactic acid derivatives of the following formulas (III) , (IV) and (V) are also suitable for the ⁇ : RO-PAD-COO-W 9 CH2C00M C ⁇ M (III) wherein W-M' is CH 2 CO0M 0 r CH — CH 2 C00M ;
- the PAD is a member selected from the group consisting of D,L-polylactic acid, D-polylactic acid, polymandehc acid, a copolymer of D,L-lactic acid and glycolic acid, a copolymer of D,L-lactic acid and mandelic acid, a copolymer of D,L-Lactic acid and caprolactone, and a copolymer of D,L- lactic acid and l,4-dioxan-2-one;
- R and M are the same as defined in Formula (I).
- S-O-PAD-CC H _L L _c H - ⁇ (IV) wherein S is ( CH 2 ) a — C00M- ⁇ _ is -NR ⁇ - or -O-; Ri is a hydrogen atom or . l oalkyl; Q is CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , or CH 2 C 6 H 5 ; a is an integer from 0 to 4; b is an integer from 1 to 10; R and M are the same as defined in Formula (I); and PAD is the same as defined in Formula (III).
- the initiator for the synthesis of the polymers includes glycerol, erythritol, threltol, pentaerytritol, xylitol, adonitol, sorbitol and mannitol.
- the polymeric composition of the present invention may contain 0.1 to 99.9 wt% of the amphiphilic block copolymer and 0.1 to 99.9 wt% of the polylactic acid derivative based on the total weight of the amphiphilic block copolymer and the polylactic acid derivative.
- the polymeric composition of the present invention contains 20 to 95 wt% of the amphiphilic block copolymer and 5 to 80 wt% of the polylactic acid derivative.
- the polymeric composition of the present invention contains 50 to 90 wt% of the amphiphilic block copolymer and 10 to 50 wt% of the polylactic acid derivative.
- the polylactic acid derivatives of the present invention alone can form micelles in an aqueous solution with a pH 4 or higher
- the polymeric compositions comprising amphiphilic block copolymer and polylactic acid derivatives can form micelles in an aqueous solution irrespective of the pH of the solution
- the polymeric compositions of the present invention may be used at a pH within the range of 1 to 10, preferably at a pH within the range of 4 to 8.
- the particle size of the micelles or nanoparticles prepared from the polymeric compositions of the present invention may be adjusted to be within the range of 1 to 400 nm, and preferably from 5 to 200 nm, depending on the molecular weight of the polymers and the ratio of the polylactic acid derivative to the amphiphilic block copolymer.
- the carboxyl terminal group of the polylactic acid derivative is bound or fixed with a di- or tri-valent metal ion.
- the metal ion-fixed polymeric composition can be prepared by adding the di- or tri-valent metal ion to the polymeric composition of the amphiphilic block copolymer and the polylactic acid derivative.
- the polymeric micelles or nanoparticles may be formed by changing the amount of the di- or tri-valent metal ion added for binding or fixing the carboxyl terminal group of the polylactic acid derivative.
- the di- or tri-valent metal ion is preferably a member selected from the group consisting of Ca 2+ , Mg 2+ , Ba 2+ , Cr 3+ , Fe 3+ , Mn 2+ , Ni 2+ , Cu 2+ , Zn 2+ , and Al 3+ .
- the di- or trivalent metal ion may be added to the polymeric composition of the amphiphilic block copolymer and the polylactic acid derivative in the form of a sulfate, chloride, carbonate, phosphate or hydroxylate, and preferably, in the form of CaCl 2 , MgCl 2 , ZnCl 2 , A1C1 3 , FeCl 3 , CaCO 3 , MgCO 3 , Ca 3 (PO 4 ) 2 , Mg 3 (PO 4 ) 2 , AlPO 4 , MgSO 4 , Ca(OH) 2 , Mg(OH) 2 , Al(OH) 3 , or Zn(OH) 2 .
- Either polymeric micelles or nanoparticles can be prepared by changing the number of equivalents of the metal ion added. Specifically, if a divalent metal ion is added at 0.5 equivalents or less with respect to the carboxyl terminal groups, the metal ion that can form bonds with the carboxyl terminal group of the polylactic acid derivative is insufficient; and thus, polymeric micelles are formed. If a divalent metal ion is added at 0.5 equivalents or more, the metal ion that can form bonds with the carboxyl terminal group of the polylactic acid derivative is sufficient to firmly fix the micelles; and thus, nanoparticles are formed.
