WO2020063419A1 - 一种聚酯-聚酯型生物可降解两亲性嵌段共聚物、其制备方法及应用 - Google Patents

一种聚酯-聚酯型生物可降解两亲性嵌段共聚物、其制备方法及应用 Download PDF

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WO2020063419A1
WO2020063419A1 PCT/CN2019/106417 CN2019106417W WO2020063419A1 WO 2020063419 A1 WO2020063419 A1 WO 2020063419A1 CN 2019106417 W CN2019106417 W CN 2019106417W WO 2020063419 A1 WO2020063419 A1 WO 2020063419A1
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segment
monomer
drug
copolymer
caprolactone
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French (fr)
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赵书强
于文占
魏明星
周思祥
袁峰泉
潘缘媛
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银谷制药有限责任公司
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • 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
    • C08G63/68—Polyesters containing atoms other than carbon, hydrogen and oxygen
    • C08G63/688—Polyesters containing atoms other than carbon, hydrogen and oxygen containing sulfur
    • C08G63/6882—Polyesters containing atoms other than carbon, hydrogen and oxygen containing sulfur derived from hydroxy carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • 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
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
    • C08G63/08—Lactones or lactides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • 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
    • C08G63/68—Polyesters containing atoms other than carbon, hydrogen and oxygen
    • C08G63/688—Polyesters containing atoms other than carbon, hydrogen and oxygen containing sulfur

Definitions

  • the invention relates to the technical field of polymer materials and medicine, in particular to a polyester-polyester type biodegradable amphiphilic block copolymer, a preparation method thereof and application thereof.
  • Block copolymers are polymers composed of different segments combined in a certain order.
  • amphiphilic block copolymers due to their hydrophilic and hydrophobic segments, they can pass through in a specific solution. Assemble to form polymer micelles.
  • amphiphilic block copolymers can form "normal phase” micelles with a hydrophilic segment as a shell and a hydrophobic segment as a core in water, and can form a hydrophobic segment with a shell and a hydrophilic segment in an organic solvent.
  • Nuclear "inverted" micelles In the application of normal phase micelles, one can embed a hydrophobic drug at the hydrophobic end, while the hydrophilic end is outside, which can greatly increase the water solubility of the hydrophobic drug.
  • Nano drug-loaded micelles formed by amphiphilic block copolymers can reduce or avoid recognition and elimination by the reticuloendothelial system, extend circulation in the blood, and enrich at the lesion site through the EPR effect to achieve targeting .
  • amphiphilic block copolymers commonly used are mostly polyethylene glycol (PEG) or polyethylene glycol monomethyl ether (MPEG) as the hydrophilic segment, and polylactic acid, polycaprolactone, etc. as the hydrophobic segment. Diblock, triblock, and multiblock copolymers.
  • Polyethylene glycol (PEG) and polyethylene glycol monomethyl ether (MPEG) have excellent hydrophilicity, biocompatibility and bio-inertness, and have no immunogenicity. They have been widely used as important medical auxiliary materials in biology.
  • PEG is bonded to drug molecules to form long-cycle polymer drug formulations, combined with biodegradable polymers to form diblock and triblock copolymers, or self-assembled in solution to form micelles and temperature-sensitive gels , For the solubilization and slow release of drugs.
  • PEG is non-biodegradable. Polyethylene glycol with a lower degree of polymerization can be excreted through the kidney pathway. The clearance rate of polyethylene with a higher degree of polymerization is significantly reduced through the kidney and will accumulate in the human body. Therefore, PEGs with a molecular weight range of 400Da-20kDa (some literatures claim that PEGs below 400Da are more toxic) are currently used, which limits the application of PEG.
  • anti-PEG antibodies have been produced in about 25% of the human body.
  • Multiple administrations of PEG-containing drugs may also cause patients to produce anti-PEG antibodies, which limits the use of PEG polymers in clinical medicine.
  • the inventors of the present application use modification of certain ring-opening polymerizable cyclic monomers to introduce hydrophilic groups to them, so that the modified cyclic monomers undergo polymer ring-opening polymerization It is hydrophilic; because the cyclic monomer used is an FDA-approved biodegradable polymer monomer, the hydrophilic segment is also biodegradable, and has an alternative advantage over PEG.
  • Modified cyclic monomers are copolymerized with other biodegradable polymer blocks to form biodegradable amphiphilic block copolymers, which can self-assemble into nanomicelles in aqueous solutions with extremely low critical micelle concentration
  • the nano-micelle has a uniform particle size and good stability, and has potential application prospects in the fields of biomedicine and medical diagnosis.
  • the present application provides a triblock copolymer comprising a hydrophilic segment A and a hydrophobic segment B.
  • the general formula of the triblock copolymer is ABA or BAB, and the hydrophilic segment A is a homogeneous segment.
  • Polymer segment, the hydrophobic segment B is a homopolymer segment or a copolymer segment (eg, a random copolymer segment);
  • the formula of the monomer of the hydrophilic segment A is MX- (CH 2 -CH 2 -O) k -CH 3 , where M is a cyclic monomer, and the cyclic monomer is selected from glycolide Lactide Trimethylene carbonate P-dioxane ⁇ -caprolactone ⁇ -valerolactone ⁇ -caprolactone and ⁇ -valerolactone are preferred;
  • the monomer of the hydrophobic segment B is selected from glycolide Lactide Trimethylene carbonate P-dioxane ⁇ -caprolactone ⁇ -valerolactone One or more of them, preferably ⁇ -caprolactone and / or ⁇ -valerolactone;
  • X is selected from: amido (-CO-NH-), ether (-O-), thioether (-S-), sulfone (-SO 2- ), sulfoxide (-SO-), carbonyl (-CO-); preferably sulfone (-SO 2- ); optionally, X and M are connected via a methylene group;
  • k is selected from 1, 2, 3, 4, 5 and preferably 2 or 3.
  • the monomer of the hydrophilic segment A has the general formula M-CH 2 -X- (CH 2 -CH 2 -O) k -CH 3 , wherein M is ⁇ -caprolactone or ⁇ -valerolactone, X is sulfone (-SO 2- ), and k is 2 or 3; in some embodiments, the monomer of the hydrophobic segment B is ⁇ -caprolactone and / or ⁇ -pentyl Lactone.
  • the monomer forming the hydrophilic segment A is selected from:
  • the monomer forming the hydrophilic segment A is the following monomers a1 or a2:
  • the monomer forming the hydrophilic segment A is monomer a1 or a2
  • the monomer forming the hydrophobic segment B is ⁇ -caprolactone
  • the molecular weight of the segment is not particularly limited.
  • the number average molecular weight of segment A and segment B is independently selected from 1 to 100 kDa, such as 1 to 5 kDa, 5 to 10 kDa, 10 to 20 kDa, 20 to 30 kDa, 30 to 40 kDa, 40 to 50 kDa , 50-60 kDa, 60-70 kDa, 70-80 kDa, 80-90 kDa, or 90-100 kDa.
  • the general formula of the triblock copolymer is A-B-A
  • the molecular weights of the two hydrophilic segments A may be the same or different.
  • the general formula of the triblock copolymer is B-A-B
  • the molecular weights of the two hydrophobic segments B may be the same or different.
  • the degree of polymerization of segment A is independently 5 to 50 (eg, 5 to 10 (eg, 5, 6, 7, 8, 9, or 10), 10 to 20, 20 to 30, 30 to 40 Or 40 to 50), the degree of polymerization of the segment B is independently 10 to 60 (for example, 10 to 15 (for example, 10, 11, 12, 13, 14 or 15), 15 to 20, 20 to 30, 30 to 40, 40-50 or 50-60).
  • the triblock copolymer has the general formula A-B-A
  • the polymerization degrees of the two hydrophilic sections A may be the same or different.
  • the general formula of the triblock copolymer is B-A-B
  • the polymerization degrees of the two hydrophobic segments B may be the same or different.
  • the triblock copolymer of the present invention may further include an initiator residue in its structure, such as benzyl, n-dodecyl, CH 3 O- (CH 2 CH 2 O) 2 -CH 2 CH 2- , or CH 3 O-CH 2 CH 2 O-CH 2 CH 2- .
  • the initiator residue is CH 3 O-CH 2 CH 2 O-CH 2 CH 2 -.
  • the present application also provides a diblock copolymer having the following general formula: AB, where A is a hydrophilic segment, B is a hydrophobic segment, and the hydrophilic segment A is a homopolymer segment,
  • the hydrophobic segment B is a homopolymer segment or a copolymer segment (for example, a random copolymer segment);
  • the monomer of the hydrophilic segment A has a general formula of MX- (CH 2 -CH 2 -O) k -CH 3 , where M is a cyclic monomer selected from the group consisting of glycolide Lactide Trimethylene carbonate P-dioxane ⁇ -caprolactone Preferably ⁇ -caprolactone;
  • the monomer of the hydrophobic segment B is selected from glycolide Lactide Trimethylene carbonate P-dioxane ⁇ -caprolactone ⁇ -valerolactone One or more of them, preferably ⁇ -caprolactone and / or ⁇ -valerolactone;
  • X is selected from: amido (-CO-NH-), ether (-O-), thioether (-S-), sulfone (-SO 2- ), sulfoxide (-SO-), carbonyl (-CO-); preferably sulfone (-SO 2- ); optionally, X and M are connected via a methylene group;
  • k is selected from 1, 2, 3, 4, 5 and preferably 2 or 3.
  • the monomer of the hydrophilic segment A has a general formula of M-CH 2 -X- (CH 2 -CH 2 -O) k -CH 3 , wherein M is ⁇ -caprolactone, X is a sulfone group (-SO 2- ), and k is 2 or 3; in some embodiments, the monomer forming the hydrophilic segment A is the monomer a2; in some embodiments, the hydrophobic segment B The monomers are ⁇ -caprolactone and / or ⁇ -valerolactone.
  • the monomer forming the hydrophilic segment A is selected from:
  • the molecular weight of the segment is not particularly limited.
  • the number average molecular weight of segment A and segment B is independently selected from 1 to 100 kDa, such as 1 to 5 kDa, 5 to 10 kDa, 10 to 20 kDa, 20 to 30 kDa, 30 to 40 kDa, 40 to 50 kDa , 50-60 kDa, 60-70 kDa, 70-80 kDa, 80-90 kDa, or 90-100 kDa.
  • the degree of polymerization of segment A is 5 to 50 (eg, 5 to 10 (eg, 5, 6, 7, 8, 9, or 10), 10 to 20, 20 to 30, 30 to 40, or 40 ⁇ 50), the degree of polymerization of segment B is 10 to 60 (for example, 10 to 15 (for example, 10, 11, 12, 13, 14 or 15), 15 to 20, 20 to 30, 30 to 40, 40 to 50, or 50-60).
  • the diblock copolymer of the present invention may further include an initiator residue in its structure, such as benzyl, n-dodecyl, CH 3 O- (CH 2 CH 2 O) 2 -CH 2 CH 2- , or CH 3 O-CH 2 CH 2 O-CH 2 CH 2- .
  • the initiator residue is CH 3 O-CH 2 CH 2 O-CH 2 CH 2 -.
  • the present application also provides a diblock copolymer having the following general formula: AB, where A is a hydrophilic segment, B is a hydrophobic segment, and the hydrophilic segment A is a homopolymer segment,
  • the hydrophobic segment B is a homopolymer segment or a copolymer segment (for example, a random copolymer segment);
  • the monomer of the hydrophilic segment A has the following general formula: MX- (CH 2 -CH 2 -O ) k -CH 3 , where M is ⁇ -valerolactone X is selected from: amido (-CO-NH-), ether (-O-), thioether (-S-), sulfone (-SO 2- ), sulfoxide (-SO-), carbonyl (-CO-), preferably sulfone (-SO 2- ); k is selected from 1, 2, 3, 4, 5, preferably 2 or 3; optionally, X and M are connected through a methylene group;
  • the monomer of the hydrophobic segment B is selected from: trimethylene carbonate P-dioxane ⁇ -valerolactone One or more of them.
