WO2019158037A1 - 一种两亲性嵌段共聚物及其制备方法和纳米胶束载药系统 - Google Patents

一种两亲性嵌段共聚物及其制备方法和纳米胶束载药系统 Download PDF

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WO2019158037A1
WO2019158037A1 PCT/CN2019/074816 CN2019074816W WO2019158037A1 WO 2019158037 A1 WO2019158037 A1 WO 2019158037A1 CN 2019074816 W CN2019074816 W CN 2019074816W WO 2019158037 A1 WO2019158037 A1 WO 2019158037A1
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block copolymer
amphiphilic block
formula
group
segment
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PCT/CN2019/074816
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English (en)
French (fr)
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张富尧
邵玉湘
李火明
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上海时莱生物技术有限公司
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Priority to US16/969,397 priority Critical patent/US11225551B2/en
Priority to JP2020543305A priority patent/JP6912048B2/ja
Priority to EP19755134.4A priority patent/EP3753966B1/en
Priority to CN201980013304.2A priority patent/CN111819217B/zh
Publication of WO2019158037A1 publication Critical patent/WO2019158037A1/zh
Priority to US17/450,902 priority patent/US20220098367A1/en

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    • C08G65/32—Polymers modified by chemical after-treatment
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    • C08G65/334—Polymers modified by chemical after-treatment with organic compounds containing sulfur
    • C08G65/3344—Polymers modified by chemical after-treatment with organic compounds containing sulfur containing oxygen in addition to sulfur
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/334—Polymers modified by chemical after-treatment with organic compounds containing sulfur

Definitions

  • the invention relates to a novel polyether-linker-polyester amphiphilic block copolymer and a preparation method thereof, and a stable micelle drug-loading system formed by the copolymer and a poorly soluble drug, belonging to the technical field of nano drug preparations .
  • poorly soluble drugs The delivery of poorly soluble drugs has always been a problem in the pharmaceutical preparation process, and only the dissolved drugs can be absorbed by the mucosa of the gastrointestinal epithelial cells. According to statistics, more than 40% of the drugs currently on the market are poorly soluble drugs. With the wide application of combinatorial chemistry and high-throughput screening in the development of new drugs, the proportion of poorly soluble drugs will become larger and larger. The poorer the solubility of the drug, the lower the oral bioavailability, and thus it is not suitable for development into an oral preparation.
  • a conventional method is to develop it into an injection, and to improve the solubility of the drug by adjusting pH, salt formation, use of a solubilizing agent, or preparation of an oil-soluble injection.
  • these pathways often introduce other drawbacks while solving the solubility of the drug.
  • paclitaxel docetaxel, cabazitaxel, and lyonol
  • antitumor drugs that induce and promote tubulin polymerization, prevent depolymerization, and stabilize Microtubules. These effects cause the cells to fail to form spindles and spindles during mitosis, inhibit cell division and proliferation, and thus exert anti-tumor effects.
  • the taxane is very hydrophobic and can only be administered by the injection route, and anhydrous ethanol is used as a solvent.
  • a large amount of polyoxyethylene castor oil or Tween 80 or the like is usually used as a solubilizing agent to promote dissolution of the drug.
  • solubilizers cause allergic reactions and hematological toxicity.
  • patients need desensitization before treatment, and on the other hand, they limit the therapeutic dose and cannot exert the best therapeutic effect of taxanes.
  • the solubility of the taxane drug will decrease and precipitate, resulting in inaccurate dosage, so that the injection process needs to be precisely controlled, otherwise an unstable therapeutic effect will be produced. Therefore, there is an urgent need to develop a safe and stable new drug delivery system.
  • the amphiphilic block polymer will form a copolymer micelle having a spherical core-shell structure in an aqueous solution by self-assembly, the hydrophobic portion of which forms an inner core, and the hydrophilic portion forms an outer shell.
  • the core can be used as a container for hydrophobic drugs, solubilizing the drug in the core, increasing drug loading and reducing toxic side effects.
  • the outer shell protects the drug and improves the stability of the drug.
  • the particle size of the micelle is much larger than that of the small molecule drug itself, usually between 10 and 200 nm, which can reduce the absorption of the drug by the renal excretion and the reticuloendothelial system, prolong the circulation time in the body, and improve the bioavailability.
  • passive targeting of tumor cells can be achieved through high permeability and retention effects (EPR effect), promoting selective distribution in tumor tissues, increasing drug efficacy and reducing system side effects.
  • PEG-PLA polyethylene glycol polylactic acid copolymer
  • PEG polyethylene glycol
  • PLA polylactic acid/polylactide
  • the final product formed by degradation in vivo is carbon dioxide and water.
  • the intermediate metabolite lactic acid is also a normal metabolite in the body. Accumulation or toxic side effects in the body. Therefore PEG-PLA is a very safe biomedical material.
  • the above-mentioned catalyst for initiating the polymerization of lactide uses stannous octoate, and the reaction temperature is about 130 degrees.
  • Tin reagents are highly toxic, and trace amounts of residues will have a large impact on the safety of the polymer.
  • Studies have also shown that excessive tin content in the polymer will significantly affect the kinetic stability of the micellar system.
  • chain back biting of polylactic acid is likely to occur (back-biting, J. Am. Chem. Soc. 2016, 138, 8674-8677), resulting in a broadening of the molecular weight distribution of the copolymer, resulting in a drug.
  • the release is uncontrollable.
  • very cumbersome purification means are often required to obtain a qualified copolymer suitable for drug delivery.
  • the patent CN106349466A it is necessary to carry out molecular weight cut-off by means of ultrafiltration of a membrane to obtain a copolymer having a narrow molecular weight distribution.
  • the patent CN103768013A is treated with a cation exchange resin to reduce the tin content introduced by the catalyst in the mixture.
  • the patent CN103980466B uses active sodium metal and organic naphthalene as a catalyst. Although it avoids stannous octoate, the active metal is very sensitive to air and moisture and requires high operational skills.
  • the use of a large amount of ether with explosive and anesthetic properties during the precipitation purification of the copolymer also creates a huge hazard in the scale-up process.
  • the existing PEG-PLA-loaded drug micelles have the disadvantages of low drug loading (the drug/copolymer ratio is only 20:90), the reaction conditions of the copolymer are harsh, and the purification method is cumbersome.
  • it is urgent to modify the structure of the copolymer more systematically, and to ensure the safety and the drug loading and micelle stability to a greater extent, and also need to develop a A method for synthesizing a copolymer with stable process, controllable quality and environmental friendliness.
  • the object of the present invention is to overcome the shortcomings of low drug loading, poor stability, harsh synthesis conditions of the copolymer, and cumbersome purification methods, and provide a novel polyether-linker-polyester amphiphilic block.
  • the present invention modifies an amphiphilic copolymer by using a linker containing an aromatic ring, and a linker containing an aromatic ring has a strong conjugation effect with a poorly soluble drug, particularly a drug containing an aromatic ring ( ⁇ ) - ⁇ accumulation), so that the drug molecule is firmly locked in the hydrophobic core of the micelle, which not only improves the stability of the drug-loaded micelle, but also greatly increases the drug-loading amount of the copolymer.
  • the present invention introduces a small molecule fragment containing an aromatic ring to a biosafety polyethylene glycol or a single protective polyethylene glycol, introduces a linker, and promotes by using DBU, TBD or MTBD as a catalyst.
  • the polymerization of lactide forms an amphiphilic copolymer having the structure of R 1 -PEG-linker-PLA-R 2 wherein R 1 and R 2 are independently a hydroxy protecting group or hydrogen.
  • the linker moiety is a natural amino acid fragment, the metabolite produced by the amphiphilic copolymer in the body is harmless to the human body and has significant biosafety.
  • the reaction conditions are mild, and a copolymer having a narrow molecular weight distribution range is easily obtained; the DBU catalyst itself is less harmful and can be removed by simple pickling, and there is no safety hazard of heavy metal tin residue;
  • the precipitation of the copolymer by the tert-butyl ether in place of diethyl ether also increases the safety during the process of scale-up production.
  • the novel synthesis process of the amphiphilic copolymer provided by the invention is mild, the quality is controllable, and is suitable for industrial scale-up production.
  • the mass ratio of the drug/amphiphilic copolymer in the lyophilized preparation of the nano drug-loaded micelle system provided by the present invention is up to 70:100, and after reconstitution by physiological saline, it forms a bluish color at room temperature.
  • the opalescent clear solution can be stored at room temperature for up to 72 h; on the other hand it can significantly increase the solubility of aryl-substituted, poorly soluble drugs, and through high permeability and retention effects on tumors (EPR) Effect), greatly improve the therapeutic effect on the tumor, and reduce the side effects of the drug.