- the drag release rate from the polymeric micelles or nanoparticles may be adjusted by changing the number of equivalents of the metal ion added. If the metal ion is present at 1 equivalent or less with respect to that of the carboxyl group of the polylactic acid derivative, the number available to bond to the carboxyl terminal group of the polylactic acid derivative is decreased, and so the drag release rate is increased. If the metal ion is present at 1 equivalent or more, the number available to bond to the carboxyl terminal group of the polylactic acid derivative is increased, and so the drug release rate is decreased. Therefore, to increase the drag release rate in the blood, the metal ion is used in a small equivalent amount, and to decrease the drag release rate, the metal ion is used in a large equivalent amount.
- the metal ion-fixed polymeric compositions of the present invention may contain 5 to 95wt% of the amphiphilic block copolymer, 5 to 95wt% of the polylactic acid derivative and 0.01 to 10 equivalents of the di- or tri-valent metal ion with respect to the number of equivalents of the carboxyl terminal groups of the polylactic acid derivatives.
- they contain 20 to 80wt% of the amphiphilic block copolymer, 20 to 80wt% of the polylactic acid derivative and 0.1 to 5 equivalents of the di- or tri-valent metal ion, and more preferably, 20 to 60wt% of the amphiphilic block copolymer, 40 to 80wt% of the polylactic acid derivative and 0.2 to 2 equivalents of the di- or tri-valent metal ion.
- the drug carrier of the present invention can be a polymeric micelle or a nanoparticle formed from polymeric compositions comprising an amphiphilic block copolymer which is comprised of a hydrophilic block and a hydrophobic block wherein said hydrophobic block has a terminal hydroxyl group that is substituted with a tocopherol or cholesterol group, and a polylactic acid derivative having at least one terminal carboxyl group at the end of the polymer.
- the nanoparticles or micelles of the present invention can be formed from polymeric compositions of an amphiphilic block copolymer comprised of a hydrophilic block and a hydrophobic block, wherein the hydrophobic block has a hydroxyl terminal group which is substituted with a tocopherol or cholesterol group, a polylactic acid derivative having at least one terminal carboxyl group at the end which is bound or fixed with a di- or tri-valent metal ion.
- the bioactive agents can be entrapped in the micelles or nanoparticles or they can be incorporated within the micelles or nanoparticles of the present invention by formation of a stable ionic complex with the carboxyl group of the biodegradable polylactic acid derivative according to the bioactive agents.
- the amphiphilic block copolymer, the polylactic acid derivative, and the poorly water-soluble drag at certain ratios can be dissolved in one or more mixed organic solvents selected from the group consisting of acetone, ethanol, methanol, ethyl acetate, acetonitrile, methylene chloride, chloroform, acetic acid and dioxane.
- the organic solvent can be removed therefrom to prepare a homogenous mixture of the poorly water-soluble drag and the polymer.
- the homogenous mixture of the poorly water-soluble drug and the polymeric composition of the present invention can be added to an aqueous solution with a pH of 4 to 8, at 0 to 80 °C, resulting in poorly water-soluble drag-containing mixed polymeric micelle aqueous solution.
- the above drug-containing polymeric micelle aqueous solution can then be lyophilized to prepare the polymeric micelle composition in the form of a solid.
- An aqueous solution containing 0.001 to 2 M of the di- or tri-valent metal ion is added to the poorly water-soluble drug-containing mixed polymeric micelle aqueous solution.
- the mixture is slowly stirred at room temperature for 0.1 to 1 hour and then lyophilized to prepare the metal ion-fixed polymeric micelle or nanoparticle composition in the form of a solid.
- the bioactive agent is entrapped in the drag carrier and is thereby solubilized.
- the metal ion-fixed polymeric micelles or nanoparticles are retained in the bloodstream for a long period of time and accumulate in the target lesions.
- the bioactive agent is released from the hydrophobic core of the micelles to exert a pharmacological effect while the micelles are degraded.