  • the molecular weight of the segment is not particularly limited.
  • the number average molecular weight of segment A and segment B is independently selected from 1 to 100 kDa, such as 1 to 5 kDa, 5 to 10 kDa, 10 to 20 kDa, 20 to 30 kDa, 30 to 40 kDa, 40 to 50 kDa , 50-60 kDa, 60-70 kDa, 70-80 kDa, 80-90 kDa, or 90-100 kDa.
  • the degree of polymerization of segment A is 5 to 50 (eg, 5 to 10 (eg, 5, 6, 7, 8, 9, or 10), 10 to 20, 20 to 30, 30 to 40, or 40 ⁇ 50), the degree of polymerization of segment B is 10 to 60 (for example, 10 to 15 (for example, 10, 11, 12, 13, 14 or 15), 15 to 20, 20 to 30, 30 to 40, 40 to 50, or 50-60).
  • the diblock copolymer of the present invention may further include an initiator residue in its structure, such as benzyl, n-dodecyl, CH 3 O- (CH 2 CH 2 O) 2 -CH 2 CH 2- , or CH 3 O-CH 2 CH 2 O-CH 2 CH 2- .
  • the initiator residue is CH 3 O-CH 2 CH 2 O-CH 2 CH 2 -.
  • the block copolymer of the present invention includes, but is not limited to, a triblock copolymer or a diblock copolymer having the following structure:
  • X is a sulfone group (-SO 2- );
  • k 3;
  • R is CH 3 O- (CH 2 CH 2 O) 2 -CH 2 CH 2- ;
  • n is 5 to 50 (for example, 5 to 10 (for example, 5, 6, 7, 8, 9, or 10), 10 to 20, 20 to 30, 30 to 40, or 40 to 50); n is 10 to 60 (for example, 10 -15 (for example, 10, 11, 12, 13, 14 or 15), 15-20, 20-30, 30-40, 40-50, or 50-60; m 'is 5-50 (for example, 5-10 ( For example, 5, 6, 7, 8, 9 or 10), 10-20, 20-30, 30-40, or 40-50).
  • the triblock copolymer of the present invention has a structural formula:
  • X is a sulfone group (-SO 2- );
  • k is 3;
  • R is CH 3 O- (CH 2 CH 2 O) 2 -CH 2 CH 2- ;
  • m is 5-10;
  • n is 10-15;
  • m ' is 5-10.
  • the triblock copolymer of the present invention has a structural formula:
  • X is a sulfone group (-SO 2- );
  • k is 3;
  • R is CH 3 O- (CH 2 CH 2 O) 2 -CH 2 CH 2- ;
  • m is 5-10;
  • n is 10-15;
  • m ' is 5-10.
  • the general formula of the block copolymer indicates the composition of the block copolymer, and does not limit the manner or sequence in which the segments in the block copolymer are formed.
  • the block copolymer AB can be formed by first forming the segment A, and then using the segment A as a macro initiator to initiate the polymerization of the monomers of the segment B to form the segment B, thereby obtaining the block copolymer AB; It is also possible to form the segment B first, and then use the segment B as a macroinitiator to initiate the polymerization of the monomer of the segment A to form the segment A, thereby obtaining the block copolymer AB; in addition, such a formation method is not excluded That is, the segment A and the segment B are respectively formed, and the segment A and the segment B are connected by an appropriate chemical reaction to obtain a block copolymer AB.
  • the molecular weight of a polymer is a statistical average value, and its value may vary according to different measurement methods.
  • Methods for determining the molecular weight of polymers include, but are not limited to, gel permeation chromatography (GPC).
  • the degree of polymerization of the polymer can be estimated or binding segment H NMR (1 HNMR) the molecular weight measured by GPC.
  • the present application also provides a method for preparing a block copolymer having the general formula A-B or A-B-A.
  • the method includes the following steps:
  • Step 1 Provide a monomer of the hydrophilic segment A and perform ring-opening polymerization to obtain the hydrophilic segment A;
  • Step 2 Use the hydrophilic segment A as a macromolecular initiator to initiate the ring-opening polymerization of the monomers in the hydrophobic segment B to obtain a block copolymer A-B;
  • the method further includes step 3: using the block copolymer A-B as a macro-initiator, initiating the monomer of the hydrophilic segment A, and performing ring-opening polymerization to obtain the block copolymer A-B-A.
  • the present application also provides a method for preparing a block copolymer having the general formula A-B or B-A-B.
  • the method includes the following steps:
  • Step 1 ' Provide a monomer of the hydrophobic segment B and perform ring-opening polymerization to obtain the hydrophobic segment B;
  • Step 2 ' Use the hydrophobic segment B as a macromolecular initiator to initiate the ring-opening polymerization of the monomers in the hydrophilic segment A to obtain a block copolymer A-B;
  • the method further includes step 3 ': the block copolymer A-B is used as a macromolecular initiator to initiate the monomer of the hydrophobic segment B, and ring-opening polymerization is performed to obtain the block copolymer B-A-B.
  • the ring-opening polymerization in steps 1, 2, 3, 1 ', 2', or 3 ' is independently performed in the presence of an initiator and / or a catalyst.
  • the initiators in steps 1, 2, 3, 1 ', 2', or 3 ' are each independently selected from benzyl alcohol, n-dodecanol, triethylene glycol monomethyl ether, and diamine.
  • benzyl alcohol n-dodecanol
  • triethylene glycol monomethyl ether triethylene glycol monomethyl ether
  • diamine diamine
  • the catalysts in steps 1, 2, 3, 1 ', 2', or 3 ' are each independently selected from 1,5,7-triazabicyclo [4.4.0] dec- 5-ene (TBD), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), diphenyl phosphate, methanesulfonic acid, 4-dimethylaminopyridine (DMAP) Or one or more of an organoaluminum compound, a tin-based compound, and a rare earth compound.
  • the method has one or more of the following characteristics:
  • step 1, 2, 3, 1 ', 2', or 3 ' is independently performed for 2 to 48 hours or 24 to 240 hours;
  • each of the ring-opening polymerizations is terminated using a quencher independently; preferably, the quencher is selected from triethylamine, pyridine, and basic alumina;
  • step 2 ', 3, or 3' is purified (e.g., by dialysis).
  • the method is used to prepare a diblock copolymer A-B, which includes the following steps:
  • the initiator is one of benzyl alcohol, n-dodecanol, triethylene glycol monomethyl ether, and diethylene glycol monomethyl ether;
  • the catalyst is 1,5,7-triazabicyclo [4.4.0] dec-5-ene (TBD), 1,8-diazabicyclo [5.4.0] undec- At least one of 7-ene (DBU), diphenyl phosphate, methanesulfonic acid, 4-dimethylaminopyridine (DMAP), an organoaluminum compound, a tin-based compound, a rare earth compound, and the like.
  • step (2) adding the monomer of hydrophobic segment B to the polyester obtained in step (1), after removing water and oxygen, the environment of inert gas (such as nitrogen or argon) is under the action of catalyst at 20-200 ° C, The ring-opening polymerization was performed for 2 to 48 hours to obtain a block copolymer AB.
  • inert gas such as nitrogen or argon
  • step (3) adding an alkaline quencher to the polymerization bottle of step (2) to quench the reaction, dissolving the reactants in the polymerization bottle with an organic solvent, transferring to a pear-shaped bottle, and rotary evaporation;
  • the basic quencher is at least one of triethylamine, pyridine, basic alumina, and the like;
  • the organic solvent is at least one of methanol, ethanol, tert-butanol, ethyl acetate, dichloromethane, chloroform, acetone, acetonitrile, tetrahydrofuran, and the like.
  • step (3) (4) adding a solvent to the polymer after the spin-dissolving in step (3), dissolving it, transferring it to a dialysis bag for dialysis;
  • the solvent is at least one of water, methanol, ethanol, tert-butanol, ethyl acetate, dichloromethane, chloroform, acetone, acetonitrile, and the like, and tetrahydrofuran;
  • the dialysis bag has a molecular weight cut-off of 1-5 kDa.
  • step (4) The polymer solution in the dialysis bag obtained in step (4) is lyophilized, and the lyophilization time is 24 to 96 hours.
  • the method is used to prepare a triblock copolymer A-B-A, and the method includes the following steps:
  • the initiator is one of benzyl alcohol, n-dodecanol, triethylene glycol monomethyl ether, and diethylene glycol monomethyl ether;
  • the catalyst is 1,5,7-triazabicyclo [4.4.0] dec-5-ene (TBD), 1,8-diazabicyclo [5.4.0] undecyl- At least one of 7-ene (DBU), diphenyl phosphate, methanesulfonic acid, 4-dimethylaminopyridine (DMAP) or an organoaluminum compound, a tin-based compound, a rare earth compound, and the like;
  • step (2) adding the monomer of hydrophobic segment B to the polyester obtained in step (1), after removing water and oxygen, the environment of inert gas (such as nitrogen or argon) is under the action of catalyst at 20-200 ° C, Ring-opening polymerization for 2 to 48 hours to obtain a diblock copolymer;
  • inert gas such as nitrogen or argon
  • step (3) Add the monomer of hydrophilic section A to the diblock copolymer obtained in step (2). After removing water and oxygen, the environment of inert gas (such as nitrogen or argon) is opened at 20 ⁇ 200 °C. Ring polymerization for 2 to 48 hours to obtain triblock copolymer ABA;
  • inert gas such as nitrogen or argon
  • step (3) (4) adding an alkaline quencher to the polymerization bottle of step (3) to quench the reaction, dissolving the reactants in the polymerization bottle with an organic solvent, transferring to a pear-shaped bottle, and rotary evaporation;
  • the basic quencher is at least one of triethylamine, pyridine, basic alumina, and the like;
  • the organic solvent is at least one of methanol, ethanol, tert-butanol, ethyl acetate, dichloromethane, chloroform, acetone, acetonitrile, tetrahydrofuran, and the like.
  • step (4) adding a solvent to the polymer after spin-dissolving in step (4), dissolving it, transferring it to a dialysis bag for dialysis;
  • the solvent is at least one of water, methanol, ethanol, tert-butanol, ethyl acetate, dichloromethane, chloroform, acetone, acetonitrile, and the like, and tetrahydrofuran;
  • the dialysis bag has a molecular weight cut-off of 1-5 kDa.
  • step (5) The polymer solution in the dialysis bag obtained in step (5) is lyophilized, and the lyophilization time is 24 to 96 hours.
  • the present application also provides a micelle comprising a triblock copolymer and / or a diblock copolymer of the present invention.
  • the particle size of the micelles is 20 to 100 nm, such as 20 to 30 nm, 30 to 40 nm, 40 to 50 nm, 50 to 60 nm, 60 to 70 nm, 70 to 80 nm, 80 to 90 nm, or 90 to 100nm.
  • the application also provides a drug-loaded micelle comprising one or more drugs, and a triblock copolymer and / or a diblock copolymer of the present invention.
  • the particle size of the drug-loaded micelles is 20 to 100 nm, such as 20 to 30 nm, 30 to 40 nm, 40 to 50 nm, 50 to 60 nm, 60 to 70 nm, 70 to 80 nm, 80 to 90 nm, or 90 ⁇ 100nm.
  • the drug is an anti-tumor drug, such as doxorubicin, epirubicin, pyramycin, compstatin, compstatin disodium disodium, methotrexate, paclitaxel, One or more of docetaxel, cisplatin, kappa, oxaliplatin, alprostadil, vitamin k, bortezomib, camptothecin, shikonin.