  • an amphiphilic block copolymer comprising a hydrophilic segment, a hydrophobic segment, and a linking of a hydrophilic segment and a hydrophobic chain
  • the linker of the segment, the linker is a linker
  • the structure of the linker is one or more substitutions including an aromatic ring, a carbon-carbon double bond, a carbon-carbon triple bond, a conjugated double bond, and a conjugated triple bond.
  • the aromatic ring, carbon-carbon double bond, carbon-carbon triple bond, conjugated double bond or conjugated triple bond in the linker structure may be located in the amphiphilic block copolymer. In the chain, it may also be located on the side chain of the amphiphilic block copolymer.
  • the structure of the linker linker is a straight chain or a side chain containing an aromatic ring substituted with a C 1 -C 30 small molecule fragment.
  • the linear or side chain contains an aromatic ring-substituted C 1 -C 30 small molecule fragment with or without a hetero atom substitution, the hetero atom being selected from an oxygen atom, a nitrogen atom, One or more of a sulfur atom and a phosphorus atom.
  • the structure of the linker is a C 1 -C 30 small molecule fragment, and the C 1 -C 30 small molecule fragment is substituted with an aromatic ring;
  • the aromatic ring is a C 6 -C 20 aryl group, a C 6 -C 20 aryl group substituted by R a , a C 2 -C 20 heteroaryl group or a C 2 -C 20 heteroaryl group substituted by R b ,
  • the number of R a is one or more, and when the number of the R a is plural, the R a is the same or different;
  • the number of the R b is one or more, and when the number of the R b is plural, the R b is the same or different;
  • R a and R b are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 4 -C 6 cycloalkyl, halogen, hydroxy or nitro;
  • the C 2 -C 20 hetero atoms, aryl, heteroaryl or substituted R b C 2 -C 20 heteroaryl group is O, S or N, the number of the hetero atom is one or more, When plural, the heteroatoms are the same or different.
  • the aromatic ring, the C 6 -C 20 aryl group or R a is substituted C 6 -C 20 aryl in C 6 -C 20 aryl is C 6 -
  • the C 10 aryl group is further preferably a phenyl group or a naphthyl group.
  • the C 2 -C 20 heteroaryl group or the C 2 -C 20 heteroaryl group in the R b -substituted C 2 -C 20 heteroaryl group is
  • the C 2 -C 10 heteroaryl group is further preferably a C 3 -C 8 heteroaryl group such as an anthracenyl group or an imidazolyl group.
  • the C 1 -C 6 alkyl group is preferably a C 1 -C 3 alkyl group.
  • the C 1 -C 6 alkoxy group is preferably a C 1 -C 3 alkoxy group.
  • R a and R b are independently C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen, hydroxy or nitro.
  • the aromatic ring is a C 6 -C 10 aryl group (e.g., phenyl or naphthyl), a C 6 -C 10 aryl group substituted with R a (e.g., phenyl or naphthyl), C. a 2 -C 10 heteroaryl group (for example, a decyl group or an imidazolyl group) or a C 2 -C 10 heteroaryl group substituted by R b (for example, an anthracenyl group or an imidazolyl group), and R a and R b are independently C 1 ⁇ C 3 alkyl, C 1 -C 3 alkoxy, halogen, hydroxy or nitro.
  • R a and R b are independently C 1 ⁇ C 3 alkyl, C 1 -C 3 alkoxy, halogen, hydroxy or nitro.
  • the C 1 -C 30 small molecule fragment is a C 2 -C 10 small molecule fragment.
  • the C 1 -C 30 small molecule fragment is substituted with 1 to 3 (eg, 1 or 2) aromatic rings.
  • the small molecule C 1 -C 30 fragment comprises or contains a substituted heteroatom, the heteroatom is selected from oxygen atom, a nitrogen atom, a sulfur atom and a phosphorus atom or a plurality.
  • the number of the hetero atom substitutions is one or more, preferably 1 to 4 (for example, 1, 2, 3 or 4).
  • the structure of the linker is selected from any of the following structures:
  • Ar is an aromatic ring, and the definition of the aromatic ring is as described above;
  • T 1 is a single bond or p is 0 or 1, q is 1, 2 or 3, and X 1 is -O-, -S- or -NH-;
  • T 2 is a single bond or r is 0, 1, 2, 3, 4 or 5,
  • T 3 is a single bond
  • T 1 is a single bond and T 2 is a single bond.
  • T 1 is p is 0, q is 2, X 1 is -S- or -NH-, and T 2 is a single bond.
  • T 1 is p is 1, q is 2, X 1 is -O-, and T 2 is a single bond.
  • the linker has the structure of an amino acid containing an aromatic ring, an amino alcohol containing an aromatic ring or a C 1 -C 30 small molecule fragment of a polypeptide containing an aromatic ring, wherein the aromatic ring may also be derived from an amino acid.
  • the aromatic ring is located in the side chain of the amino acid, amino alcohol or polypeptide, or a protecting group at the hydroxyl, thiol, amine or carboxyl group of the amino acid, amino alcohol or polypeptide.
  • the amino acid in the aromatic ring-containing amino acid can be in the R configuration, the S configuration, or the racemate.
  • the amino alcohol in the aromatic ring-containing amino alcohol may be in the R configuration, the S configuration, or the racemate.
  • the aromatic ring-containing amino acid is selected from one of phenylalanine, histidine, tyrosine, tryptophan, and 3-(2-naphthyl)-alanine. Multiple.
  • one or more of the aromatic ring-containing polypeptides are derived from phenylalanine, histidine, tyrosine, tryptophan, and 3-(2-naphthyl)- One or more of alanine.
  • the phenylalanine, histidine, tyrosine, tryptophan or 3-(2-naphthyl)-alanine may be in the R configuration, the S configuration or the external Racemate.
  • the aromatic ring-containing amino alcohol is selected from one of phenylalaninol, histamine, tyrosol, tryptophan, and 3-(2-naphthyl)-alaninol. Multiple; phenylalaninol, histamine, tyrosol, tryptophan, 3-(2-naphthyl)-alaninol from phenylalanine, histidine, tyrosine, tryptophan Reduction of 3-(2-naphthyl)-alanine.
  • the phenylalaninol, histamine, tyrosol, tryptophan or 3-(2-naphthyl)-alaninol may be in the R configuration, the S configuration or the external Racemate.
  • the linear or side chain contains an aromatic ring-substituted C 1 -C 30 small molecule fragment containing an aromatic ring amino acid, an amino alcohol or a polypeptide, wherein the aromatic ring may also be derived from an amino acid, A protecting group for a hydroxyl group, a thiol group, an amine group or a carboxyl group on an amino alcohol or polypeptide.
  • the aromatic ring is located in the side chain of the amino acid, amino alcohol or polypeptide, or a protecting group at the hydroxyl, thiol, amine or carboxyl group of the amino acid, amino alcohol or polypeptide.
  • the hydrophilic segment is a polyethylene glycol segment or a single protected polyethylene glycol segment having a number average molecular weight between 400 and 20,000.
  • the monoprotected polyethylene glycol segment is preferably a polyethylene glycol segment having a hydroxy protecting group with a single terminal group.
  • the hydrophobic segment is selected from the group consisting of polylactide segments having a number average molecular weight between 400 and 20,000, mono-protected polylactide segments, polyglycolide segments, and mono-protected Polyglycolide segment, polyglycolide segment, mono-protected polyglycolide segment, polycaprolactone segment, mono-protected polycaprolactone segment, polycarbonate segment, single One of a protected polycarbonate segment, a polydioxanone segment, or a monoprotected polydioxanone segment.
  • the mono-protected polylactide segment, the mono-protected polyglycolide segment, the mono-protected polyglycolide segment, the protected polycaprolactone segment, the mono-protected polycarbonate segment, and The monoprotections in the monoprotected polydioxanone segments are each independently preferably a single terminal group which is a hydroxy protecting group.
  • the hydrophobic segment is selected from the group consisting of a polylactide segment having a number average molecular weight between 400 and 20,000 or a monoprotected polylactide segment, said monoprotected polylactide segment Preferred are polylactide segments in which the single terminal group is a hydroxy protecting group.
  • amphiphilic block copolymer has the structure: R 1 -PEG-linker-PLA-R 2 ,
  • R 1 and R 2 are independently selected from a hydroxy protecting group or hydrogen
  • PEG is a polyethylene glycol block having a number average molecular weight of 400 to 20,000
  • linker is a linker
  • PLA is a polylactide block having a number average molecular weight of 400 to 20,000, a number of polyethylene glycol blocks and polylactide blocks.
  • the average molecular weight ratio is 1: (0.5 to 2).