- the polymeric composition may be administered intravenously, intramuscularly, intraperitoneally, transnasally, intrarectally, intraocularly, or intrapulmonarily.
- the bioactive agent is mixed with the drag carrier of the present invention, and then administered in the form of a tablet, capsule, or aqueous solution.
- the polymeric composition of the invention may be administered with various ranges according to the requirements of the particular drag. As is well known in the medical arts, dosages for any one patient depends upon many factors, including the patient's weight, body surface area, age, the particular compound to be administered, sex, time and route of administration general health, and other drags being administered concurrently.
- Cellular internalization of a bioactive agent can be studied with flow cytometry and confocal microscopy using drag-containing compositions.
- human uterine cancer cell lines (MES-SA; MES-SA/Dx-5) and human breast cancer cell lines(MCF-7; MCF-7/ADR) were treated with the drug compositions of the present invention.
- Cell lines MES-SA and MCF-7 are doxorubicin-sensitive and cell lines MES-SA/Dx-5; MCF-7/ADR are doxorubicin-resistant. As shown in Figs.
- the drag enters more effectively into the cells from the drag composition of the present invention (Composition 1) than from the conventional solution formulation (Free-Dox).
- the number of cells which absorbed the drag was five times higher from the drag composition of the present invention than from the conventional solution formulation.
- the uptake of doxorabicin into cells is remarkable in the drag resistant cell line.
- the confocal images in Figs. 4 A to 4H visualize the flow cytometry results: much higher amounts of drug were absorbed by the cells when the drug composition of the present invention was treated. In Figs.
- the left side pictures are the confocal images after treatment with the conventional solution formulation and the images on the right side are after treatment with the compositions of the present invention.
- the micelles or nanoparticles were detected in the cytoplasmic and nuclear compartments.
- the MTT assay results shown in Figs. 5A to 5B and Table 3 support the results of the flow cytometry and confocal microscopy studies.
- composition 1 a doxorubicin-containing composition of the present invention (Composition 1) and a conventional doxorabicin formulation (Free-Dox) were tested on the human uterine cancer cell lines MES-SA (doxorubicin-sensitive cell line) and MES-SA/Dx-5 (doxorubicin- resistant cell line).
- MES-SA doxorubicin-sensitive cell line
- MES-SA/Dx-5 doxorubicin- resistant cell line
- the cytotoxic activity on the doxorubicin-sensitive cells was similar in both compositions as shown in Figs. 5 A, but the drug composition of the present invention showed 6.7 times higher activity at three days after treatment than the conventional solution formulation when treating the doxorubicin-resistant cells as shown in Fig. 5B.
- Fig 1 This cellular internalization process is schematically shown in Fig 1 : 1 represents a drag; 2 represents the inner core of a micelle or nanoparticle; 3 represents the outer shell of a micelle or nanoparticle; 4 represents the extracellular fluid; 5 represents the cell membrane; and represents the cytoplasm.
- a pharmacokinetic experiment was performed with Sprague-Dawley rats
- compositions of the present invention exhibited prolonged blood circulation time compared to the conventional doxorabicin formulation.
- the bioavailability calculated from the area under the blood concentration-time curve (AUC) for the composition 1 of the present invention was 63 times higher than that of conventional doxorabicin formulation.
- the drag carriers of the present invention can provide for a prolonged systemic circulation time due to their small size ( ⁇ 100nm), their hydrophilic shell which minimizes uptake by the MPS, and their high molecular weight which prevents renal excretion.
- the drag carriers of the present invention can be used as carriers for water-soluble drags, peptides and proteins as well as for poorly water-soluble drags.
- the bioactive agent-containing compositions of the present invention form such stable micelles or nanoparticles in aqueous media that they enter the cytoplasm in the form of micelles or nanoparticles by endocytosis without collapse of their structure.
- higher accumulation of a bioactive agent in tumor tissue can be achieved with the composition of the present invention.