  • an anti-tumor drug such as doxorubicin, epirubicin, pyramycin, compstatin, compstatin disodium disodium, methotrexate, paclitaxel, One or more of docetaxel, cisplatin, kappa, oxaliplatin, alprostadil, vitamin k, bortezomib, camptothecin, shikonin.
  • the present application also provides a method for preparing the above-mentioned drug-loaded micelles, comprising the following steps:
  • Step 1 Dissolve the one or more drugs and the triblock copolymer and / or diblock copolymer of the present invention in an organic solvent to obtain a solution;
  • Step 2 Remove the organic solvent from the solution obtained in Step 1 to obtain a gel film
  • Step 3 The gel film obtained in step 2 is dissolved in water, filtered and lyophilized to obtain the micelles.
  • the method for preparing a drug-loaded micelle has one or more of the following characteristics:
  • step 1 the organic solvent is acetonitrile
  • step 2 the organic solvent is removed by distillation under reduced pressure
  • step 3 the dissolution of the gel film is promoted by heating and / or shaking;
  • step 3 filtration is performed using a 0.22 ⁇ m filter.
  • the application also provides a pharmaceutical composition comprising one or more drug-loaded micelles of the invention.
  • the pharmaceutical composition further comprises a second therapeutic agent and / or a pharmaceutically acceptable carrier and / or excipient.
  • the pharmaceutical composition comprises two drug-loaded micelles, the two drug-loaded micelles comprising the same drug, and one of the drug-loaded micelles comprises a block copolymer as described above Any one of the triblock copolymers, and the other drug-containing micelle contains a block copolymer as described above.
  • the diblock copolymer drug-loaded micelles and the triblock copolymer drug-loaded micelles loaded with the same drug can be reconstituted separately, and then the two micellar solutions can be adjusted according to a certain mass ratio or Mixing the volume ratio to obtain a compound micelle delivery system can play a role in reducing the exposure of the drug to normal tissues and organs and increasing the accumulation of the drug in the tumor site.
  • the application also provides the use of the above-mentioned drug-loaded micelles for preparing a pharmaceutical preparation for preventing and / or treating a tumor disease in a subject.
  • the application also provides a method for preventing and / or treating tumor diseases, comprising administering to a subject in need thereof an effective dose of the drug-loaded micelles of the present invention.
  • the application also provides the above-mentioned drug-loaded micelles for preventing and / or treating a tumor disease in a subject.
  • the tumor or tumor disease includes, but is not limited to, brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, uterus Endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer, carcinoma in situ, lymphoma, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, Brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma or sarcoma.
  • the application also provides the use of the diblock copolymer and triblock copolymer of the present invention for preparing micelles or drug-loaded micelles.
  • the application also provides the use of the micelle of the present invention as a carrier for preparing a pharmaceutical preparation.
  • pharmaceutically acceptable carriers and / or excipients may be included, including but not limited to sterile liquids, such as water and oil, including those of petroleum, animal, plant or synthetic origin Oil, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • sterile liquids such as water and oil, including those of petroleum, animal, plant or synthetic origin Oil, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Oil such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • water is an exemplary carrier.
  • Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, especially for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene glycol, water, Ethanol and so on.
  • a small amount of a wetting agent, an emulsifying agent, or a pH buffering agent may be included.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like.
  • the pharmaceutical composition of the present invention may act systemically and / or locally. To this end, they can be administered by a suitable route, such as by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal; orally, buccal, nasal, transmucosal, topical, It is administered in the form of an ophthalmic preparation or by inhalation. For these routes of administration, the pharmaceutical composition of the present invention can be administered in a suitable dosage form.
  • pharmaceutical preparations include, but are not limited to, tablets, capsules, lozenges, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous Suspensions, injectable solutions, elixirs, syrups.
  • an "effective dose” refers to the amount of a compound that, after being administered, will to some extent alleviate one or more symptoms of the condition being treated. The effective dose may depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the handling of the drug, and the judgment of the prescribing physician.
  • subject refers to an animal, such as a vertebrate.
  • the subject is a mammal, such as a human, bovine, equine, feline, canine, rodent or primate.
  • the subject is a human.
  • a block copolymer comprising a hydrophilic segment A and a hydrophobic segment B, the general formula of the block copolymer is AB, ABA or BAB, and the hydrophilic segment A is a homopolymer segment,
  • the hydrophobic segment B is a homopolymer segment or a copolymer segment (for example, a random copolymer segment);
  • the formula of the monomer of the hydrophilic segment A is MX- (CH 2 -CH 2 -O) k -CH 3 , wherein M is a cyclic monomer, and the cyclic monomer is selected from glycolide Lactide Trimethylene carbonate P-dioxane ⁇ -caprolactone ⁇ -valerolactone ⁇ -caprolactone and ⁇ -valerolactone are preferred;
  • the monomer of the hydrophobic segment B is selected from glycolide Lactide Trimethylene carbonate P-dioxane ⁇ -caprolactone ⁇ -valerolactone ⁇ -caprolactone and ⁇ -valerolactone are preferred;
  • X is selected from: amido (-CO-NH-), ether (-O-), thioether (-S-), sulfone (-SO 2- ), sulfoxide (-SO-), carbonyl (-CO-); preferably sulfone (-SO 2- );
  • k is selected from 1, 2, 3, 4, 5 and preferably 2 or 3.
  • Embodiment 2 The block copolymer of Embodiment 1 has a general formula of AB, and the monomer of the hydrophilic segment A has a general formula of MX- (CH 2 -CH 2 -O) k -CH 3 , where M is Cyclic monomer selected from glycolide Lactide Trimethylene carbonate P-dioxane ⁇ -caprolactone Preferably ⁇ -caprolactone;
  • the monomer of the hydrophobic segment B is selected from glycolide Lactide Trimethylene carbonate P-dioxane ⁇ -caprolactone ⁇ -valerolactone One or more of them, preferably ⁇ -caprolactone and / or ⁇ -valerolactone.
  • Embodiment 3 The block copolymer of Embodiment 1 has a general formula of AB, and the monomer of the hydrophilic segment A has a general formula of MX- (CH 2 -CH 2 -O) k -CH 3 , where M is Cyclic monomer, which is ⁇ -valerolactone
  • the monomer of the hydrophobic segment B is selected from: trimethylene carbonate P-dioxane ⁇ -valerolactone One or more of them.
  • Embodiment 4 The block copolymer of any one of Embodiments 1-3, the number average molecular weight of the segment A is 1 to 100 kDa, and the number average molecular weight of the segment B is 1 to 100 kDa.
  • Embodiment 5 The block copolymer according to any one of Embodiments 1 to 4, wherein the degree of polymerization of the segment A is 10 to 50, and the degree of polymerization of the segment B is 20 to 60.
  • Embodiment 7 The block copolymer of any one of Embodiments 1 to 6, wherein the monomer of the hydrophilic segment A is the following monomer a1 or a2:
  • X is a sulfone group (-SO 2- );
  • k 3;
  • R is CH 3 O- (CH 2 CH 2 O) 2 -CH 2 CH 2- ;
  • n is 10 to 60; n 'is 10 to 50.
  • Scheme 9 A method for preparing the block copolymer of any one of Schemes 1-8, wherein the general formula of the block copolymer is A-B or A-B-A, and the method includes the following steps:
  • Step 1 Provide a monomer of the hydrophilic segment A and perform ring-opening polymerization to obtain the hydrophilic segment A;
  • Step 2 Use the hydrophilic segment A as a macromolecular initiator to initiate the ring-opening polymerization of the monomers in the hydrophobic segment B to obtain a block copolymer A-B;
  • the method further includes step 3: using the block copolymer A-B as a macro-initiator, initiating the monomer of the hydrophilic segment A, and performing ring-opening polymerization to obtain the block copolymer A-B-A.
  • Embodiment 10 A method for preparing the block copolymer of any one of Embodiments 1-8, wherein the general formula of the block copolymer is A-B or B-A-B, and the method includes the following steps:
  • Step 1 ' Provide a monomer of the hydrophobic segment B and perform ring-opening polymerization to obtain the hydrophobic segment B;
  • Step 2 ' Use the hydrophobic segment B as a macromolecular initiator to initiate the ring-opening polymerization of the monomers in the hydrophilic segment A to obtain a block copolymer A-B;
  • the method further includes step 3 ': the block copolymer A-B is used as a macromolecular initiator to initiate the monomer of the hydrophobic segment B, and ring-opening polymerization is performed to obtain the block copolymer B-A-B.
  • Scheme 11 The method of Scheme 9 or 10, wherein the ring-opening polymerization in steps 1, 2, 3, 1 ', 2', or 3 'is independently performed in the presence of an initiator and / or a catalyst;
  • the initiators in the steps 1, 2, 3, 1 ', 2' or 3 ' are each independently selected from benzyl alcohol, n-dodecanol, triethylene glycol monomethyl ether and diethylene glycol mono One of methyl ether;
  • the catalysts in said steps 1, 2, 3, 1 ', 2' or 3 ' are each independently selected from 1,5,7-triazabicyclo [4.4.0] dec-5-ene ( TBD), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), diphenyl phosphate, methanesulfonic acid, 4-dimethylaminopyridine (DMAP) or organoaluminum compounds Or more of tin compounds and rare earth compounds.
  • Embodiment 12 The method of any one of Embodiments 9-11, which has one or more of the following characteristics:
  • step 1, 2, 3, 1 ', 2', or 3 ' is independently performed for 2 to 48 hours or 24 to 240 hours;
  • each of the ring-opening polymerizations is terminated using a quencher independently; preferably, the quencher is selected from triethylamine, pyridine, and basic alumina;
  • step 2 ', 3, or 3' is purified (e.g., by dialysis).
  • Embodiment 13 A micelle comprising the block copolymer of any one of Embodiments 1-8;
  • the particle diameter of the micelles is 20-100 nm.
  • Embodiment 14 A drug-loaded micelle comprising the block copolymer of any one of Embodiments 1-8 and a drug;
  • the particle diameter of the drug-loaded micelles is 20 to 100 nm;
  • the drug is an antitumor drug, such as doxorubicin, epirubicin, pyramycin, compstatin, compstatin disodium disodium, methotrexate, paclitaxel, docetaxel, One or more of cisplatin, kappa, oxaliplatin, alprostadil, vitamin k, bortezomib, camptothecin, shikonin.
  • an antitumor drug such as doxorubicin, epirubicin, pyramycin, compstatin, compstatin disodium disodium, methotrexate, paclitaxel, docetaxel,
  • doxorubicin such as doxorubicin, epirubicin, pyramycin, compstatin, compstatin disodium disodium, methotrexate, paclitaxel, docetaxel
  • Scheme 15 A method for preparing a drug-loaded micelle of Scheme 14, comprising the following steps:
  • Step 1 Dissolve the drug and the block copolymer of any of Schemes 1-8 in an organic solvent to obtain a solution;
  • Step 2 Remove the organic solvent from the solution obtained in Step 1 to obtain a gel film
  • Step 3 The gel film obtained in step 2 is dissolved in water, filtered and lyophilized to obtain the micelles.
  • Embodiment 16 The method of embodiment 15 having one or more of the following features:
  • step 1 the organic solvent is acetonitrile
  • step 2 the organic solvent is removed by distillation under reduced pressure
  • step 3 the dissolution of the gel film is promoted by heating and / or shaking;
  • step 3 filtration is performed using a 0.22 ⁇ m filter.
  • Embodiment 17 A pharmaceutical composition comprising the drug-loaded micelles of Embodiment 14;
  • the pharmaceutical composition further comprises a second therapeutic agent and / or a pharmaceutically acceptable carrier and / or excipient.
  • Embodiment 18 Use of the drug-loaded micelles of Embodiment 14 for the preparation of a medicament for the prevention and / or treatment of a tumor disease.