  • Another object of the present invention is to provide a process for the preparation of the above amphiphilic block copolymer.
  • the preparation method of the above amphiphilic block copolymer comprises the following steps:
  • step 2) In the organic solvent, the product of step 1) and DL-lactide, L-lactide, D-lactide, glycolide, DL-lactide and glycolide under the action of a catalyst Mixtures of different ratios, mixtures of different ratios of L-lactide and glycolide, mixtures of different ratios of D-lactide and glycolide, mixtures of caprolactone, bisphenol A and diphenyl carbonate or two Oxycyclohexanone is polymerized,
  • the polymer obtained in the step 2) is subjected to terminal hydroxyl protection.
  • the method of preparing the amphiphilic block copolymer comprises the steps of:
  • a polyethylene glycol having a number average molecular weight of 400 to 20,000 or a single protective polyethylene glycol is modified with a small molecule fragment containing an aryl group to obtain an R 1 -PEG-linker;
  • R 1 -PEG-linker-PLA PLA terminal hydroxyl group for protection optionally, for R 1 -PEG-linker-PLA PLA terminal hydroxyl group for protection, to obtain R 1 -PEG-linker-PLA- R 2.
  • the obtained PLA is a polylactide having a number average molecular weight of 400 to 20,000;
  • R 1 and R 2 are independently a hydroxy protecting group or hydrogen.
  • the catalyst in the method for preparing the amphiphilic block copolymer, in the step 2), is 1,8-diazabicycloundec-7-ene (DBU), Stannous octoate, magnesium 2-ethylhexanoate, 1,5,7-triazabicyclo[4.4.0]non-5-ene (TBD) and 7-methyl-1,5,7-triazo One or more of heterobicyclo[4.4.0]non-5-ene (MTBD). Preference is given to 1,8-diazabicycloundec-7-ene (DBU) and/or stannous octoate.
  • DBU 1,8-diazabicycloundec-7-ene
  • TBD 1,5,7-triazabicyclo[4.4.0]non-5-ene
  • MTBD heterobicyclo[4.4.0]non-5-ene
  • step 2 in the method of preparing the amphiphilic block copolymer, a step is added after step 2):
  • the resulting product (for example, R 1 -PEG-linker-PLA described above) is purified.
  • step 3 in the preparation method of the amphiphilic block copolymer, after step 3), a step is added: the obtained product (for example, the above R 1 -PEG-linker-PLA-R 2 ) is purified. .
  • a step is added after the step 2): the obtained product (for example, the above R 1 -PEG-linker-PLA) is purified, and A step is added after step 3): the resulting product (for example, R 1 -PEG-linker-PLA-R 2 described above) is purified.
  • amphiphilic block copolymer has the structure:
  • linker R 1 , and R 2 are as described above.
  • amphiphilic block copolymer is selected from any of the following structures:
  • R 1 , R 2 , n and m are as defined above;
  • Ar is an aromatic ring as described above;
  • T 1 is a single bond or p is 0 or 1, q is 1, 2 or 3 (for example 2), and X 1 is -O-, -S- or -NH-;
  • T 2 is a single bond or r is 0, 1, 2, 3, 4 or 5 (for example 3),
  • T 3 is a single bond
  • T 1 is a single bond and T 2 is a single bond.
  • T 1 is p is 0, q is 2, X 1 is -S- or -NH-, and T 2 is a single bond.
  • T 1 is p is 1, q is 2, X 1 is -O-, and T 2 is a single bond.
  • amphiphilic copolymer has the structure:
  • R 1 , R 2 and Ar are as defined above;
  • amphiphilic block copolymer is further preferably selected from any of the following structures:
  • n and m are as defined above.
  • amphiphilic block copolymer may also be selected from any of the following structures:
  • n and m are as defined above.
  • the invention also provides a polymer as shown in formula II,
  • linker and n are as defined in formula I;
  • R 1 is a hydroxy protecting group or hydrogen.
  • polymer of Formula II is selected from any of the following structures:
  • R 1 , n, T 1 , T 2 , T 3 and Ar are as defined above.
  • polymer of Formula II is selected from any of the following structures:
  • n and Ar are as described above.
  • the present invention also provides a method for preparing a polymer as shown in Formula II, wherein the polymer of Formula II is obtained by modifying a polymer of Formula III by small molecule modification.
  • linker and n are as defined in formula I;
  • R 1 is a hydroxy protecting group or hydrogen.
  • the present invention also provides a method for preparing a polymer as shown in Formula II-1, wherein the polymer represented by Formula II-1 is obtained by a deprotection reaction of a polymer represented by Formula III-1.
  • R 1 , n, T 1 , T 2 and Ar are as defined above, and R 4 is an amino protecting group.
  • the present invention also provides a process for the preparation of a polymer of the formula II-2, wherein the polymer of the formula II-2 is obtained by a deprotection reaction of a polymer as shown in the formula III-2.
  • R 1 , n, T 1 , T 2 and Ar are as defined above, and R 3 is a hydroxy protecting group.
  • the polymer of Formula III-2 is prepared by condensation of a polymer of Formula II-1 with a compound of Formula VI-1.
  • R 1 , n, T 1 , T 2 , Ar and R 3 are as defined above.
  • the present invention also provides a method for preparing a polymer as shown in Formula II-3, wherein the polymer represented by Formula II-3 is a compound represented by Formula III-3 and a compound represented by Formula IV-D. Produced by a condensation reaction,
  • R 1 , n, T 3 and Ar are as defined above.
  • the present invention also provides a method for preparing an amphiphilic block copolymer as shown in Formula I, which comprises the steps of:
  • linker R 1 , R 2 , m and n are as described above, and when R 2 is hydrogen, step 2) is not required.
  • the polymer of formula II is prepared by the process of polymer as shown in formula III. Small molecule fragments can be modified;
  • linker R 1 and n are as described above.
  • the present invention provides a process for the preparation of an amphiphilic block copolymer of formula I,
  • the structure of the linker is a small molecule fragment containing one or more substitutions of an aromatic ring, a carbon-carbon double bond, a carbon-carbon triple bond, a conjugated double bond or a conjugated triple bond.
  • R 1 and R 2 are independently a hydroxy protecting group or hydrogen
  • the copolymer of Formula IA is subjected to hydroxy protection to produce an amphiphilic block copolymer of Formula I.
  • the present invention also provides an amphiphilic block copolymer of the formula IC',
  • n, m and Ar are as defined above;
  • R 5 is a substituted or unsubstituted C 1 -C 10 alkyl group, a C 6 -C 20 aryl group or an amino acid residue.
  • R 5 is substituted or unsubstituted C 1 -C 6 alkyl (eg methyl), C 6 -C 8 aryl (eg phenyl) or amino acid residue (eg R 5 is preferably an unsubstituted C 1 -C 3 alkyl group (for example methyl group), a phenyl group or an amino acid residue (for example) ).
  • the present invention also provides a method for preparing an amphiphilic block copolymer represented by the formula IC', wherein the amphiphilic block copolymer represented by the formula IC' is copolymerized by an amphiphilic block represented by the formula IB.
  • the substance is obtained by acyl protection,
  • the present invention also provides an amphiphilic block copolymer as shown in Formula IC,
  • Ar is a substituted or unsubstituted aryl group.
  • the present invention also provides a process for the preparation of an amphiphilic block copolymer of the formula IC, an amphiphilic block copolymer of the formula IC from an amphiphilic block copolymer of the formula IB Made by acetyl protection,
  • Ar is a substituted or unsubstituted aryl group.
  • the present invention also provides an amphiphilic block copolymer as shown in Formula IB,
  • n, m and Ar are as described above.
  • the present invention also provides a method for preparing an amphiphilic block copolymer represented by Formula IB, wherein the amphiphilic block copolymer represented by Formula IB is initiated by a catalyst represented by Formula IIA under the action of a catalyst.
  • a catalyst represented by Formula IIA Made by polymerization of lactide,
  • n, m and Ar are as described above.
  • the present invention also provides a polymer as shown in Formula IIA,
  • n and Ar are as described above.
  • the present invention also provides a method for preparing a polymer as shown in Formula IIA, wherein the polymer represented by Formula IIA is obtained by a hydrolysis reaction of a polymer represented by Formula IIIA.
  • R 3 is a hydroxy protecting group
  • n and Ar are as described above.
  • the present invention also provides a polymer as shown in Formula IIIA,
  • R 3 , n and Ar are as defined above.
  • the invention also provides a preparation method of the polymer represented by the formula IIIA, wherein the polymer represented by the formula IIIA is obtained by condensation reaction of the polymer represented by the formula IVA,
  • R 3 , n and Ar are as defined above.