- Preparation Example 1 Amphiphilic block copolymer of PEG and PLA (mPEG-PLA) A mixture of 20g of monomethoxy polyethyleneglycol (mPEG with a molecular weight of 2,000), 20g of D,L-lactide which was recrystallized from ethyl acetate, and 0.2g of stannous octoate which was dissolved in 5ml toluene were added to a reactor equipped with a mechanical stiner and a distillation set. Residual toluene was evaporated at 120 ° C. The reaction was carried out under vacuum (25mmHg).
- the resulting polymer was dissolved in dichloromethane and poured into cold diethyl ether (4 ° C) to precipitate the polymer.
- the precipitated polymer was washed twice with diethyl ether and dried under vacuum (O.lmmHg) for 24 hours.
- the molecular weight of the block copolymer determined by nuclear magnetic resonance (NMR) spectroscopy was 2,000-1,800 (2,000 for PEG block and 1,800 for PLA block).
- Preparation Example 3 Amphiphilic block copolymer of PEG and PCL (mPEG-PCL) A diblock copolymer (mPEG-PCL) was prepared by the same procedure described in Preparation Example 1, using 20g of ⁇ -caprolactone instead of D,L-lactide. The molecular weight of the block copolymer determined by NMR was 2,000-1,800 (2,000 for the PEG block and 1 ,800 for the PCL block).
- Preparation Example 4 Amphiphilic block copolymer of PEO and PLA (PLA-PEO-PLA) A triblock copolymer (PLA-PEO-PLA) was prepared by the same procedure described in Preparation Example 1, using 20g of polyethyleneglycol (PEG with a molecular weight of 2,000) instead of monomethoxy polyethyleneglycol (mPEG with a molecular weight of 2,000). The molecular weight of the block copolymer determined by
- NMR was 850-2,000-850 (2,000 for the PEO block and 900 for each PLA block).
- Tocopherol succinate A mixture of 8.6g of tocopherol, 2.4g of succinic anhydride and 2.9g of 4- (dimethylamino) pyridine (DMAP) were dissolved in 100 ml of 1,4-dioxane in a reactor equipped with a mechanical stirrer. The reaction was carried out at room temperature.
- DMAP 4- (dimethylamino) pyridine
- Preparation Example 7 Amphiphilic block copolymer having a tocopherol group at the end of the hydrophobic block (mPEG-PLA-Toco)
- mPEG-PLA-Toco hydrophobic block
- a mixture of 10.0 g (2.6mmole) of mPEG-PLA prepared from Preparation Example 1 and 1.7 g (3.2mmole) of tocopherol succinate prepared from Preparation Example 5 were dissolved in 50 ml of acetonitrile in a reactor equipped with a mechanical stirrer.
- 0.78g (3.8mmole) of dicyclohexylcarbodiimide (DCC) and 0.046 g (0.38mmole) of 4-(dimethylamino)pyridine (DMAP) were used as catalysts.
- the polymer product was then added to 0.1 liter of distilled water, and the pH of the aqueous solution was adjusted between 6 and 8 by the addition of sodium hydrogen carbonate portionwise thereto dissolving the polymer.
- the water-insoluble polymer was separated and removed by centrifugation or filtration.
- a 1 N hydrochloric acid solution was added dropwise thereto and the polymer was precipitated in the aqueous solution.
- the number average molecular weight of the polymer determined by NMR was 1,100.
- the resulting polymer was dissolved in acetone and an aqueous NaHCO 3 solution (0.2 N) was added dropwise thereto to precipitate the polymer.
- the precipitated polymer was washed three times with distilled water and dried under reduced pressure to give a white powder form of the polymer (3arm- PLA-OH).
- the molecular weight of the polymer determined by NMR spectroscopy was 3,050.
- the precipitated polymer was dissolved in an aqueous NaHCO 3 solution (0.2 N) at 60 °C, and aqueous HC1 solution (IN) was added dropwise thereto to precipitate the polymer.
- the precipitated polymer was washed three times with distilled water and dried under vacuum to give a white powder form of the polymer (3arm-PLA-COOH).
- the molecular weight of the polymer determined by NMR spectroscopy was 3,200.