  • the diblock and triblock copolymers disclosed by the present invention have good biocompatibility and biodegradability, have good safety, can self-assemble into micelles in aqueous solution, and have extremely low critical micelles.
  • the concentration, the size of the micelles are on the nanometer scale, and the drug load and drug stability are greatly improved.
  • the developed polymerizable monomer was combined with more other cyclic monomers to obtain a series of amphiphilic block copolymers, which expanded the application range and has potential application prospects in the fields of biomedicine and medical diagnosis. .
  • the drug-loaded micelles formed by the triblock copolymer and the drug-loaded micelles formed by the diblock copolymer have different release behaviors, and can be formed into a compound micelle for administration, which is likely to be an ideal
  • the drug-loading system can reduce the exposure of drugs in normal tissues and organs and increase the accumulation of drugs in tumor sites.
  • FIG. 1 is a gel chromatogram of the diblock copolymer prepared in Example 1.
  • FIG. 1 is a gel chromatogram of the diblock copolymer prepared in Example 1.
  • FIG. 2 is a nuclear magnetic spectrum of the diblock copolymer obtained in Example 1.
  • FIG. 3 is a gel chromatogram of the triblock copolymer obtained in Example 3.
  • FIG. 3 is a gel chromatogram of the triblock copolymer obtained in Example 3.
  • FIG. 4 is a NMR spectrum of the triblock copolymer obtained in Example 3.
  • FIG. 4 is a NMR spectrum of the triblock copolymer obtained in Example 3.
  • FIG. 5 is a release curve of two drug-loaded micelles in Example 7.
  • anhydrous monomer a1 (3.240 g, 10 mmol), initiator triethylene glycol monomethyl ether (0.016 g, 0.1 mmol), and catalyst to a 25 mL reaction flask under the conditions of anhydrous and oxygen-free nitrogen.
  • 0.025 g of diphenyl phosphate was stirred and reacted at 25 ° C for 24 hours to form a hydrophilic polymer segment.
  • the monomer ⁇ -caprolactone (1.141 g, 10 mmol) was added and the polymerization reaction was continued for 3 hours to obtain a crude diblock copolymer.
  • X is a sulfone group (-SO 2- ); k is 3; R is CH 3 O- (CH 2 CH 2 O) 2 -CH 2 CH 2- ; according to the results of GPC combined with 1 HNMR spectrum, estimate M is 10; n is 10.
  • anhydrous a2 (3.380 g, 10 mmol), initiator triethylene glycol monomethyl ether (0.016 g, 0.1 mmol), and catalyst to a 25 mL reaction bottle under the conditions of anhydrous and oxygen-free nitrogen.
  • 0.025 g of diphenyl phosphate was stirred and reacted at 25 ° C for 36 hours to form a hydrophilic polymer segment.
  • the monomer ⁇ -caprolactone (1.141 g, 10 mmol) was added and the polymerization reaction was continued for 3 hours to obtain a crude diblock copolymer.
  • X is a sulfone group (-SO 2- ); k is 3; R is CH 3 O- (CH 2 CH 2 O) 2 -CH 2 CH 2- ; according to the results of GPC combined with 1 HNMR spectrum, estimate M is 10; n is 11.
  • anhydrous monomer a1 (3.240 g, 10 mmol), initiator triethylene glycol monomethyl ether (0.016 g, 0.1 mmol), and catalyst to a 25 mL reaction flask under the conditions of anhydrous and oxygen-free nitrogen.
  • 0.025 g of diphenyl phosphate was stirred and reacted at 25 ° C for 24 hours to form a hydrophilic polymer segment.
  • the monomer ⁇ -caprolactone (1.141 g, 10 mmol) was added to continue the polymerization reaction for 3 hours, and the monomer a1 (3.240 g, 10 mmol) was further added to continue the reaction for 36 hours to obtain a crude triblock copolymer.
  • X is a sulfone group (-SO 2- ); k is 3; R is CH 3 O- (CH 2 CH 2 O) 2 -CH 2 CH 2- ; according to the results of GPC combined with 1 HNMR spectrum, estimate M is 5; n is 12; m 'is 6.
  • anhydrous a2 (3.380 g, 10 mmol), initiator triethylene glycol monomethyl ether (0.016 g, 0.1 mmol), and catalyst to a 25 mL reaction bottle under the conditions of anhydrous and oxygen-free nitrogen.
  • 0.025 g of diphenyl phosphate was stirred and reacted at 25 ° C for 36 hours to form a hydrophilic polymer segment.
  • the monomer ⁇ -caprolactone (1.141 g, 10 mmol) was added to continue the polymerization reaction for 3 hours, and the monomer a2 (3.380 g, 10 mmol) was further added to continue the polymerization reaction for 48 hours to obtain a crude triblock copolymer.
  • X is a sulfone group (-SO 2- ); k is 3; R is CH 3 O- (CH 2 CH 2 O) 2 -CH 2 CH 2- ; according to the results of GPC combined with 1 HNMR spectrum, estimate M is 5; n is 11; m 'is 5.
  • paclitaxel 0.30 g of paclitaxel, 1.70 g of the diblock copolymer obtained in Example 2 and 20 ml of acetonitrile were added to a pear-shaped bottle, and the solution was stirred until completely dissolved. The acetonitrile was removed by rotary evaporation at 30 ° C under reduced pressure to obtain a transparent gel film. Add 20ml of water and shake to dissolve 20Min in a 60 ° C water bath to obtain a solution. The solution is filtered through a 0.22 micron filter membrane and lyophilized to obtain a drug-loaded micelle lyophilized product.
  • paclitaxel 0.30 g of paclitaxel, 1.70 g of the triblock copolymer obtained in Example 3, and 20 ml of acetonitrile were added to a pear-shaped bottle, and the mixture was stirred until completely dissolved.
  • the acetonitrile was removed by rotary evaporation at 30 ° C under reduced pressure to obtain a transparent gel film.
  • the solution is filtered through a 0.22 micron filter membrane and lyophilized to obtain a drug-loaded micelle lyophilized product.
  • the diblock polymer drug-loaded micelles have a significant sustained-release effect on paclitaxel (more than 90% drug release in 48 hours).