  • the present invention also provides a polymer as shown in Formula IVA,
  • n and Ar are as described above.
  • the invention also provides a preparation method of the polymer represented by the formula IVA, wherein the polymer represented by the formula IVA is obtained by the hydrolysis reaction of the amine group based on the polymer represented by the formula VA.
  • R 4 is an amino protecting group
  • n and Ar are as described above.
  • the invention also provides a polymer as shown in formula VA,
  • R 4 , n and Ar are as defined above.
  • the invention also provides a method for preparing a polymer as shown in formula VA, wherein the polymer represented by formula VA is obtained by condensation reaction of a polymer represented by formula VIA with a compound of formula VIIA.
  • R 4 , n and Ar are as defined above;
  • the configuration of the amino acid compound VIIA may be the S configuration, the R configuration or the racemate.
  • n, m, R 3 , R 4 , R 5 and Ar are as defined above.
  • the configuration of the amino acid compound VIIA may be the S configuration, the R configuration or the racemate.
  • amphiphilic block polymer of the formula IB is subjected to an esterification reaction under the action of an acylating agent to obtain an amphiphilic block copolymer of the formula IC'.
  • step 5 an amphiphilic block copolymer as shown in Formula IB Purification was carried out.
  • the present invention also provides a method for preparing an amphiphilic block copolymer represented by Formula IB, wherein the amphiphilic block copolymer represented by Formula IB is initiated by a catalyst represented by Formula IVA under the action of a catalyst.
  • a catalyst represented by Formula IVA Made by polymerization of lactide,
  • n, m and Ar are as described above.
  • R 4 , n, m and Ar are as defined above.
  • the configuration of the amino acid compound VIIA may be the S configuration, the R configuration or the racemate.
  • amphiphilic block copolymer of formula IB is purified.
  • the present invention also provides an amphiphilic block polymer as shown by Formula ID,
  • n, m and Ar are as described above.
  • the present invention also provides a method for preparing an amphiphilic block copolymer represented by Formula ID, wherein the amphiphilic block copolymer represented by Formula ID is initiated by a catalyst represented by Formula IID under the action of a catalyst.
  • a catalyst represented by Formula IID Made by polymerization of lactide,
  • n, m and Ar are as described above.
  • the invention also provides a polymer as shown in formula IID,
  • n and Ar are as described above.
  • the invention also provides a preparation method of a polymer represented by the formula IID, wherein the polymer represented by the formula IID is obtained by condensation reaction of a polymer represented by the formula IIID with a compound represented by the formula IVD.
  • the configuration of the amino alcohol compound IVD may be the S configuration, the R configuration or the racemate.
  • the present invention also provides a polymer as shown in Formula IIID,
  • n is as defined above.
  • the invention also provides a preparation method of the polymer as shown in formula IIID, wherein the polymer represented by formula IIID is obtained by subjecting a polymer represented by formula VIA to a compound represented by formula VID by ring-opening condensation reaction.
  • n is as defined above.
  • the present invention provides a method of preparing an amphiphilic block copolymer as shown in Formula ID,
  • n, m and Ar are as described above.
  • the configuration of the amino alcohol compound IVD may be the S configuration, the R configuration or the racemate.
  • step 3 the amphiphilic block copolymer as shown in formula ID is purified.
  • the catalyst for initiating the polymerization of lactide is 1,8-diazabicycloundec-7-ene (DBU), stannous octoate, magnesium 2-ethylhexanoate. 1,1,5,7-triazabicyclo[4.4.0]non-5-ene (TBD) and 7-methyl-1,5,7-triazabicyclo[4.4.0] ⁇ -5
  • DBU 1,8-diazabicycloundec-7-ene
  • stannous octoate magnesium 2-ethylhexanoate.
  • TBD 1,1,5,7-triazabicyclo[4.4.0]non-5-ene
  • MTBD 7-methyl-1,5,7-triazabicyclo[4.4.0] ⁇ -5
  • MTBD olefins
  • Preference is given to 1,8-diazabicycloundec-7-ene (DBU) and/or stannous octoate.
  • the invention also provides a purification method of the amphiphilic block copolymer as follows:
  • the crude amphiphilic copolymer prepared according to the solution of the present invention is dissolved in an organic solvent, washed with a dilute acid (for example, dilute hydrochloric acid) and saturated sodium chloride, and concentrated, and then a precipitating agent is added to precipitate a polymer, followed by filtration to obtain a pure Amphiphilic block copolymer of solid nature.
  • a dilute acid for example, dilute hydrochloric acid
  • saturated sodium chloride saturated sodium chloride
  • a precipitating agent is added to precipitate a polymer, followed by filtration to obtain a pure Amphiphilic block copolymer of solid nature.
  • the organic solvent is dichloromethane.
  • the precipitating agent is methyl tert-butyl ether.
  • the crude amphiphilic block copolymer of the present invention is dissolved in dichloromethane, washed with dilute hydrochloric acid and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to a small amount.
  • Dichloromethane, or concentrated to dryness was dissolved in a small amount of dichloromethane, and then methyl tert-butyl ether was added to sufficiently precipitate the polymer, followed by filtration, and the solid was dried in vacuo to give a pure solid amphiphilic block copolymer.
  • a nanomicelle drug-loading system comprising at least an amphiphilic block copolymer and a medicament of the invention.
  • the drug is preferably a poorly soluble drug.
  • the weight ratio of the drug to the amphiphilic block copolymer is from (0.5 to 100): 100, preferably from (1 to 70): 100.
  • the poorly soluble drug is selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, 7-epichelin, t-acetyl paclitaxel, 10-deacetylpaclitaxel, 10-deacetyl- 7-epitaxol, 7-xylosyl taxol, 10-deacetyl-7-glutaryl paclitaxel, 7-N,N-dimethylglycyl paclitaxel, 7-L-alanyl paclitaxel, ⁇ Taxol, doxorubicin, epirubicin, SN-38, irinotecan, topotecan, cyclophosphamide, ifosfamide, estramustine, mitoxantrone, ampicillin, cisplatin, Carboplatin, oxaliplatin, etoposide, teniposide, vinblastine, vincristine, vin
  • the nanomicelle drug delivery system further comprises a pharmaceutically acceptable pharmaceutical excipient.
  • the pharmaceutical excipients comprise from 0 to 99.9%, preferably from 0 to 50% by weight of the total system.
  • the pharmaceutical excipient is a lyophilized excipient.
  • the lyophilized excipient is at least one of lactose, mannose, sucrose, trehalose, fructose, glucose, sodium alginate, and gelatin.
  • the lyophilized excipient comprises from 0 to 99.9%, preferably from 0 to 50% by weight of the total system.
  • the nanomicelle drug-loading system comprises at least the amphiphilic block copolymer of the present invention, a poorly soluble drug, and a pharmaceutically acceptable pharmaceutical excipient.
  • the nanomicelle drug-loading system of the invention can be used for the preparation of medicaments for treating tumors, inflammation, diabetes, central nervous diseases, cardiovascular diseases, mental diseases and the like. It is preferably used to treat cancer and central nervous diseases.
  • the nanomicelle drug-loading system of the present invention can be used for the treatment of tumors, inflammation, diabetes, central nervous diseases, cardiovascular diseases, mental diseases, etc., preferably for the treatment of cancer and central nervous diseases.
  • the therapeutically effective amount referred to in the present invention means that the amount of the drug contained in the above nanomicelle drug-loading system is effective for treating diseases (specifically, cancer and central nervous diseases, etc.).
  • the nanomicelle drug-loading system of the present invention can be administered by oral, inhalation or injection route, preferably by injection route, and is generally prepared as a lyophilized powder preparation. Further, those skilled in the art can refer to the existing drug.
  • the dose determines the dose to be administered and adjusts it up and down depending on individual conditions.
  • the present invention also provides a method of preparing the nanomicelle drug-loading system, which comprises a dialysis method, a solvent evaporation method or a film hydration method, preferably a film hydration method.
  • the invention also provides a preparation method of the nano-micelle drug-loading system formed by the amphiphilic block copolymer and the aromatic ring-containing drug, which comprises a dialysis method, a solvent evaporation method, a film hydration method, and preferably a film hydration method.
  • the specific steps of the film hydration method are as follows: a certain proportion of the polymer and the drug are dissolved in an organic solvent, and after removing the organic solvent by evaporation, the drug-loaded micelle solution is obtained by adding the water for injection at 20° C. to 80° C. Ground, lyophilized excipients are added, and the micelles are lyophilized by filtration to obtain a micelle lyophilized powder.
  • the core-shell structure of the micelle without any modifying group is shown (the stretch portion of the shell is PEG, the core portion is PLA, and the dot is a poorly soluble drug).