- Example 1 Drug-containing composition (Composition 1 : Doxorubicin / mPEG-PLA-Toco / PLMA-COONa) lOmg of doxorabicin hydrochloride was dissolved in 5ml of ethanol-water (9:1 v/v) in a round-bottomed flask. 810mg of the amphiphilic block copolymer prepared from preparation example 7 (mPEG-PLA-Toco) and 180mg of the biodegradable polyester prepared from Preparation Example 12 (PLMA-COONa) are added thereto and completely dissolved giving clear solution. The solvent was evaporated at an elevated temperature (60 °C) under vacuum with a rotary evaporator.
- a 3ml aqueous solution of lactose (20% by weight) was added and the flask was rotated at 100 rpm at 60 °C with a rotary evaporator to form micelles or nanoparticles in the aqueous medium.
- the solution was filtered using 0.22 jura PVDF membrane filter.
- the filtered solution was freeze-dried and stored in a refrigerator until use. Particle size of the micelles or nanoparticles in the filtered solution was measured by a dynamic light scattering method (DLS, ZetaPlus, Brookhaven instruments Ltd.).
- the loading efficiency (wt.% of drag incorporated in the micelles or nanoparticles with respect to the initial drug used) was calculated from the doxorabicin content analyzed by HPLC using daunorabicin as the internal standard.
- the conditions for HPLC assay were as follows: Injection volume: 75 ⁇ t Flow rate: l.Oml/min Mobile phase: gradient increase of Solvent B from 15% to 85% for 40 minutes (Solvent A: 1% acetic acid; Solvent B: acetonitrile) Temperature: Room Temperature Column: C-18 (Vydac, multi-ring, pore size : 5 jum) Wavelength; 485nm And the particle size was measured according to a Dynamic Light Scattering (DLS) Method. The results are summarized in Table 1.
- Example 2 Drug-containing composition (Composition 2: Doxorubicin / mPEG-PLGA-Toco / PLMA-COONa)
- composition 2 Doxorubicin / mPEG-PLGA-Toco / PLMA-COONa
- composition 2 A drag-containing composition (composition 2) was prepared by the same procedure described in Example 1, using mPEG-PLGA-Toco prepared from Preparation Example 8 instead of mPEG-PLA-Toco. The results are summarized in Table 1.
- Example 3 Drug-containing composition (Composition 3: Doxorubicin / mPEG-PCL-Toco / 3arm-PLA-COOK)
- composition 3 A drug-containing composition (composition 3) was prepared by the same procedure described in Example 1, using mPEG-PCL-Toco prepared from Preparation Example 9 and 3arm-PLA-COOK prepared from Preparation Example 13 instead of mPEG-PLA-Toco and PLMA-COONa. The results are summarized in Table 1.
- Example 4 Drug-containing composition (Composition 4 : Doxorubicin / Toco-PLA-PEO-PLA-Toco / 4arm-PLA-COONa)
- a drag-containing composition (composition 4) was prepared by the same procedure described in Example 1, using Toco-PLA-PEO-PLA-Toco prepared from preparation example 10 and 4arm-PLA-COONa prepared from Preparation Example 14 instead of mPEG-PLA-Toco and PLMA-COONa. The results are summarized in Table 1.
- Example 5 Drug-containing composition (Composition 5: Doxorubicin / mPEG-PLA-Chol / PLMA-COONa)
- composition 5 A drug-containing composition (composition 5) was prepared by the same procedure described in Example 1, using mPEG-PLA-Chol prepared from preparation Example 11 instead of mPEG-PLA-Toco.
- Example 6 Drug-containing composition (Composition 6: Epirubicin / mPEG-PLA-Toco / PLMA-COONa)
- composition 6 was prepared by the same procedure described in Example 1, using epirubicin instead of doxorabicin. The results are summarized in Table 1.
- Example 7 Drug-containing composition (Composition 7: Ca 2+ -fixed Paclitaxel / mPEG-PLA-Toco / PLA-COONa) (1) Preparation of paclitaxel-containing aqueous solution A mixture of 248.1 g PLA-COONa prepared from Preparation Example 15, 7.5 mg of paclitaxel, and 744.3 mg of mPEG-PLA-Toco prepared from Preparation Example 7 were completely dissolved in 5 ml of ethanol to obtain a clear solution. Ethanol was removed therefrom to prepare a paclitaxel-containing polymeric composition. Distilled water(6.2 ml) was added thereto and the mixture was stirred for 30 minutes at 60 °C to prepare the paclitaxel-containing aqueous solution.