  • the release rate of triblock polymer drug-loaded micelles is significantly accelerated (over 90% drug release in 24 hours), which improves the early burst release and solves the problem that drug-loaded polymer micelles release drugs too slowly.
  • Compound micelle delivery system The drug-loaded micelles obtained in Examples 5 and 6 were reconstituted according to the method of Example 7, and then the two micelle solutions were mixed according to a certain mass ratio or volume ratio to obtain a compound micelle.
  • the beam delivery system can play a role in reducing the exposure of drugs in normal tissues and organs and increasing the accumulation of drugs in tumor sites.

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Abstract

公开了一种聚酯-聚酯型生物可降解两亲性嵌段共聚物、其制备方法及应用，属于高分子材料和医药技术领域。还公开了由所述嵌段共聚物得到的载药胶束，以及包含所述载药胶束的药物组合物。

Description

一种聚酯-聚酯型生物可降解两亲性嵌段共聚物、其制备方法及应用 技术领域
本发明涉及高分子材料和医药技术领域，具体涉及一种聚酯-聚酯型生物可降解两亲性嵌段共聚物、其制备方法及其应用。
背景技术
随着制药技术的迅猛发展，辅料在药物制剂中所起的作用越来越大，特别是在缓控释制剂的开发方面，可以说起到了至关重要的作用。大多数抗肿瘤药物水溶性差，导致生物利用度低，副作用大。人们在对抗肿瘤药物的增溶增效的研究中，逐步将目光集中到两亲性嵌段共聚物作为载体在药物缓控释制剂开发的应用上。
嵌段共聚物是由不同的链段按照一定的次序结合而组成的聚合物，而对于两亲性嵌段共聚物，由于其具有亲水链段和疏水链段，可在特定溶液中通过自组装而形成高分子胶束。例如，两亲性嵌段共聚物在水中可形成亲水链段为壳、疏水链段为核的“正相”胶束，在有机溶剂中可形成疏水链段为壳、亲水链段为核的“反相”胶束。在正相胶束的应用上，人们可把疏水性药物包埋于疏水端，而亲水端在外，可大大增加疏水性药物的水溶性。由两亲性嵌段共聚物形成的纳米载药胶束，可减少或避免被网状内皮系统识别及清除，延长在血液中的循环，通过EPR效应在病灶部位富集，从而达到靶向作用。
目前常用的两亲性嵌段共聚物，多以聚乙二醇(PEG)或聚乙二醇单甲醚(MPEG)作为亲水段，以聚乳酸、聚己内酯等为疏水段，形成两嵌段、三嵌段和多嵌段共聚物。聚乙二醇(PEG)和聚乙二醇单甲醚(MPEG)具有优良的亲水性，生物相容性和生物惰性，无免疫原性，已作为一种重要的医用辅料广泛应用于生物医学的各个领域，尤其是作为一种可有效提高药物的体内循环时间以及稳定性、有效性的药物输送材料随后被广泛用于蛋白质、多肽及小分子药物的输送，在药物输送领域发挥着关键作用。例如，PEG与药物分子键合形成长循环高分子药物制剂，与生物可降解高分子结合形成两嵌段和三嵌段共聚物，或在溶液中可自组装形成胶束和温敏型凝胶，用于药物的增溶与缓释等。
然而，随着基于PEG的药物输送系统的广泛使用，PEG的一些潜在的缺点和不足也逐渐引起了人们越来越多的关注。首先，PEG是不可生物降解的，较低聚合度的聚乙二醇可以通过肾脏途径排出体外，较高聚合度的聚乙二醇通过肾脏的清除速率显著降低，将会 在人体内积累。所以目前多采用400Da-20kDa(有文献称，低于400Da的PEG毒性较大)分子量范围的PEG，使得PEG的应用受到一定限制。其次，由于我们使用的日化产品(如洗发水、沐浴露和增白保湿化妆品等)和食用的一些食品中添加了大量PEG类添加剂，造成约25％的人体中产生了抗PEG抗体，加之含PEG类药物的多次给药也可能使患者产生抗PEG抗体，从而限制了PEG类聚合物在临床药物上的使用。
发明内容
本申请的发明人利用对某些可开环聚合的环状单体的改性修饰，为其引入亲水性基团，使得该修饰后的环状单体开环聚合后的高分子链段具备了亲水性；由于采用的环状单体为FDA认可的可生物降解聚合物的单体，从而该亲水性链段也具有了生物可降解性，具备了优于PEG的替代优势。修饰后的环状单体与其他可生物降解聚合物嵌段共聚，形成可生物降解的两亲性嵌段共聚物，在水溶液中可自组装成纳米胶束，具备极低的临界胶束浓度，纳米胶束粒径均匀，稳定性好，在生物医药、医疗诊断等领域具有潜在的应用前景。由此提供了下述发明：
在一个方面，本申请提供了一种三嵌段共聚物，其含有亲水段A和疏水段B，所述三嵌段共聚物的通式为A-B-A或B-A-B，所述亲水段A为均聚物链段，所述疏水段B为均聚物链段或共聚物链段(例如无规共聚物链段)；
所述亲水段A的单体的通式为M-X-(CH 2-CH 2-O) k-CH 3，其中M为环状单体，所述环状单体选自：乙交酯
Figure PCTCN2019106417-appb-000001
丙交酯
Figure PCTCN2019106417-appb-000002
三亚甲基碳酸酯
Figure PCTCN2019106417-appb-000003
对二氧环己酮
Figure PCTCN2019106417-appb-000004
ε-己内酯
Figure PCTCN2019106417-appb-000005
和δ-戊内酯
Figure PCTCN2019106417-appb-000006
优选ε-己内酯和δ-戊内酯；
所述疏水段B的单体选自：乙交酯
Figure PCTCN2019106417-appb-000007
丙交酯
Figure PCTCN2019106417-appb-000008
三亚甲基碳酸酯
Figure PCTCN2019106417-appb-000009
对二氧环己酮
Figure PCTCN2019106417-appb-000010
ε-己内酯
Figure PCTCN2019106417-appb-000011
和δ-戊内酯
Figure PCTCN2019106417-appb-000012
中的一种或多种，优选ε-己内酯和/或δ-戊内酯；
X选自：酰胺基(-CO-NH-)、醚基(-O-)、硫醚基(-S-)、砜基(-SO 2-)、亚砜基 (-SO-)、羰基(-CO-)；优选砜基(-SO 2-)；任选地，X与M之间通过亚甲基相连；
k选自1、2、3、4、5，优选2或3。
在某些实施方案中，所述亲水段A的单体的通式为M-CH 2-X-(CH 2-CH 2-O) k-CH 3，其中M为ε-己内酯或δ-戊内酯，X为砜基(-SO 2-)，k为2或3；在某些实施方案中，所述疏水段B的单体为ε-己内酯和/或δ-戊内酯。
在某些实施方案中，形成亲水段A的单体选自：
Figure PCTCN2019106417-appb-000013
在某些实施方案中，形成亲水段A的单体为以下单体a1或a2：
Figure PCTCN2019106417-appb-000014
在某些实施方案中，形成亲水段A的单体为单体a1或a2，形成疏水段B的单体为ε-己内酯。
本发明的三嵌段共聚物中，链段的分子量没有特殊的限制。在某些实施方案中，链段A和链段B的数均分子量独立地选自1～100kDa，例如1～5kDa、5～10kDa、10～20kDa、20～30kDa、30～40kDa、40～50kDa、50～60kDa、60～70kDa、70～80kDa、80～90kDa或90～100kDa。当所述三嵌段共聚物的通式为A-B-A时，两个亲水段A的分子量可以相同或不同。所述三嵌段共聚物的通式为B-A-B时，两个疏水段B的分子量可以相同或不同。
在某些实施方案中，链段A的聚合度独立地为5～50(例如5～10(例如5、6、7、8、9或10)、10～20、20～30、30～40或40～50)，链段B的聚合度独立地为10～60(例如10～15(例如10、11、12、13、14或15)、15～20、20～30、30～40、40～50或50～60)。当所述三嵌段共聚物的通式为A-B-A时，两个亲水段A的聚合度可以相同或不同。所述三嵌段 共聚物的通式为B-A-B时，两个疏水段B的聚合度可以相同或不同。
本发明的三嵌段共聚物，其结构中还可能包含引发剂残基，例如苄基、正十二烷基、CH 3O-(CH 2CH 2O) 2-CH 2CH 2-或CH 3O-CH 2CH 2O-CH 2CH 2-。在某些实施方案中，所述引发剂残基为CH 3O-CH 2CH 2O-CH 2CH 2-。
在一个方面，本申请还提供了一种两嵌段共聚物，其具有以下通式：A-B，其中A为亲水段，B为疏水段，所述亲水段A为均聚物链段，所述疏水段B为均聚物链段或共聚物链段(例如无规共聚物链段)；所述亲水段A的单体的通式为M-X-(CH 2-CH 2-O) k-CH 3，其中M为环状单体，所述环状单体选自：乙交酯
Figure PCTCN2019106417-appb-000015
丙交酯
Figure PCTCN2019106417-appb-000016
三亚甲基碳酸酯
Figure PCTCN2019106417-appb-000017
对二氧环己酮
Figure PCTCN2019106417-appb-000018
ε-己内酯
Figure PCTCN2019106417-appb-000019
优选ε-己内酯；
所述疏水段B的单体选自：乙交酯
Figure PCTCN2019106417-appb-000020
丙交酯
Figure PCTCN2019106417-appb-000021
三亚甲基碳酸酯
Figure PCTCN2019106417-appb-000022
对二氧环己酮
Figure PCTCN2019106417-appb-000023
ε-己内酯
Figure PCTCN2019106417-appb-000024
和δ-戊内酯
Figure PCTCN2019106417-appb-000025
中的一种或多种，优选ε-己内酯和/或δ-戊内酯；
X选自：酰胺基(-CO-NH-)、醚基(-O-)、硫醚基(-S-)、砜基(-SO 2-)、亚砜基(-SO-)、羰基(-CO-)；优选砜基(-SO 2-)；任选地，X与M之间通过亚甲基相连；
k选自1、2、3、4、5，优选2或3。
在某些实施方案中，所述亲水段A的单体的通式为M-CH 2-X-(CH 2-CH 2-O) k-CH 3，其中M为ε-己内酯，X为砜基(-SO 2-)，k为2或3；在某些实施方案中，形成亲水段A的单体为单体a2；在某些实施方案中，所述疏水段B的单体为ε-己内酯和/或δ-戊内酯。
在某些实施方案中，形成亲水段A的单体选自：
Figure PCTCN2019106417-appb-000026
本发明的两嵌段共聚物中，链段的分子量没有特殊的限制。在某些实施方案中，链段A和链段B的数均分子量独立地选自1～100kDa，例如1～5kDa、5～10kDa、10～20kDa、20～30kDa、30～40kDa、40～50kDa、50～60kDa、60～70kDa、70～80kDa、80～90kDa或90～100kDa。
在某些实施方案中，链段A的聚合度为5～50(例如5～10(例如5、6、7、8、9或10)、10～20、20～30、30～40或40～50)，链段B的聚合度为10～60(例如10～15(例如10、11、12、13、14或15)、15～20、20～30、30～40、40～50或50～60)。
本发明的两嵌段共聚物，其结构中还可能包含引发剂残基，例如苄基、正十二烷基、CH 3O-(CH 2CH 2O) 2-CH 2CH 2-或CH 3O-CH 2CH 2O-CH 2CH 2-。在某些实施方案中，所述引发剂残基为CH 3O-CH 2CH 2O-CH 2CH 2-。
在一个方面，本申请还提供了一种两嵌段共聚物，其具有以下通式：A-B，其中A为亲水段，B为疏水段，所述亲水段A为均聚物链段，所述疏水段B为均聚物链段或共聚物链段(例如无规共聚物链段)；所述亲水段A的单体具有以下通式：M-X-(CH 2-CH 2-O) k-CH 3，其中，M为δ-戊内酯
Figure PCTCN2019106417-appb-000027
X选自：酰胺基(-CO-NH-)、醚基(-O-)、硫醚基(-S-)、砜基(-SO 2-)、亚砜基(-SO-)、羰基(-CO-)，优选砜基(-SO 2-)；k选自1、2、3、4、5，优选2或3；任选地，X与M之间通过亚甲基相连；