  • the aromatic ring modifying group is located at the end of the chain of PEG and PLA (as described in the patents CN103772686B, CN105287377A)
  • all of the aromatic functional groups in the copolymer are crowded at the very center of the core structure and are capable of solubilizing the drug by interaction.
  • the area is very small (as shown in Figure 22) and thus does not significantly increase the drug loading relative to unmodified PEG-PLA.
  • the aromatic functional group modification site used in the present invention is located between PEG and PLA, and exhibits a uniform distribution in the binding portion of the core shell on the micelle structure, and thus can be significantly more compatible with hydrophobic drugs, especially those containing aromatic rings.
  • the large interaction surface area (shown in Figure 23) is ultimately manifested by a significant increase in drug loading and good micelle stability.
  • the present invention has the following characteristics:
  • the present invention couples polyethylene glycol and polylactide by using a small molecule fragment containing an aromatic ring, especially an amino acid containing an aromatic ring, an amino alcohol or a polypeptide fragment, and the resulting amphiphilic block copolymer is difficult to contain.
  • Soluble drugs especially those containing aromatic rings, in the process of self-assembly to form micelles, the additional introduction of the aromatic ring improves the hydrophobic properties of the copolymer, and also enhances the conjugation between the copolymer and the drug, thereby greatly It promotes the loading capacity of micelles on drugs and also improves the stability of micelle drugs.
  • the mass ratio of the drug/copolymer in the micelle lyophilized powder obtained by the invention can be up to 70:100, and can be stabilized up to 72 h after reconstitution with physiological saline; as shown in Fig. 15, the unmodified PEG-PLA (Korea When the drug loading is 20:100 (drug: copolymer mass ratio), visible turbidity appears 6 hours after reconstitution, and obvious particle precipitation occurs in 24 hours. On the other hand, the aromatic ring-modified amphiphilic block copolymer used in the solution of the present invention was clearly clarified at 72 hours when the paclitaxel was loaded at a drug loading of 20:100 (drug: copolymer mass ratio). As shown in FIG. 16, at a drug loading of 20:100, 30:100, 40:100, 60:100, the amphiphilic block copolymer used in the solution of the present invention and the micelle formed by paclitaxel are 72 hours is still stable.
  • the aromatic ring-containing small molecule fragment used in the present invention is used as a linker, and in particular, an amphiphilic block copolymer using an aromatic ring-containing amino acid fragment as a linker produces metabolites in vivo.
  • a substance with good biocompatibility is a safe biomedical material;
  • the catalyst used in the process of initiating the polymerization of lactide, especially DBU, has a polymerization temperature of room temperature and does not require strict anhydrous and oxygen-free operation, and a copolymer having a narrow molecular weight distribution can be obtained.
  • the catalyst can be removed simply by pickling, the purification method is simple, and there is no problem of heavy metal tin residue;
  • the invention adopts a precipitating agent which is safer than diethyl ether in the preparation of copolymer precipitation, especially methyl tert-butyl ether, which is suitable for industrial scale production;
  • Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (i.e., a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, more preferably benzene.
  • a phenyl group is most preferred.
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane.
  • An alkylthio group is preferably a hydroxyl group.
  • hydroxy, thiol and carboxy protecting groups of the present invention are suitable for the protection of hydroxy, thiol and carboxy groups known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GM Wuts). Hydroxyl protecting group.
  • the hydroxy protecting group may be a C 1-10 alkyl group or a substituted alkyl group, for example: methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxy.
  • Ethyl, 2-tetrahydropyranyl (THP), etc. may be (C 1-10 alkyl or aryl) acyl group, for example: formyl, acetyl, benzoyl, etc.; may be (C 1-6 An alkyl group or a C 6-10 aryl)sulfonyl group; also a (C 1-6 alkoxy group or a C 6-10 aryloxy)carbonyl group; or a (C 1-10 alkyl group or an aryl group) 3 silyl group, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and the like.
  • the amine protecting group of the present invention is a suitable group for amine group protection known in the art, see the amine protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts). .
  • the amine protecting group may be an amide protecting group, a carbamate protecting group or the like.
  • the poorly soluble drug of the present invention refers to a drug having a solubility in an aqueous medium of less than 1 g/1000 mL according to the Chinese Pharmacopoeia.
  • the number average molecular weight is calculated by the nuclear magnetic resonance spectrum.
  • Figure 7 is a nuclear magnetic resonance spectrum of the copolymer Ia
  • Figure 8 is a nuclear magnetic resonance spectrum of the copolymer Ib
  • Figure 9 is a nuclear magnetic resonance spectrum of the copolymer Ic
  • Figure 10 is a nuclear magnetic resonance spectrum of the copolymer Id
  • Figure 11 is a nuclear magnetic resonance spectrum of the copolymer Ie
  • Figure 12 is a nuclear magnetic resonance spectrum of the copolymer Il
  • Figure 13 is a transmission electron micrograph of micelles formed by copolymer Ia and paclitaxel
  • Figure 14 is a particle size diagram of micelles formed by copolymer Ia and paclitaxel
  • Figure 15 is a graph showing the stability of micelles formed by unmodified PEG-PLA (Korea Sanyo) and paclitaxel (weight ratio of paclitaxel to copolymer is 20:100) and the copolymer of the present invention Ia and paclitaxel form micelles (Paclitaxel and a stability comparison chart of the copolymer weight ratio of 20:100);
  • Figure 16 is a graph showing the stability of different paclitaxel-copolymer Ia drug loading ratios
  • Figure 17 is a graph showing the inhibitory effect of paclitaxel micelles, Genexol-PM paclitaxel micelles and paclitaxel injection on the tumor volume of Colo-205 cells;
  • Figure 18 is a graph showing changes in body weight of paclitaxel micelles, Genexol-PM paclitaxel micelles, and paclitaxel injections in nude mice;
  • Figure 19 is a graph showing the inhibitory effect of paclitaxel micelles, Genexol-PM paclitaxel micelles and paclitaxel injection on the tumor volume of MCF-7 cells;
  • Figure 20 is a graph showing changes in body weight of paclitaxel micelles, Genexol-PM paclitaxel micelles, and paclitaxel injections in nude mice;
  • Figure 21 is a schematic view showing the morphology of unmodified PEG-PLA micelles
  • Figure 22 is a schematic view showing the morphology of PLA end-modified PEG-PLA micelles
  • Figure 23 is a schematic view showing the morphology of a PLA-linker-PLA micelle of the present invention.
  • a polyethylene glycol monomethyl ether having a number average molecular weight of 4000, a racemic tryptophan, and a DL-lactide are used as a raw material, and a compound is obtained by introducing a linker and initiating polymerization. If, the number average molecular weight is 7900 and the PDI is 1.07.
  • a polyethylene glycol monomethyl ether having a number average molecular weight of 5000, tyrosine, and DL-lactide is used as a raw material, and a compound Ig is obtained by introducing a linker and initiating polymerization.
  • the average molecular weight was 10,000 and the PDI was 1.09.
  • a polyethylene glycol monomethyl ether having a number average molecular weight of 2000, histidine, and DL-lactide is used as a raw material, and a compound Ih is obtained by introducing a linker and initiating polymerization.
  • the average molecular weight was 5000 and the PDI was 1.05.
  • a polyethylene glycol monobenzyl ether, a phenylalanine, a DL-lactide having a number average molecular weight of 2000 is used as a raw material, and a compound Ii is obtained by introducing a linker and initiating polymerization.
  • the number average molecular weight was 4000 and the PDI was 1.06.
  • a polyethylene glycol monobenzyl ether, a phenylalanine, a glycine, a DL-lactide having a number average molecular weight of 10,000 is used as a raw material, and a compound is obtained by introducing a linker and initiating polymerization.
  • Ij has a number average molecular weight of 20,000 and a PDI of 1.08.
  • a polyethylene glycol monomethyl ether having a number average molecular weight of 6000, phenylalanine, glycine, D-tyrosine, and DL-lactide is used as a raw material, and a linker is introduced.
  • the polymerization was initiated to obtain a compound Ik having a number average molecular weight of 14,000 and a PDI of 1.07.
  • polyethylene glycol monomethyl ether, phenylalanine and DL-lactide having a number average molecular weight of 2000 are used as raw materials, by introducing a linker and initiating polymerization, and protecting with an acetyl group.
  • the compound Il was obtained, the number average molecular weight was 7,000, and the PDI was 1.06.
  • a polyethylene glycol monomethyl ether having a number average molecular weight of 2000, phenylalanine, DL-lactide is used as a raw material, a linker is introduced and polymerization is initiated, and a benzoyl group is used.