- Composition 7 Ca 2+ -fixed Paclitaxel / mPEG-PLA-Toco / PLA-COONa
- Example 8 Drug-containing composition (Composition 8: Mg 2+ -f ⁇ xed Paclitaxel / mPEG-PLGA-Toco / PLMA-COONa)
- Composition 8 Mg 2+ -fixed paclitaxel-containing composition was prepared by the same procedure described in Example 7 except that 248.
- Img of PLMA-COONa (Mn: 1,096) of Preparation Example 12 7.5 mg of paclitaxel, 744.3 mg of mPEG-PLGA-Toco of preparation Example 8 and 0.230 ml (0.113 mmol) of a 0.5M aqueous solution of magnesium chloride 6 hydrate (Mw:203.31) were used .
- the results are summarized in Table 1.
- Example 9 Drug-containing composition (Composition 9: Ca 2+ -f ⁇ xed Paclitaxel / mPEG-PLA-Toco / PLMA-COONa)
- Composition 9 Ca 2+ -f ⁇ xed Paclitaxel / mPEG-PLA-Toco / PLMA-COONa
- a Cg 2+ -fixed paclitaxel-containing composition was prepared by the same procedure described in Example 7 except that 248.
- Img of PLMA-COONa of Preparation Example 12 7.5 mg of paclitaxel, 744.4 mg of mPEG-PLA-Toco of Preparation Example 7 and 0.230 ml (0.113 mmol) of a 0.9 M aqueous solution of anhydrous calcium chloride were used.
- Table 1 The results are summarized in Table 1.
- Example 10 Drug-containing composition (Composition 10: Ca 2+ -f ⁇ xed Paclitaxel / mPEG-PLA-Chol / PLMA-COONa)
- Composition 10 Ca 2+ -f ⁇ xed Paclitaxel / mPEG-PLA-Chol / PLMA-COONa
- a Ca 2+ -fixed paclitaxel-containing composition was prepared by the same procedure described in Example 7 except that 248. Img of PLMA-COONa of Preparation Example 12, 7.5 mg of paclitaxel, 744.4 mg of mPEG-PLA-Chol of Preparation Example 11 and 0.230 ml (0.113 mmol) of a 0.9 M aqueous solution of anhydrous calcium chloride were used. The results are summarized in Table 1.
- Example 11 Evaluation of the intracellular uptake of a drug: Flow cytometry To evaluate the intracellular uptake of a bioactive agent, the doxorubicin- containing composition of the present invention (Composition 1 in example 1) and the conventional doxorabicin formulation (aqueous solution of doxorabicin hydrochloride, Free-Dox) were tested on the human uterine cancer cell lines, MES-SA (doxorubicin- sensitive cell line) and MES-SA/Dx-5 (doxorubicin-resistant cell line). The flow cytometry study was performed with the FACStarPlus (Becton Dickinson) according to the method of Walker et al. (Experimental Cell Research 207: 142(1993)).
- MES-SA doxorubicin- sensitive cell line
- MES-SA/Dx-5 doxorubicin-resistant cell line
- Example 12A Confocal microscopy: doxorubicin-containing composition in MES-SA cells
- the doxorubicin- containing composition of the present invention Composition 1 in Example 1
- the conventional doxorabicin formulation aqueous solution of doxorabicin hydrochloride, Free-Dox
- MES-SA doxorubicin- sensitive cell line
- MES-SA/Dx-5 doxorubicin-resistant cell line
- Figs. 4Ato 4D the left side pictures are the confocal images after treatment with the conventional solution formulation and the images on the right side are after treatment with the compositions of the present invention. And as shown in Figs. 4B and 4D, the micelles or nanoparticles were detected in the cytoplasmic and nuclear compartments.
- Example 12B Confocal microscopy: epirubicin-containing composition in MCF-7 cells
- an epirubicin-containing composition of the present invention Composition 6 in Example 6
- the conventional epirubicin formulation aqueous solution of epirubicin hydrochloride
- Figs. 4E to 4H The confocal images were obtained by the same procedure described in example 12A, using RPMI medium (Invitrogen Corp.) instead of McCoy's 5 A medium, and the results are shown in Figs. 4E to 4H.