所述疏水段B的单体选自：三亚甲基碳酸酯
Figure PCTCN2019106417-appb-000028
对二氧环己酮
Figure PCTCN2019106417-appb-000029
和δ-戊内酯
Figure PCTCN2019106417-appb-000030
中的一种或多种。
本发明的两嵌段共聚物中，链段的分子量没有特殊的限制。在某些实施方案中，链段A和链段B的数均分子量独立地选自1～100kDa，例如1～5kDa、5～10kDa、10～20kDa、 20～30kDa、30～40kDa、40～50kDa、50～60kDa、60～70kDa、70～80kDa、80～90kDa或90～100kDa。
在某些实施方案中，链段A的聚合度为5～50(例如5～10(例如5、6、7、8、9或10)、10～20、20～30、30～40或40～50)，链段B的聚合度为10～60(例如10～15(例如10、11、12、13、14或15)、15～20、20～30、30～40、40～50或50～60)。
本发明的两嵌段共聚物，其结构中还可能包含引发剂残基，例如苄基、正十二烷基、CH 3O-(CH 2CH 2O) 2-CH 2CH 2-或CH 3O-CH 2CH 2O-CH 2CH 2-。在某些实施方案中，所述引发剂残基为CH 3O-CH 2CH 2O-CH 2CH 2-。
本发明的嵌段共聚物包括但不限于具有以下结构的三嵌段共聚物或两嵌段共聚物：
Figure PCTCN2019106417-appb-000031
Figure PCTCN2019106417-appb-000032
其中，
X为砜基(-SO 2-)；
k为3；
R为CH 3O-(CH 2CH 2O) 2-CH 2CH 2-；
m为5～50(例如5～10(例如5、6、7、8、9或10)、10～20、20～30、30～40或40～50)；n为10～60(例如10～15(例如10、11、12、13、14或15)、15～20、20～30、30～40、40～50或50～60)；m’为5～50(例如5～10(例如5、6、7、8、9或10)、10～20、20～30、30～40或40～50)。
在某些实施方案中，本发明的三嵌段共聚物的结构式为：
Figure PCTCN2019106417-appb-000033
其中，X为砜基(-SO 2-)；k为3；R为CH 3O-(CH 2CH 2O) 2-CH 2CH 2-；m为5～10；n为10～15；m’为5～10。
在某些实施方案中，本发明的三嵌段共聚物的结构式为：
Figure PCTCN2019106417-appb-000034
其中，X为砜基(-SO 2-)；k为3；R为CH 3O-(CH 2CH 2O) 2-CH 2CH 2-；m为5～10；n为10～15；m’为5～10。
本发明中，嵌段共聚物的通式表示的是嵌段共聚物的组成，而并不限定嵌段共聚物中各链段形成的方式或先后顺序。例如，嵌段共聚物A-B的形成方式可以是先形成链段A，之后以链段A为大分子引发剂引发链段B的单体聚合，形成链段B，进而得到嵌段共聚物A-B；也可以是先形成链段B，之后以链段B为大分子引发剂引发链段A的单体聚合，形成链段A，进而得到嵌段共聚物A-B；此外，也不排除这样的形成方式，即，分别形成链段A和链段B，通过适当的化学反应将链段A和链段B连接，进而得到嵌段共聚物A-B。
此外，本领域技术人员应当理解，聚合物的分子量为统计平均值，其数值可能会因为测定方法的不同而不同。测定聚合物分子量的方法包括但不限于凝胶渗透色谱法(GPC)。在示例性的实施方案中，可以根据GPC测得的分子量结合核磁共振氢谱( 1HNMR)对聚合物或其链段的聚合度进行估算。
在另一方面，本申请还提供了制备通式为A-B或A-B-A的嵌段共聚物的方法，所述方法包括以下步骤：
步骤1：提供亲水段A的单体，并进行开环聚合，得到亲水段A；
步骤2：以亲水段A为大分子引发剂，引发疏水段B的单体进行开环聚合，得到嵌段共聚物A-B；
可选地，所述方法还包含步骤3：以嵌段共聚物A-B为大分子引发剂，引发亲水段A的单体，并进行开环聚合，得到嵌段共聚物A-B-A。
本申请还提供了制备通式为A-B或B-A-B的嵌段共聚物的方法，所述方法包括以下步骤：
步骤1’：提供疏水段B的单体，并进行开环聚合，得到疏水段B；
步骤2’：以疏水段B为大分子引发剂，引发亲水段A的单体进行开环聚合，得到嵌段共聚物A-B；
可选地，所述方法还包含步骤3’：以嵌段共聚物A-B为大分子引发剂，引发疏水段B的单体，并进行开环聚合，得到嵌段共聚物B-A-B。
在某些实施方案中，步骤1、2、3、1’、2’或3’中的开环聚合独立地在引发剂和/或催化剂存在的条件下进行。
在某些实施方案中，所述步骤1、2、3、1’、2’或3’中的引发剂各自独立地选自苯甲醇、正十二醇、三乙二醇单甲醚和二乙二醇单甲醚中的一种。
在某些实施方案中，所述步骤1、2、3、1’、2’或3’中的催化剂各自独立地选自1,5,7-三氮杂二环[4.4.0]癸-5-烯(TBD)、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、磷酸二苯酯、甲烷磺酸、4-二甲氨基吡啶(DMAP)或有机铝化合物、锡类化合物和稀土化合物中的一种或多种。
在某些实施方案中，所述方法具有以下特征中的一个或多个：
(1)步骤1、2、3、1’、2’或3’中的开环聚合各自独立地在惰性气体(例如氮气或氩气)环境下进行；
(2)步骤1、2、3、1’、2’或3’中的开环聚合各自独立地在20～200℃下进行；
(3)步骤1、2、3、1’、2’或3’中的开环聚合各自独立地进行2～48小时或24～240小时；
(4)在步骤2、2’、3或3’中，各自独立地使用淬灭剂结束开环聚合；优选地，所述淬灭剂选自三乙胺、吡啶、碱性氧化铝；
(5)对步骤2、2’、3或3’得到的嵌段共聚物进行纯化(例如通过透析进行纯化)。
在某些实施方案中，所述方法用于制备两嵌段共聚物A-B，其包括如下步骤：
(1)在聚合瓶中加入亲水段A的单体，并加入引发剂和催化剂，经除水除氧后，惰性气体(例如氮气或氩气)环境下在20～200℃下进行开环聚合24～240小时，得到亲水段聚酯均聚物；
优选地，所述引发剂为苯甲醇、正十二醇、三乙二醇单甲醚和二乙二醇单甲醚中的一种；
优选地，所述催化剂为1,5,7-三氮杂二环[4.4.0]癸-5-烯(TBD)、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、磷酸二苯酯、甲烷磺酸、4-二甲氨基吡啶(DMAP)或有机铝化合物、锡类化合物和稀土化合物等中的至少一种。
(2)向步骤(1)得到的聚酯中加入疏水段B的单体，经除水除氧后，惰性气体(例如氮气或氩气)环境在20～200℃下在催化剂的作用下，开环聚合2～48小时，得到嵌段共聚物A-B。
(3)向步骤(2)的聚合瓶中加入碱性淬灭剂淬灭反应，以有机溶剂溶解聚合瓶中的反应物，转移至梨形瓶中，旋转蒸发；
优选地，所述碱性淬灭剂为三乙胺、吡啶、碱性氧化铝等中的至少一种；
优选地，所述有机溶剂为甲醇、乙醇、叔丁醇、乙酸乙酯、二氯甲烷、三氯甲烷、丙酮、乙腈、四氢呋喃等中的至少一种。
(4)向步骤(3)旋蒸后的聚合物中加入溶剂溶解，转移至透析袋中进行透析；
优选地，所述溶剂为水、甲醇、乙醇、叔丁醇、乙酸乙酯、二氯甲烷、三氯甲烷、丙酮、乙腈等、四氢呋喃中的至少一种；
优选地，所述透析袋截留分子量为1-5kDa。
(5)将步骤(4)所得透析袋内聚合物溶液进行冻干，所述冻干时间为24～96小时。
在某些实施方案中，所述方法用于制备三嵌段共聚物A-B-A，所述方法包括如下步骤：
(1)在聚合瓶中加入亲水段A的单体，并加入引发剂和催化剂，经除水除氧后，惰性气体(例如氮气或氩气)环境下在20～200℃下进行开环聚合24～240小时，得到亲水段聚酯均聚物；
优选地，所述引发剂为苯甲醇、正十二醇、三乙二醇单甲醚和二乙二醇单甲醚中的一种；
优选地，所述催化剂为1,5,7-三氮杂二环[4.4.0]癸-5-烯(TBD)、1,8-二氮杂二环[5.4.0] 十一碳-7-烯(DBU)、磷酸二苯酯、甲烷磺酸、4-二甲氨基吡啶(DMAP)或有机铝化合物、锡类化合物和稀土化合物等中的至少一种；
(2)向步骤(1)得到的聚酯中加入疏水段B的单体，经除水除氧后，惰性气体(例如氮气或氩气)环境在20～200℃下在催化剂的作用下，开环聚合2～48小时，得到两嵌段共聚物；
(3)向步骤(2)得到的两嵌段共聚物中加入亲水段A的单体，经除水除氧后，惰性气体(例如氮气或氩气)环境在20～200℃下，开环聚合2～48小时，得到三嵌段共聚物A-B-A；
(4)向步骤(3)的聚合瓶中加入碱性淬灭剂淬灭反应，以有机溶剂溶解聚合瓶中的反应物，转移至梨形瓶中，旋转蒸发；
优选地，所述碱性淬灭剂为三乙胺、吡啶、碱性氧化铝等中的至少一种；
优选地，所述有机溶剂为甲醇、乙醇、叔丁醇、乙酸乙酯、二氯甲烷、三氯甲烷、丙酮、乙腈、四氢呋喃等中的至少一种。
(5)向步骤(4)旋蒸后的聚合物中加入溶剂溶解，转移至透析袋中进行透析；
优选地，所述溶剂为水、甲醇、乙醇、叔丁醇、乙酸乙酯、二氯甲烷、三氯甲烷、丙酮、乙腈等、四氢呋喃中的至少一种；
优选地，所述透析袋截留分子量为1-5kDa。
(6)将步骤(5)所得透析袋内聚合物溶液进行冻干，所述冻干时间为24～96小时。
在一个方面，本申请还提供了一种胶束，其包含本发明的三嵌段共聚物和/或两嵌段共聚物。
在某些实施方案中，所述胶束的粒径为20～100nm，例如20～30nm、30～40nm、40～50nm、50～60nm、60～70nm、70～80nm、80～90nm或90～100nm。
本申请还提供了一种载药胶束，其包含一种或多种药物，以及本发明的三嵌段共聚物和/或两嵌段共聚物。
在某些实施方案中，所述载药胶束的粒径为20～100nm，例如20～30nm、30～40nm、40～50nm、50～60nm、60～70nm、70～80nm、80～90nm或90～100nm。
在某些实施方案中，所述药物为抗肿瘤药物，例如阿霉素、表阿霉素、吡喃阿霉素、康普他汀、康普他汀膦酸二钠、甲氨蝶呤、紫杉醇、多西紫杉醇、顺铂、卡伯、奥沙利铂、前列地尔、维生素k、硼替佐米、喜树碱、紫草素中的一种或多种。
在一个方面，本申请还提供了制备上述载药胶束的方法，包含以下步骤：
步骤1：将所述一种或多种药物和本发明的三嵌段共聚物和/或两嵌段共聚物溶于有机溶剂得到溶液；
步骤2：将步骤1所得溶液中的有机溶剂除去，得到凝胶膜；
步骤3：将步骤2得到的凝胶膜溶解在水中，进行过滤、冻干，得到所述胶束。
在某些实施方案中，所述制备载药胶束的方法具有以下特征中的一个或多个：
(1)步骤1中，所述有机溶剂为乙腈；
(2)步骤2中，通过减压蒸馏除去有机溶剂；
(3)步骤3中，通过加热和/或震荡促进凝胶膜的溶解；
(4)步骤3中，使用0.22μm的滤膜进行过滤。
在一个方面，本申请还提供了一种药物组合物，包含本发明的一种或多种载药胶束。任选地，所述药物组合物还包含第二治疗剂和/或药学上可接受的载体和/或赋形剂。
在某些实施方案中，所述药物组合物包含2种载药胶束，所述2种载药胶束包含相同的药物，其中一种载药胶束包含的嵌段共聚物为如上所述的任一种三嵌段共聚物，另一种载药胶束包含的嵌段共聚物为如上所述的任一种两嵌段共聚物。
在某些实施方案中，可以将负载有相同药物的两嵌段共聚物载药胶束和三嵌段共聚物载药胶束分别复溶，之后将两种胶束溶液按照一定的质量比或体积比混合，得到复合胶束给药体系，可以起到降低药物在正常组织器官的暴露和提高药物在肿瘤部位蓄积的作用。
本申请还提供了上述载药胶束用于制备药物制剂的用途，所述药物制剂用于预防和/或治疗受试者的肿瘤疾病。
本申请还提供了一种预防和/或治疗肿瘤疾病的方法，包括给有此需要的受试者施予有效剂量的本发明的载药胶束。
本申请还提供了上述载药胶束，其用于预防和/或治疗受试者的肿瘤疾病。
本发明中，所述肿瘤或肿瘤疾病包括但不限于脑瘤、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、前列腺癌、雌性生殖道癌、原位癌、淋巴瘤、神经纤维瘤、甲状腺癌、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、前列腺肿瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、胶质瘤或肉瘤。
本申请还提供了本发明的两嵌段共聚物和三嵌段共聚物用于制备胶束或载药胶束的用途。
本申请还提供了本发明的胶束作为载体用于制备药物制剂的用途。
在本发明的药物组合物或药物制剂中，可包含药学上可接受的载体和/或赋形剂，包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。
本发明的药物组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射、静脉内、动脉内、皮下、腹膜内、肌内或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。对于这些给药途径，可以适合的剂型给药本发明的药物组合物。