  • the PLA end was protected to obtain a compound Im having a number average molecular weight of 4,500 and a PDI of 1.06.
  • polyethylene glycol monomethyl ether, phenylalanine, DL-lactide having a number average molecular weight of 2000 is used as a raw material, a linker is introduced and polymerization is initiated, and Boc protection is used.
  • the phenylalanine protected the PLA end to obtain the compound In, the number average molecular weight was 5,000, and the PDI was 1.04.
  • a polyethylene glycol monomethyl ether having a number average molecular weight of 2000, dithiodipropionic acid, phenylalaninol or DL-lactide is used as a raw material, and a linker is introduced.
  • the polymerization was initiated to obtain a compound Ip having a number average molecular weight of 4,300 and a PDI of 1.09.
  • polyethylene glycol monomethyl ether, phthalimide, tert-butoxycarbonyl protected phenylalanine, DL-lactide having a number average molecular weight of 2000 were used as raw materials.
  • a linker was introduced and polymerization was initiated to obtain a compound Iq having a number average molecular weight of 5,000 and a PDI of 1.07.
  • a polyethylene glycol monomethyl ether having a number average molecular weight of 2000, thioglycolic acid, tert-butoxycarbonyl protected phenylalanine, DL-lactide is used as a raw material, and a linker is introduced. And polymerization was initiated to obtain a compound Ir having a number average molecular weight of 6000 and a PDI of 1.07.
  • a polyethylene glycol monomethyl ether having a number average molecular weight of 4000, butyrolactone, t-butoxycarbonyl protected phenylalanine, DL-lactide is used as a raw material, and a linker is introduced ( Linker) and polymerization was initiated to obtain a compound Is having a number average molecular weight of 8,000 and a PDI of 1.07.
  • a polyethylene glycol monomethyl ether having a number average molecular weight of 5000, a phenylalanine protected by a tert-butoxycarbonyl group, and a DL-lactide are used as raw materials, and a linker is introduced.
  • the polymerization was initiated to obtain the compound It, the number average molecular weight was 9000, and the PDI was 1.07.
  • a polyethylene glycol monomethyl ether having a number average molecular weight of 3000, D-phenylalanine protected by tert-butoxycarbonyl, and DL-lactide are used as raw materials, and a linker is introduced. And polymerization was initiated to obtain a compound Iu having a number average molecular weight of 8,000 and a PDI of 1.07.
  • a polyethylene glycol monomethyl ether having a number average molecular weight of 10,000, L-tryptophan protected by t-butoxycarbonyl group, and DL-lactide are used as raw materials, and a linker is introduced.
  • the polymerization was initiated to obtain a compound Iv having a number average molecular weight of 30,000 and a PDI of 1.07.
  • a polyethylene glycol monomethyl ether having a number average molecular weight of 20,000, Fmoc-protected L-phenylalanine, glycine, DL-lactide is used as a raw material, and a linker is introduced.
  • the polymerization was initiated to obtain a compound Iw having a number average molecular weight of 40,000 and a PDI of 1.07.
  • polyethylene glycol monomethyl ether (1 g) having a number average molecular weight of 2000, L-phenylalanine (132 mg) protected by Boc, and DL-lactide (970 mg) were used as raw materials.
  • Compound Ix was obtained by introducing a linker and initiating polymerization, and the number average molecular weight was 4,200, and the PDI was 1.07.
  • polyethylene glycol monomethyl ether (1 g) having a number average molecular weight of 2000, L-phenylalanine (132 mg) protected by Boc, and DL-lactide (1.22 g) were used as raw materials.
  • the compound Iy was obtained by introducing a linker and initiating polymerization, and had a number average molecular weight of 4,700 and a PDI of 1.07.
  • polyethylene glycol monomethyl ether (1 g) having a number average molecular weight of 2000, L-phenylalanine (132 mg) protected by Boc, and DL-lactide (2.73 g) were used as raw materials.
  • the compound Iz was obtained by introducing a linker and initiating polymerization, and the number average molecular weight was 5,000, and the PDI was 1.07.
  • polyethylene glycol monomethyl ether (1 g) having a number average molecular weight of 2000, L-phenylalanine (132 mg) protected by Boc, and DL-lactide (1.47 g) were used as raw materials.
  • Compound Iaa was obtained by introducing a linker and initiating polymerization, and the number average molecular weight was 5,200, and the PDI was 1.07.
  • 500mg amphiphilic block copolymer Ia and 100mg paclitaxel were placed in a 500mL flask, dissolved in 100mL acetonitrile; shaken in a shaker at room temperature for 30min; acetonitrile was removed by rotary evaporation to form a transparent film on the wall of the flask; Introduce 150mL of pure water at 30 ° C; shake into a uniform solution with obvious blue opalescence; pass through a 0.22 ⁇ m filter; freeze-dry to a white powdery solid on a lyophilizer; HPLC to determine the paclitaxel content of the solid after lyophilization is 16% .
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 5 mg/mL, and the stabilization time was greater than 72 h at room temperature.
  • 500mg amphiphilic block copolymer Ia and 150mg paclitaxel were placed in a 500mL flask, dissolved in 100mL acetonitrile; shaken in a shaker at room temperature for 30min; acetonitrile was removed by rotary evaporation to form a transparent film on the wall of the flask; Introduce 150 mL of pure water at 30 ° C; shake into a uniform solution with obvious blue opalescence; pass through a 0.22 ⁇ m filter; freeze-dry to a white powdery solid on a lyophilizer; HPLC to determine the paclitaxel content of the solid after lyophilization is 23% .
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 5 mg/mL, and the stabilization time was greater than 72 h at room temperature.
  • 500mg amphiphilic block copolymer Ia and 200mg paclitaxel were placed in a 500mL flask, dissolved in 100mL acetonitrile; shaken in a shaker at room temperature for 2h; acetonitrile was removed by rotary evaporation to form a transparent film on the wall of the flask;
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 5 mg/mL, and the stabilization time was greater than 72 h at room temperature.
  • Example 48 Preparation of paclitaxel micelle lyophilized powder
  • 500mg amphiphilic block copolymer Ia and 300mg paclitaxel were placed in a 500mL flask, dissolved in 100mL acetonitrile; shaken in a shaker at room temperature for 30min; acetonitrile was removed by rotary evaporation to form a transparent film on the wall of the flask; Introduce 150 mL of pure water at 30 ° C; shake into a uniform solution with obvious blue opalescence; pass through a 0.22 ⁇ m filter; freeze-dry to a white powdery solid on a lyophilizer; HPLC to determine the paclitaxel content of the solid after lyophilization is 37% .
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 5 mg/mL, and the stabilization time was greater than 72 h at room temperature.
  • 500mg amphiphilic block copolymer Ib and 300mg paclitaxel were placed in a 500mL flask, dissolved in 100mL acetonitrile; shaken in a shaker at room temperature for 1h; acetonitrile was removed by rotary evaporation to form a transparent film on the wall of the flask; Introduce 150 mL of pure water at 50 ° C; shake into a uniform solution with obvious blue opalescence; pass through a 0.22 ⁇ m filter; freeze-dry to a white powdery solid on a lyophilizer; HPLC to determine the paclitaxel content of the solid after lyophilization is 37% .
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 5 mg/mL, and the stabilization time was greater than 72 h at room temperature.
  • Example 50 Preparation of paclitaxel micelle lyophilized powder
  • 500mg amphiphilic block copolymer Ib and 50mg paclitaxel were placed in a 500mL flask, dissolved in 100mL acetonitrile; shaken in a shaker at room temperature for 1h; acetonitrile was removed by rotary evaporation to form a transparent film on the wall of the flask; Introduce 150 mL of pure water at 50 ° C; shake into a uniform solution with obvious blue opalescence; pass through a 0.22 ⁇ m filter; freeze-dry to a white powdery solid on a lyophilizer; HPLC to determine the paclitaxel content of the solid after lyophilization is 9% .
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 3 mg/mL, and the stabilization time was more than 72 h at room temperature.
  • Example 51 Preparation of paclitaxel micelle lyophilized powder
  • 500mg amphiphilic block copolymer Ic and 150mg paclitaxel were placed in a 500mL flask, dissolved in 100mL acetonitrile; shaken in a shaker at room temperature for 30min; acetonitrile was removed by rotary evaporation to form a transparent film on the wall of the flask; Introduce 150 mL of pure water at 30 ° C; shake into a uniform solution with obvious blue opalescence; pass through a 0.22 ⁇ m filter; freeze-dry to a white powdery solid on a lyophilizer; HPLC to determine the paclitaxel content of the solid after lyophilization is 23% .
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 5 mg/mL, and the stabilization time was greater than 72 h at room temperature.