- the confocal images in Figs. 4E to 4H visualize the flow cytometry results: much higher amounts of epirubicin were absorbed by the cells when the epirubicin containing composition of the present invention was treated, h Figs. 4E to 4H, the left side pictures are the confocal images after treatment with the conventional solution formulation and the images on the right side are after treatment with the compositions of the present invention.
- Example 13 In vitro cytotoxicity
- the doxorubicin-containing composition of the present invention Composition 1 in Example 1, Doxo-PNP
- the conventional doxorabicin formulation aqueous solution of doxorabicin hydrochloride, Free-Dox
- MES-SA doxorubicin-sensitive cell line
- MES-SA/Dx-5 doxorubicin-resistant cell line
- the MTT-formazan is produced from reduction of MTT-tetrazolium by enzymes present in living cells only(dead cells cannot reduce the MTT-tetrazolium to MTT-formazan).
- the fluorescence of the MTT-formazan is detected by a fluorescence reader and the optical density correlates with the number of cells. This procedure is automatized, and the cell viability and IC 50 (50% inhibitory concentration of cell growth) values are calculated by the software installed in the microplate reader.
- the cytotoxic activity of each composition was evaluated in both human tumor cell lines at five ten-fold dilutions ranging from 0.01 to 100 /zg/ml.
- MTT methylthiazoletetrazolium
- cells were harvested from an exponential phase culture growing in McCoy's 5A medium (Invitrogen Corp.) supplemented with 10% fetal bovine serum and 1% penicillin streptomycin, counted and plated in 96 well flat-bottomed microtiter plates (100 cell suspension, 5 x 10 4 cells/ml for each cell line). After a 24h recovery to allow the cells to resume exponential growth, a culture medium (24 control wells per plate) or culture medium containing drag was added to the wells. Each drag concentration was plated in triplicate. Following 3 days of continuous drug exposure, the cells were treated with 25 ⁇ of a MTT solution in sterile water (2mg/ml).
- the drag composition of the present invention showed 6.7 times higher activity at three days after treatment than the conventional solution formulation when treating the doxorubicin-resistant cells as shown in Fig. 5B.
- This difference in activity is due to the characteristics of the drag-resistant cell lines in which the P-glycoproteins (P-gp) are overexpressed and they continuously extrude the cytotoxic drags from the cell. Since free drag cannot be concentrated within the drag- resistant cells, this result implies that the drag carrier of the present invention enters together the cell with the drag incorporated in the drug carrier.
- Example 14 Pharmacokinetics in rats The drag concentrations in blood plasma were measured after intravenous administration of the doxorubicin-containing compositions in the present invention
- compositions 1 to 5 in examples 1 to 5 (Compositions 1 to 5 in examples 1 to 5) and the conventional doxorabicin formulation
- the rats (5 rats for each formulation) were injected intravenously through the tail vein at a dose of 5mg/kg.
- the blood samples were collected from the tail vein at 1, 5, 15, 30 minutes and 1, 2, 4, 8, and 24 hours after the drag injection.
- the blood samples were immediately centrifuged, and the plasma was separated.
- the plasma samples were stored at -50 ° C until analysis.
- Doxorubicin was analyzed by HPLC assay described in example 1.
- the blood concentration-time curve(C-t curve) is shown in Fig. 6, and the area under the blood concentration-time curve (AUC) was calculated using the linear trapezoidal rale.