本发明中，药物制剂包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。如本文中使用的，“有效剂量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。所述有效剂量可以取决于所治疗的个体、病症或病况的严重性、给药的速率、药物的处置及处方医师的判断。
如本文中使用的，“受试者”是指动物，例如脊椎动物。优选地，受试者为哺乳动物，例如人，牛科动物，马科动物，猫科动物，犬科动物，啮齿类动物或灵长类动物。特别优选地，受试者为人。
本申请还涉及以下技术方案：
方案1.一种嵌段共聚物，其含有亲水段A和疏水段B，所述嵌段共聚物的通式为A-B、A-B-A或B-A-B，所述亲水段A为均聚物链段，所述疏水段B为均聚物链段或共聚物链段(例如无规共聚物链段)；
所述亲水段A的单体的通式为M-X-(CH 2-CH 2-O) k-CH 3，其中，M为环状单体，所述 环状单体选自：乙交酯
Figure PCTCN2019106417-appb-000035
丙交酯
Figure PCTCN2019106417-appb-000036
三亚甲基碳酸酯
Figure PCTCN2019106417-appb-000037
对二氧环己酮
Figure PCTCN2019106417-appb-000038
ε-己内酯
Figure PCTCN2019106417-appb-000039
和δ-戊内酯
Figure PCTCN2019106417-appb-000040
优选ε-己内酯和δ-戊内酯；
所述疏水段B的单体选自：乙交酯
Figure PCTCN2019106417-appb-000041
丙交酯
Figure PCTCN2019106417-appb-000042
三亚甲基碳酸酯
Figure PCTCN2019106417-appb-000043
对二氧环己酮
Figure PCTCN2019106417-appb-000044
ε-己内酯
Figure PCTCN2019106417-appb-000045
和δ-戊内酯
Figure PCTCN2019106417-appb-000046
优选ε-己内酯和δ-戊内酯；
X选自：酰胺基(-CO-NH-)、醚基(-O-)、硫醚基(-S-)、砜基(-SO 2-)、亚砜基(-SO-)、羰基(-CO-)；优选砜基(-SO 2-)；
k选自1、2、3、4、5，优选2或3。
方案2.方案1的嵌段共聚物，其通式为A-B，所述亲水段A的单体的通式为M-X-(CH 2-CH 2-O) k-CH 3，其中，M为环状单体，所述环状单体选自：乙交酯
Figure PCTCN2019106417-appb-000047
丙交酯
Figure PCTCN2019106417-appb-000048
三亚甲基碳酸酯
Figure PCTCN2019106417-appb-000049
对二氧环己酮
Figure PCTCN2019106417-appb-000050
ε-己内酯
Figure PCTCN2019106417-appb-000051
优选ε-己内酯；
所述疏水段B的单体选自：乙交酯
Figure PCTCN2019106417-appb-000052
丙交酯
Figure PCTCN2019106417-appb-000053
三亚甲基碳酸酯
Figure PCTCN2019106417-appb-000054
对二氧环己酮
Figure PCTCN2019106417-appb-000055
ε-己内酯
Figure PCTCN2019106417-appb-000056
和δ-戊内酯
Figure PCTCN2019106417-appb-000057
中的一种或多种，优选ε-己内酯和/或δ-戊内酯。
方案3.方案1的嵌段共聚物，其通式为A-B，所述亲水段A的单体的通式为M-X-(CH 2-CH 2-O) k-CH 3，其中，M为环状单体，所述环状单体为δ-戊内酯
Figure PCTCN2019106417-appb-000058
所述疏水段B的单体选自：三亚甲基碳酸酯
Figure PCTCN2019106417-appb-000059
对二氧环己酮
Figure PCTCN2019106417-appb-000060
和δ-戊内酯
Figure PCTCN2019106417-appb-000061
中的一种或多种。
方案4.方案1-3任一项的嵌段共聚物，所述链段A的数均分子量为1～100kDa，所述链段B的数均分子量为1～100kDa。
方案5.方案1-4任一项的嵌段共聚物，所述链段A的聚合度为10～50，所述链段B的聚合度为20～60。
方案6.方案1-5任一项的嵌段共聚物，其结构中还包含引发剂残基，例如苄基、正十二烷基、CH 3O-(CH 2CH 2O) 2-CH 2CH 2-或CH 3O-CH 2CH 2O-CH 2CH 2-。
方案7.方案1-6任一项的嵌段共聚物，亲水段A的单体为以下单体a1或a2：
Figure PCTCN2019106417-appb-000062
方案8.一种嵌段共聚物，其结构式为：
Figure PCTCN2019106417-appb-000063
Figure PCTCN2019106417-appb-000064
其中，
X为砜基(-SO 2-)；
k为3；
R为CH 3O-(CH 2CH 2O) 2-CH 2CH 2-；
m为10～50；n为20～60；m’为10～50。
方案9.制备方案1-8任一项的嵌段共聚物的方法，所述嵌段共聚物的通式为A-B或A-B-A，所述方法包括以下步骤：
步骤1：提供亲水段A的单体，并进行开环聚合，得到亲水段A；
步骤2：以亲水段A为大分子引发剂，引发疏水段B的单体进行开环聚合，得到嵌段共聚物A-B；
可选地，所述方法还包含步骤3：以嵌段共聚物A-B为大分子引发剂，引发亲水段A的单体，并进行开环聚合，得到嵌段共聚物A-B-A。
方案10.制备方案1-8任一项的嵌段共聚物的方法，所述嵌段共聚物的通式为A-B或B-A-B，所述方法包括以下步骤：
步骤1’：提供疏水段B的单体，并进行开环聚合，得到疏水段B；
步骤2’：以疏水段B为大分子引发剂，引发亲水段A的单体进行开环聚合，得到嵌段共聚物A-B；
可选地，所述方法还包含步骤3’：以嵌段共聚物A-B为大分子引发剂，引发疏水段B的单体，并进行开环聚合，得到嵌段共聚物B-A-B。
方案11.方案9或10的方法，步骤1、2、3、1’、2’或3’中的开环聚合独立地在引发剂和/或催化剂存在的条件下进行；
优选地，所述步骤1、2、3、1’、2’或3’中的引发剂各自独立地选自苯甲醇、正十二醇、三乙二醇单甲醚和二乙二醇单甲醚中的一种；
优选地，所述步骤1、2、3、1’、2’或3’中的催化剂各自独立地选自1,5,7-三氮杂二环[4.4.0]癸-5-烯(TBD)、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、磷酸二苯酯、甲烷磺酸、4-二甲氨基吡啶(DMAP)或有机铝化合物、锡类化合物和稀土化合物中的一种或多种。
方案12.方案9-11任一项的方法，其具有以下特征中的一个或多个：
(1)步骤1、2、3、1’、2’或3’中的开环聚合各自独立地在惰性气体(例如氮气或氩气)环境下进行；
(2)步骤1、2、3、1’、2’或3’中的开环聚合各自独立地在20～200℃下进行；
(3)步骤1、2、3、1’、2’或3’中的开环聚合各自独立地进行2～48小时或24～240小时；
(4)在步骤2、2’、3或3’中，各自独立地使用淬灭剂结束开环聚合；优选地，所述淬灭剂选自三乙胺、吡啶、碱性氧化铝；
(5)对步骤2、2’、3或3’得到的嵌段共聚物进行纯化(例如通过透析进行纯化)。
方案13.一种胶束，其包含方案1-8任一项的嵌段共聚物；
优选地，所述胶束的粒径为20～100nm。
方案14.一种载药胶束，其包含方案1-8任一项的嵌段共聚物和药物；
优选地，所述载药胶束的粒径为20～100nm；
优选地，所述药物为抗肿瘤药物，例如阿霉素、表阿霉素、吡喃阿霉素、康普他汀、康普他汀膦酸二钠、甲氨蝶呤、紫杉醇、多西紫杉醇、顺铂、卡伯、奥沙利铂、前列地尔、维生素k、硼替佐米、喜树碱、紫草素中的一种或多种。
方案15.制备方案14的载药胶束的方法，包含以下步骤：
步骤1：将药物和方案1-8任一项的嵌段共聚物溶于有机溶剂得到溶液；
步骤2：将步骤1所得溶液中的有机溶剂除去，得到凝胶膜；
步骤3：将步骤2得到的凝胶膜溶解在水中，进行过滤、冻干，得到所述胶束。
方案16.方案15的方法，其具有以下特征中的一个或多个：
(1)步骤1中，所述有机溶剂为乙腈；
(2)步骤2中，通过减压蒸馏除去有机溶剂；
(3)步骤3中，通过加热和/或震荡促进凝胶膜的溶解；
(4)步骤3中，使用0.22μm的滤膜进行过滤。
方案17.一种药物组合物，包含方案14的载药胶束；
任选地，所述药物组合物还包含第二治疗剂和/或药学上可接受的载体和/或赋形剂。
方案18.方案14的载药胶束用于制备药物的用途，所述药物用于预防和/或治疗肿瘤疾病。
有益效果
本发明公开的两嵌段和三嵌段共聚物，具有良好的生物相容性和生物可降解性，具有良好的安全性，可在水溶液中自组装成胶束，具备极低的临界胶束浓度，胶束粒径纳米级，载药量和载药稳定性得到更大的提高。开发的可聚合单体与更多的其他环状单体进行了有益组合，得到了一系列两亲性嵌段共聚物，扩大了应用范围，在生物医药、医疗诊断等领域具有潜在的应用前景。
本发明中，三嵌段共聚物形成的载药胶束与两嵌段共聚物形成的载药胶束具有不同的释放行为，可以形成复合胶束给药，很有可能会是一种较为理想的载药系统，可起到降低 药物在正常组织器官的暴露和提高药物在肿瘤部位蓄积的作用。
下面将结合附图和实施例对本发明的实施方案进行详细描述，但是，本领域技术人员将理解，下列附图和实施例仅用于说明本发明，而不是对本发明的范围的限定。根据附图和优选实施方案的下列详细描述，本发明的各种目的和有利方面对于本领域技术人员来说将变得显然。
附图说明
图1为实施例1制得的两嵌段共聚物的凝胶色谱图。
图2为实施例1制得的两嵌段共聚物的核磁谱图。
图3为实施例3制得的三嵌段共聚物的凝胶色谱图。
图4为实施例3制得的三嵌段共聚物的核磁谱图。
图5为实施例7中两种载药胶束的释放曲线。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1
在手套箱中，无水无氧，氮气保护条件下，向一个25mL反应瓶中加入单体a1(3.240g，10mmol)、引发剂三乙二醇单甲醚(0.016g，0.1mmol)、催化剂磷酸二苯酯0.025g，25℃下搅拌反应24小时，形成亲水性聚合物链段。加入单体ε-己内酯(1.141g，10mmol)继续聚合反应3小时，得两嵌段共聚物粗产品。加入20mL二氯甲烷，三乙胺0.300g，转移至梨形瓶中旋转蒸发除去溶剂；粗产物以20mL乙腈溶解转移入透析袋(截留分子量为1kDa)，在乙腈溶液中透析48小时，将经透析的聚合物溶液冷冻干燥即得两嵌段聚酯产物3.15g，微黄色半固体。凝胶渗透色谱(GPC)检测：M n＝4505.8，M w＝5405.6，PDI＝1.20。GPC和 1HNMR谱图见图1、图2。得到的两嵌段聚酯结构如下：
Figure PCTCN2019106417-appb-000065
其中，X为砜基(-SO 2-)；k为3；R为CH 3O-(CH 2CH 2O) 2-CH 2CH 2-；根据GPC的结果并结合 1HNMR谱图，估算出m为10；n为10。
实施例2
在手套箱中，无水无氧，氮气保护条件下，向一个25mL反应瓶中加入单体a2(3.380g，10mmol)、引发剂三乙二醇单甲醚(0.016g，0.1mmol)、催化剂磷酸二苯酯0.025g，25℃下搅拌反应36小时，形成亲水型聚合物链段。加入单体ε-己内酯(1.141g，10mmol)继续聚合反应3小时，得两嵌段共聚物粗产品。加入20mL二氯甲烷，三乙胺0.3克，转移至梨形瓶中旋转蒸发除去溶剂；粗产物以20mL乙腈溶解转移入透析袋(截留分子量为1kDa)，在乙腈溶液中透析48小时，将经透析的聚合物溶液冷冻干燥即得两嵌段聚酯产物3.07g，微黄色半固体。凝胶渗透色谱(GPC)检测：M n＝4839.8，M w＝5917.2，PDI＝1.22。得到的两嵌段聚酯结构如下：
Figure PCTCN2019106417-appb-000066
其中，X为砜基(-SO 2-)；k为3；R为CH 3O-(CH 2CH 2O) 2-CH 2CH 2-；根据GPC的结果并结合 1HNMR谱图，估算出m为10；n为11。
实施例3