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 5 mg/mL, and the stabilization time was more than 48 h at room temperature.
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 5 mg/mL, and the stabilization time was more than 48 h at room temperature.
  • Example 54 Preparation of irinotecan micelle lyophilized powder
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 3 mg/mL, and the stabilization time was more than 24 h at room temperature.
  • 200mg amphiphilic block copolymer Ih and 20mg SN-38 were placed in a 250mL flask, dissolved in 50mL acetonitrile; shaken in a shaker at room temperature for 2h; acetonitrile was removed by rotary evaporation to form a transparent film on the wall of the flask; Introduce 50 mL of pure water at 40 ° C into the flask; shake it into a uniform solution with obvious blue opalescence; pass through a 0.22 ⁇ m filter; freeze-dry to a white powdery solid on a lyophilizer; HPLC to detect SN-38 of the solid after lyophilization The content is 9%.
  • the lyophilized powder was reconstituted with a physiological saline solution to a solution having a concentration of 1.5 mg/mL, and the stabilization time was more than 24 h at room temperature.
  • Example 56 Preparation of fulvestrant micelle freeze-dried powder
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 2 mg/mL, and the stabilization time was more than 72 h at room temperature.
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 2 mg/mL, and the stabilization time was more than 72 h at room temperature.
  • Example 58 Preparation of GW6471 micelle lyophilized powder
  • 200mg amphiphilic block copolymer Is and 50mg GW6471 were placed in a 250mL flask, dissolved in 50mL of acetone; shaken in a shaker at room temperature for 2h; acetone was evaporated to form a transparent film on the wall of the flask; quickly into the flask Introduce 50mL of pure water at 40 ° C; shake into a uniform solution with obvious blue opalescence; pass through a 0.22 ⁇ m filter; freeze-dry to a white powdery solid on a lyophilizer; HPLC to determine the GW6471 content of the solid after lyophilization is 20% .
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 2 mg/mL, and the stabilization time was more than 72 h at room temperature.
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 2 mg/mL, and the stabilization time was more than 72 h at room temperature.
  • Example 60 Preparation of dexamethasone micelle lyophilized powder
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 2 mg/mL, and the stabilization time was more than 72 h at room temperature.
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 2 mg/mL, and the stabilization time was more than 72 h at room temperature.
  • the lyophilized powder was reconstituted with physiological saline to a solution having a concentration of 2 mg/mL, and the stabilization time was more than 72 h at room temperature.
  • paclitaxel micelle the paclitaxel lyophilized powder prepared by the invention of Example 46, the weight ratio of paclitaxel to copolymer (PEG-linker-PLA) Ia is 30:100;
  • Genexol-PM micelle Korean three-domesic paclitaxel micelle lyophilized powder, the weight ratio of paclitaxel to copolymer (PEG-PLA) is 20:100;
  • Paclitaxel injection paclitaxel injection purchased from Beijing Shuanglu Pharmaceutical Co., Ltd., 30mg/5ml*10 package, product batch number: 20170501.
  • Paclitaxel micelle lyophilized powder or Genexol-PM Weigh an appropriate amount of the sample, add an appropriate amount of physiological saline, shake at a speed of 200 r / min for about 20 min until clear, for intravenous administration.
  • Intravenous administration 3 male Sprague-Dawley rats of each test compound were intravenously administered after fasting overnight, at a dose of 3 mg/kg, and the administration volume was 3 mL/kg.
  • the jugular vein puncture (about 0.15 mL per time point) of each animal was performed on polypropylene tubes before and after administration of 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours after administration.
  • Blood was collected and all blood samples were transferred to pre-chilled EDTA-K2 tubes or pre-chilled plastic microcentrifuge tubes containing 3 [mu]L of 0.5 M EDTA-K2 as anticoagulant and placed on wet ice until centrifugation.
  • Each collected blood was centrifuged at 4 ° C for 15 minutes, plasma was collected, and all plasma was stored in a freezer at approximately -80 ° C until LCMS/MS was detected.
  • the half-life of paclitaxel in the paclitaxel micelle of the present invention is significantly higher than that of the paclitaxel injection group and the Sanxon Genexol-PM of Korea, indicating that the paclitaxel micelle of the present invention may have a better therapeutic effect.
  • mice BALB/c nude mice, 5 weeks old, weighing 14-16 grams, female, provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal certificate number: 20130016001491.
  • the animals were started after 7 days of feeding in the experimental environment. Animals were housed in an IVC (independent air supply system) cage at the SPF level animal house (4 per cage). Each cage animal information card indicates the number of animals in the cage, gender, strain, date of receipt, dosing schedule, experiment number, group, and start date of the experiment. All cages, litter and drinking water are sterilized prior to use. Cage, feed and drinking water are changed twice a week.
  • IVC independent air supply system
  • Colo-205 cells Human colorectal cancer Colo-205 cells (ATCC-CCL-222) were cultured in vitro, cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin, 37 ° C5 %CO2 incubator culture. Passage was routinely digested with trypsin-EDTA twice a week. When the cell saturation is 80%-90%, when the number reaches the requirement, the cells are collected, counted, and inoculated. 0.2 mL (5 x 106) Colo-205 cells were subcutaneously inoculated into the right back of each mouse. When the average tumor volume reached 163 mm 3 , the animals were started to be administered in random groups.
  • paclitaxel micelle the paclitaxel lyophilized powder prepared by the invention of Example 46, the weight ratio of paclitaxel to copolymer (PEG-linker-PLA) Ia is 30:100;
  • Genexol-PM micelle Korean three-domesic paclitaxel micelle lyophilized powder, the weight ratio of paclitaxel to copolymer (PEG-PLA) is 20:100;
  • Paclitaxel injection paclitaxel injection purchased from Beijing Shuanglu Pharmaceutical Co., Ltd., 30mg/5ml*10 package, product batch number: 20170501.
  • Paclitaxel micelle lyophilized powder or Genexol-PM Weigh an appropriate amount of the sample, add an appropriate amount of physiological saline, shake at a speed of 200 r / min for about 20 min until clear, for intravenous administration.
  • the dosage and administration schedule are shown in Table 2.
  • the tumor volume subcutaneously in nude mice was measured 2-3 times a week, the rats were weighed, and data were recorded.
  • the dosing schedule is shown in Table 2.
  • the administration volume was calculated according to the body weight, and the administration volume was 10 ⁇ l/g.
  • TGI (%) (1-T/C) ⁇ 100%.
  • the paclitaxel micelles, Genexol-PM micelles and paclitaxel injections of the present invention have significant inhibitory effects on tumor growth in Colo-205 nude mice, wherein the paclitaxel micelles of the present invention are superior to the Genexol-PM group and paclitaxel. Injection group;
  • the paclitaxel injection group showed dysuria and animal death, and the bladder was broken after dissection.
  • the paclitaxel micelle group of the present invention was all normal, indicating that the paclitaxel micelle of the present invention is safer than paclitaxel injection.
  • mice BALB/c nude mice, 6-8 weeks old, weighing 18-20 g, female, provided by Shanghai Lingchang Biotechnology Co., Ltd., animal certificate number: 2013001829943.
  • Human breast cancer MCF-7 cells (ECACC, Cat. No. 86012803) were cultured in vitro in a single layer, culture conditions were EMEM (EBSS) + 2 mM Glutamine + 1% Non Essential Amino Acids (NEAA) medium plus 10% fetal bovine serum, 100 U /mL penicillin and 100 ⁇ g/mL streptomycin were incubated in a 37 ° C 5% CO 2 incubator. Passage was routinely digested with trypsin-EDTA twice a week. When the cell saturation is 80%-90%, when the number reaches the requirement, the cells are collected, counted, and inoculated. 0.2 mL (1 x 107) MCF-7 cells (with matrigel, volume ratio of 1:1) were subcutaneously inoculated into the right back of each mouse, and randomized group administration was started when the average tumor volume reached 209 mm 3 .
  • EMEM EM
  • NEAA Non Essential Amino Acids
  • paclitaxel micelle the paclitaxel lyophilized powder prepared in accordance with Example 36 of the present invention, the weight ratio of paclitaxel to amphiphilic block copolymer (PEG-linker-PLA) Ia is 30:100;
  • Genexol-PM micelle Korean three-domesic paclitaxel micelle lyophilized powder, the weight ratio of paclitaxel to copolymer (PEG-PLA) is 20:100;
  • Paclitaxel injection paclitaxel injection purchased from Beijing Shuanglu Pharmaceutical Co., Ltd., 30mg/5ml*10 package, product batch number: 20170501.