- Table 4 Pharmacokinetics in Rats
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Abstract
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Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2007511292A JP4885846B2 (en) | 2004-05-06 | 2005-05-06 | Intracellular delivery system of bioactive agents based on polymeric drug carriers containing amphiphilic block copolymers and polylactic acid derivatives |
AT05739818T ATE531391T1 (en) | 2004-05-06 | 2005-05-06 | DELIVERY SYSTEM FOR BIOLOGICALLY ACTIVE AGENTS BASED ON A POLYMERIC DRUG CARRIER WITH AN AMPIPHILIC BLOCK POLYMER AND A POLYLACTIC ACID DERIVATIVE |
MXPA06012431A MXPA06012431A (en) | 2004-05-06 | 2005-05-06 | Delivery system for bioactive agents on the basis of a polymeric drug carrier comprising an amphiphilic block polymer and a polylacticacid derivative. |
CA2564719A CA2564719C (en) | 2004-05-06 | 2005-05-06 | Delivery system for bioactive agents on the basis of a polymeric drug carrier comprising an amphiphilic block polymer and a polylactic acid derivative |
US11/568,313 US20080260850A1 (en) | 2004-05-06 | 2005-05-06 | Delivery System For Bioactive Agents on the Basis of a Polymeric Drug Carrier Comprising an Amphiphilic Block Polymer and a Polylacticacid Derivative |
ES05739818T ES2375715T3 (en) | 2004-05-06 | 2005-05-06 | RELEASE SYSTEM FOR BIOACTIVE AGENTS ON THE BASIS OF A POLYMERIC CARRIER OF FÉ? RMACOS THAT INCLUDES A POLYMER OF BLOCK ANFÉ? FILO AND A POLY DERIVATIVE (�? CIDO L�? CTICO). |
AU2005239948A AU2005239948B9 (en) | 2004-05-06 | 2005-05-06 | Delivery system for bioactive agents on the basis of a polymeric drug carrier comprising an amphiphilic block polymer and a polylacticacid derivative |
NZ550856A NZ550856A (en) | 2004-05-06 | 2005-05-06 | Delivery system for bioactive agents on the basis of a polymeric drug carrier comprising an amphiphilic block polymer and a polylactic acid derivative |
EP05739818A EP1742665B1 (en) | 2004-05-06 | 2005-05-06 | Delivery system for bioactive agents on the basis of a polymeric drug carrier comprising an amphiphilic block polymer and a polylacticacid derivative |
CN200580018124.1A CN1964744B (en) | 2004-05-06 | 2005-05-06 | Delivery system for bioactive agents on the basis of a polymeric drug carrier comprising an amphiphilic block polymer and a polylacticacid derivative |
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US (1) | US20080260850A1 (en) |
EP (1) | EP1742665B1 (en) |
JP (1) | JP4885846B2 (en) |
KR (1) | KR100829799B1 (en) |
CN (1) | CN1964744B (en) |
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CA (1) | CA2564719C (en) |
ES (1) | ES2375715T3 (en) |
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2005
- 2005-05-06 AT AT05739818T patent/ATE531391T1/en active
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- 2005-05-06 CA CA2564719A patent/CA2564719C/en active Active
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- 2005-05-06 AU AU2005239948A patent/AU2005239948B9/en not_active Ceased
- 2005-05-06 US US11/568,313 patent/US20080260850A1/en not_active Abandoned
- 2005-05-06 ES ES05739818T patent/ES2375715T3/en active Active
- 2005-05-06 WO PCT/KR2005/001330 patent/WO2005107813A1/en active Application Filing
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WO2003059382A2 (en) * | 2001-12-28 | 2003-07-24 | Supratek Pharma Inc. | Pharmaceutical compositions comprising polyanionic polymers and amphiphilic block copolymers and methods of use thereof to improve gene expression |
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Also Published As
Publication number | Publication date |
---|---|
ATE531391T1 (en) | 2011-11-15 |
CN1964744A (en) | 2007-05-16 |
AU2005239948A1 (en) | 2005-11-17 |
CA2564719C (en) | 2011-11-01 |
EP1742665A1 (en) | 2007-01-17 |
ES2375715T3 (en) | 2012-03-05 |
KR100829799B1 (en) | 2008-05-16 |
JP2007536219A (en) | 2007-12-13 |
CA2564719A1 (en) | 2005-11-17 |
US20080260850A1 (en) | 2008-10-23 |
EP1742665B1 (en) | 2011-11-02 |
AU2005239948B2 (en) | 2008-09-18 |
JP4885846B2 (en) | 2012-02-29 |
KR20070002063A (en) | 2007-01-04 |
MXPA06012431A (en) | 2007-01-17 |
NZ550856A (en) | 2010-11-26 |
CN1964744B (en) | 2015-06-17 |
AU2005239948B9 (en) | 2009-04-23 |
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