在手套箱中，无水无氧，氮气保护条件下，向一个25mL反应瓶中加入单体a1(3.240g，10mmol)、引发剂三乙二醇单甲醚(0.016g，0.1mmol)、催化剂磷酸二苯酯0.025g，25℃ 下搅拌反应24小时，形成亲水性聚合物链段。加入单体ε-己内酯(1.141g，10mmol)继续聚合反应3小时，再加入单体a1(3.240g，10mmol)继续反应36小时，得三嵌段共聚物粗产品。加入30mL二氯甲烷，三乙胺0.300g，转移至梨形瓶中旋转蒸发除去溶剂；粗产物以30mL乙腈溶解转移入透析袋(截留分子量为1kDa)，在乙腈溶液中透析48小时，将经透析的聚合物溶液冷冻干燥即得三嵌段聚酯产物4.95g，微黄色半固体。M n＝5106.2，M w＝6288.6，PDI＝1.23。GPC和 1HNMR谱图见图3、图4。得到的三嵌段聚酯结构如下：
Figure PCTCN2019106417-appb-000067
其中，X为砜基(-SO 2-)；k为3；R为CH 3O-(CH 2CH 2O) 2-CH 2CH 2-；根据GPC的结果并结合 1HNMR谱图，估算出m为5；n为12；m’为6。
实施例4
在手套箱中，无水无氧，氮气保护条件下，向一个25mL反应瓶中加入单体a2(3.380g，10mmol)、引发剂三乙二醇单甲醚(0.016g，0.1mmol)、催化剂磷酸二苯酯0.025g，25℃下搅拌反应36小时，形成亲水型聚合物链段。加入单体ε-己内酯(1.141g，10mmol)继续聚合反应3小时，再加入单体a2(3.380g，10mmol)继续聚合反应48小时，得三嵌段共聚物粗产品。加入30mL二氯甲烷，三乙胺0.3克，转移至梨形瓶中旋转蒸发除去溶剂；粗产物以30mL乙腈溶解转移入透析袋(截留分子量为1kDa)，在乙腈溶液中透析48小时，将经透析的聚合物溶液冷冻干燥即得三嵌段聚酯产物5.76g，微黄色半固体。M n＝5068.8，M w＝6234.1，PDI＝1.23。得到的三嵌段聚酯结构如下：
Figure PCTCN2019106417-appb-000068
其中，X为砜基(-SO 2-)；k为3；R为CH 3O-(CH 2CH 2O) 2-CH 2CH 2-；根据GPC的结果并结合 1HNMR谱图，估算出m为5；n为11；m’为5。
实施例5
向梨形瓶内加入紫杉醇0.30g、实施例2所得两嵌段共聚物1.70g、乙腈20ml，搅拌至溶解完全，60℃下减压旋蒸30Min除去乙腈，得到透明凝胶膜。加水20ml在60℃水浴下震荡溶解20Min得到溶液，溶液经0.22微米滤膜过滤，冻干，得载药胶束冻干品。
实施例6
向梨形瓶内加入紫杉醇0.30g、实施例3所得三嵌段共聚物1.70g、乙腈20ml，搅拌至溶解完全，60℃下减压旋蒸30Min除去乙腈，得到透明凝胶膜。加水20ml在60℃水浴下震荡溶解20Min得到溶液，溶液经0.22微米滤膜过滤，冻干，得载药胶束冻干品。
实施例7
释放度测试：实施例5和实施例6所得载药胶束冻干品分别以0.9％氯化钠注射液复溶，至紫杉醇浓度为1.0mg/ml，分别取5ml该紫杉醇胶束溶液置于透析袋(截留分子量：10kDa)中。该透析袋置于1L含吐温80(0.5％，w/w)的磷酸盐缓冲液(PBS，pH7.4)中，水温37℃，搅拌速度100rpm/min。时间0、0.5、1、2、4、8、12、24、36、48小时分别取样测定紫杉醇从胶束中的释放量。释放情况见图5。
释放度检测结果分析：
由图5可知，两嵌段聚合物载药胶束对紫杉醇有明显缓释作用(48小时释药90％以上)。三嵌段聚合物载药胶束的释药速度明显加快(24小时释药90％以上)，改善了前期突释，解决了载药聚合物胶束释放药物过慢的问题。
实施例8
复合胶束给药体系：将实施例5和实施例6所得载药胶束按照实施例7的方法分别复溶，之后将两种胶束溶液按照一定的质量比或体积比混合，得到复合胶束给药体系，可以起到降低药物在正常组织器官的暴露和提高药物在肿瘤部位蓄积的作用。

Claims (13)

  1. 一种三嵌段共聚物，其含有亲水段A和疏水段B，所述三嵌段共聚物的通式为A-B-A或B-A-B，所述亲水段A为均聚物链段，所述疏水段B为均聚物链段或共聚物链段(例如无规共聚物链段)；
    所述亲水段A的单体的通式为M-X-(CH 2-CH 2-O) k-CH 3，其中，M为环状单体，所述环状单体选自：乙交酯
    Figure PCTCN2019106417-appb-100001
    丙交酯
    Figure PCTCN2019106417-appb-100002
    三亚甲基碳酸酯
    Figure PCTCN2019106417-appb-100003
    对二氧环己酮
    Figure PCTCN2019106417-appb-100004
    ε-己内酯
    Figure PCTCN2019106417-appb-100005
    和δ-戊内酯
    Figure PCTCN2019106417-appb-100006
    优选ε-己内酯和δ-戊内酯；
    所述疏水段B的单体选自：乙交酯
    Figure PCTCN2019106417-appb-100007
    丙交酯
    Figure PCTCN2019106417-appb-100008
    三亚甲基碳酸酯
    Figure PCTCN2019106417-appb-100009
    对二氧环己酮
    Figure PCTCN2019106417-appb-100010
    ε-己内酯
    Figure PCTCN2019106417-appb-100011
    和δ-戊内酯
    Figure PCTCN2019106417-appb-100012
    中的一种或多种，优选ε-己内酯和/或δ-戊内酯；
    X选自：酰胺基(-CO-NH-)、醚基(-O-)、硫醚基(-S-)、砜基(-SO 2-)、亚砜基(-SO-)、羰基(-CO-)；优选砜基(-SO 2-)；任选地，X与M之间通过亚甲基相连；
    k选自1、2、3、4、5，优选2或3；
    优选地，所述链段A的数均分子量独立地为1～100kDa，所述链段B的数均分子量独立地为1～100kDa；
    优选地，所述链段A的聚合度独立地为5～50，所述链段B的聚合度独立地为10～60；
    优选地，所述三嵌段共聚物的结构中还包含引发剂残基；
    优选地，所述亲水段A的单体的通式为M-CH 2-X-(CH 2-CH 2-O) k-CH 3，其中M为ε-己内酯或δ-戊内酯，X为砜基(-SO 2-)，k为2或3；更优选地，所述疏水段B的单体为ε-己内酯和/或δ-戊内酯；
    优选地，形成亲水段A的单体为以下单体a1或a2：
    Figure PCTCN2019106417-appb-100013
    优选地，形成亲水段A的单体为单体a1或a2，形成疏水段B的单体为ε-己内酯。
  2. 一种两嵌段共聚物，其具有以下通式：A-B，其中A为亲水段，B为疏水段，所述亲水段A为均聚物链段，所述疏水段B为均聚物链段或共聚物链段(例如无规共聚物链段)；所述亲水段A的单体的通式为M-X-(CH 2-CH 2-O) k-CH 3，其中，M为环状单体，所述环状单体选自：乙交酯
    Figure PCTCN2019106417-appb-100014
    丙交酯
    Figure PCTCN2019106417-appb-100015
    三亚甲基碳酸酯
    Figure PCTCN2019106417-appb-100016
    对二氧环己酮
    Figure PCTCN2019106417-appb-100017
    ε-己内酯
    Figure PCTCN2019106417-appb-100018
    优选ε-己内酯；
    所述疏水段B的单体选自：乙交酯
    Figure PCTCN2019106417-appb-100019
    丙交酯
    Figure PCTCN2019106417-appb-100020
    三亚甲基碳酸酯
    Figure PCTCN2019106417-appb-100021
    对二氧环己酮
    Figure PCTCN2019106417-appb-100022
    ε-己内酯
    Figure PCTCN2019106417-appb-100023
    和δ-戊内酯
    Figure PCTCN2019106417-appb-100024
    中的一种或多种，优选ε-己内酯和/或δ-戊内酯；
    X选自：酰胺基(-CO-NH-)、醚基(-O-)、硫醚基(-S-)、砜基(-SO 2-)、亚砜基(-SO-)、羰基(-CO-)；优选砜基(-SO 2-)；任选地，X与M之间通过亚甲基相连；
    k选自1、2、3、4、5，优选2或3；
    优选地，所述亲水段A的单体的通式为M-CH 2-X-(CH 2-CH 2-O) k-CH 3，其中M为ε-己内酯，X为砜基(-SO 2-)，k为2或3；更优选地，所述疏水段B的单体为ε-己内酯和/或δ-戊内酯；
    优选地，所述链段A的数均分子量为1～100kDa，所述链段B的数均分子量为1～100kDa；
    优选地，所述链段A的聚合度为5～50，所述链段B的聚合度为10～60；
    优选地，所述两嵌段共聚物的结构中还包含引发剂残基。
  3. 一种两嵌段共聚物，其具有以下通式：A-B，其中A为亲水段，B为疏水段，所述亲水段A为均聚物链段，所述疏水段B为均聚物链段或共聚物链段(例如无规共聚物链段)；所述亲水段A的单体的通式为M-X-(CH 2-CH 2-O) k-CH 3，其中，M为δ-戊内酯
    Figure PCTCN2019106417-appb-100025
    X选自：酰胺基(-CO-NH-)、醚基(-O-)、硫醚基(-S-)、砜基(-SO 2-)、亚砜基(-SO-)、羰基(-CO-)，优选砜基(-SO 2-)；任选地，X与M之间通过亚甲基相 连；k选自1、2、3、4、5，优选2或3；
    所述疏水段B的单体选自：三亚甲基碳酸酯
    Figure PCTCN2019106417-appb-100026
    对二氧环己酮
    Figure PCTCN2019106417-appb-100027
    和δ-戊内酯
    Figure PCTCN2019106417-appb-100028
    中的一种或多种；
    优选地，所述链段A的数均分子量为1～100kDa，所述链段B的数均分子量为1～100kDa；
    优选地，所述链段A的聚合度为5～50，所述链段B的聚合度为10～60；
    优选地，所述两嵌段共聚物的结构中还包含引发剂残基。
  4. 一种两嵌段共聚物，其结构式为：
    Figure PCTCN2019106417-appb-100029
    其中，
    X为砜基(-SO 2-)；
    k为3；
    R为CH 3O-(CH 2CH 2O) 2-CH 2CH 2-；
    m为5～50；n为10～60。
  5. 一种三嵌段共聚物，其结构式为：
    Figure PCTCN2019106417-appb-100030
    其中，
    X为砜基(-SO 2-)；
    k为3；
    R为CH 3O-(CH 2CH 2O) 2-CH 2CH 2-；
    m为5～50；n为10～60；m’为5～50。
  6. 一种胶束，其包含权利要求1或5的三嵌段共聚物和/或权利要求2、3或4的两嵌段共聚物；
    优选地，所述胶束的粒径为20～100nm。
  7. 一种载药胶束，其包含一种或多种药物，以及权利要求1或5的三嵌段共聚物和/或权利要求2、3或4的两嵌段共聚物；
    优选地，所述载药胶束的粒径为20～100nm；
    优选地，所述药物为抗肿瘤药物，例如阿霉素、表阿霉素、吡喃阿霉素、康普他汀、康普他汀膦酸二钠、甲氨蝶呤、紫杉醇、多西紫杉醇、顺铂、卡伯、奥沙利铂、前列地尔、维生素k、硼替佐米、喜树碱、紫草素中的一种或多种。
  8. 制备权利要求7的载药胶束的方法，包含以下步骤：
    步骤1：将所述一种或多种药物，以及所述三嵌段共聚物和/或两嵌段共聚物溶于有机溶剂得到溶液；
    步骤2：将步骤1所得溶液中的有机溶剂除去，得到凝胶膜；
    步骤3：将步骤2得到的凝胶膜溶解在水中，进行过滤、冻干，得到所述胶束。
  9. 一种药物组合物，包含一种或多种权利要求7的载药胶束；
    任选地，所述药物组合物还包含第二治疗剂和/或药学上可接受的载体和/或赋形剂；
    优选地，所述药物组合物包含2种载药胶束，所述2种载药胶束包含相同的药物，其中一种载药胶束包含的嵌段共聚物为权利要求1或5的三嵌段共聚物，另一种载药胶束包含的嵌段共聚物为权利要求2、3或4的两嵌段共聚物。
  10. 权利要求7的载药胶束用于制备药物制剂的用途，所述药物制剂用于预防和/或治疗肿瘤疾病。
  11. 权利要求1或5的三嵌段共聚物或权利要求2、3或4的两嵌段共聚物用于制备胶束或载药胶束的用途。
  12. 权利要求6的胶束作为载体用于制备药物制剂的用途。
  13. 一种预防和/或治疗肿瘤疾病的方法，包括给有此需要的受试者施予有效剂量的权利要求7的载药胶束。
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