  • Paclitaxel micelle lyophilized powder or Genexol-PM Weigh an appropriate amount of the sample, add an appropriate amount of physiological saline, shake at a speed of 200 r / min for about 20 min until clear, for intravenous administration.
  • the dosage and administration schedule are shown in Table 4.
  • the tumor volume subcutaneously in nude mice was measured 2-3 times a week, the rats were weighed, and data were recorded.
  • the dosing schedule is shown in Table 4 below.
  • the administration volume was calculated according to the body weight, and the administration volume was 10 ⁇ l/g.
  • TGI (%) (1-T/C) ⁇ 100%.
  • the inhibitory effects of the paclitaxel micelles, Genexol-P micelles and paclitaxel injections of the present invention on the tumor volume of MCF-7 cells are shown in Table 5 and Figure 19, and the body weight change curves of nude mice are shown in Fig. 20.
  • the paclitaxel micelles, the Genexol-PM group and the paclitaxel injection of the present invention all have significant effects on the tumor growth inhibition of MCF-7 nude mice, and the paclitaxel micelles of the present invention are superior to the other two groups.
  • the paclitaxel injection group showed dysuria and animal death, and the bladder was broken after dissection.
  • the paclitaxel micelle group of the present invention was all normal, indicating that the paclitaxel micelle of the present invention is safer than paclitaxel injection.
  • the "*" carbon atom is a chiral carbon atom
  • the configuration of the chiral carbon atom is an R configuration, an S configuration or a racemate.

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Abstract

本发明涉及一种如式I所示的两亲性嵌段共聚物及其制备方法，以及该共聚物与难溶性药物形成的纳米胶束载药系统。该两亲性嵌段共聚物包括亲水性链段、疏水性链段以及用于连接亲水性链段和疏水性链段的连接子。连接子含有不饱和结构，可以增强难溶性药物与共聚物的相互作用，提高胶束的载药能力和稳定性。本发明还涉及了一种纳米载药胶束系统及其制备方法，以及该纳米载药胶束系统用于制备治疗肿瘤、炎症、糖尿病、中枢神经疾病、心血管疾病、精神疾病药物方面的用途。

Description

一种两亲性嵌段共聚物及其制备方法和纳米胶束载药系统
本申请要求申请日为2018年2月13日的中国专利申请CN201810153233.3的优先权。本申请引用该中国专利申请的全文。
技术领域
本发明涉及一种新型的聚醚-连接子-聚酯两亲性嵌段共聚物及其制备方法，以及该共聚物与难溶性药物形成稳定的胶束载药系统，属于纳米药物制剂技术领域。
背景技术
难溶性药物的输送向来都是药物制剂工艺中的难题，只有溶解后的药物才能被胃肠道上皮细胞粘膜吸收。据统计，当前市场上销售的药物有40％以上属于难溶性药物。随着组合化学和高通量筛选在新药研发上的广泛应用，难溶性药物所占的比重将会越来越大。溶解性越差的药物，口服生物利用度越低，从而不适合开发为口服制剂。为了更好的输送这种类型的药物，常规的方法是将其开发为注射剂，并通过调节pH、成盐、采用增溶剂或者制成油溶性注射剂的方法，来提高药物的溶解度。但是在实际情况中，这些途径往往在解决了药物溶解度的同时，引入了其他的弊端。
以紫杉类药物为例，紫杉醇、多西他赛、卡巴他赛、莱龙泰素等，是一种广泛使用的抗肿瘤药物，它们能够诱导和促进微管蛋白聚合，防止解聚，稳定微管。这些作用导致细胞在进行有丝分裂时不能形成纺锤体和纺锤丝，抑制了细胞分裂和增殖，从而发挥抗肿瘤作用。但是紫杉类药物的疏水性非常强，只能通过注射途径给药，并采用无水乙醇作为溶剂。注射制剂工艺中通常采用大量的聚氧乙烯蓖麻油或者吐温80等作为增溶剂来促进药物的溶解。这些增溶剂会引起过敏反应和血液毒性，一方面用药前患者需要进行脱敏治疗，另一方面也限制了治疗剂量，无法发挥紫杉类药物的最佳治疗效果。另外，这种注射液进入血液经稀释后，紫杉类药物溶解度将下降从而析出，导致用药量的不准确，从而需精确控制注射过程，否则将产生不稳定的治疗效果。因此急需开发一种安全稳定的新型给药系统。
两亲性嵌段的聚合物在水溶液中将通过自组装形成具有球形内核-外壳结构的共聚物胶束，其疏水部分形成内核，亲水部分形成外壳。内核可以作为疏水性药物的容器，将药物增溶在核心，提高载药量，降低毒副作用。外壳可以对药物起保护作用，提高药物的稳定性。当胶束进入血液稀释后，球形内核-外壳结构缓慢解离，药物得到释放，从而实现缓释的作用。胶束的粒径远远大于小分子药物本身，通常在10～200nm之间，可以减 缓药物被肾排泄及网状内皮系统的吸收，延长体内的循环时间，提高生物利用度。对于抗肿瘤药物，还可以通过高通透性和滞留效应(EPR效应)实现对肿瘤细胞的被动靶向作用，促进在肿瘤组织中的选择性分布，增加药效并减少系统副作用。
PEG-PLA(聚乙二醇聚乳酸共聚物)是被研究得最广泛和深入的两亲性嵌段共聚物。PEG(聚乙二醇)具有良好的生物相容性，且易于从身体清除，是得到FDA认可的非离子型水溶性聚合物，对人体具有很低的毒性，并被广泛用于药用辅料。PLA(聚乳酸/聚丙交酯)是研究最早的聚酯类生物可降解材料之一，它在体内降解形成的最终产物是二氧化碳和水，中间代谢产物乳酸也是正常的体内代谢产物，不会在体内积蓄或产生毒副作用。因此PEG-PLA是一种非常安全的生物医学材料。
韩国三养生物制药在临床上最早采用PEG-PLA进行药物输送，并以注射用紫杉醇胶束(商品名Genexol PM)上市。在进行紫杉醇负载时，药物与聚合物的比例最高为20:100，且胶束经溶解后在室温下的稳定时间不超过24小时，存在载药量低和稳定性差的缺点(Pharmaceutical Research 2007,24,1508-1516)。当药物与聚合物的相互作用较差时，即使可以形成胶束，这种胶束进入血液以后，也会迅速解离，造成药物泄露，从而达不到有效的药物负载和被动靶向输送的目的。专利CN103772686B中报道对PEG-PLA的末端进行叔丁氧羰基保护的苯丙氨酸修饰，可以适当提高胶束的稳定性，但药物/共聚物的比例最高也仅为20:100。专利CN105287377A中，则用芴甲氧羧基和叔丁氧羰基双保护的赖氨酸对PLA末端进行修饰，也有稳定胶束的效果，其中药物/共聚物的比例最高仅为20:90。这些修饰虽然采用了天然的氨基酸，但是保护基的存在导致了共聚物进入血液中时，可能会产生对人体有害的代谢副产物。
另一方面，在共聚物的合成过程中，上述报道的引发丙交酯聚合的催化剂都采用辛酸亚锡，反应温度在130度左右。锡试剂毒性大，微量的残留将对聚合物的安全性产生很大的影响。研究也表明，聚合物中锡含量超标将会显著影响胶束系统的动力学稳定性。另外，在高温下聚合时，容易发生聚乳酸的链回咬(back-biting，J.Am.Chem.Soc.2016,138,8674-8677)，从而导致共聚物的分子量分布变宽，造成药物释放的不可控。在实际生产中，往往需要非常繁琐的纯化手段，才能够获得适合于药物输送的合格的共聚物。如专利CN106349466A中需要采用滤膜超滤的手段进行分子量截留，以得到分子量分布窄的共聚物。专利CN103768013A采用阳离子交换树脂处理，来降低混合物中因催化剂引入的锡含量。专利CN103980466B采用活泼金属钠和有机萘为催化剂，虽然避开了辛酸亚锡，但是活泼金属对空气和水分非常敏感，对操作技能要求很高。最后，在对共聚物进行沉淀纯化过程中使用了大量的具有易爆性和麻醉性的乙醚，也会在放大生产过程中产生巨大的危害。
综上所述，现有的基于PEG-PLA的载药胶束存在载药量低(药物/共聚物比例最高仅为20:90)，共聚物合成反应条件苛刻、纯化手段繁琐等缺点。为了实现安全有效稳定的胶束药物输送，急需对共聚物的结构进行更为系统的修饰，在保证安全性的同时，更大程度地提高载药量和胶束稳定性，同时也需要开发一种工艺稳定、质量可控、环境友好的共聚物合成方法。
发明内容
本发明的目的是克服现有载药胶束载药量低、稳定性差、共聚物合成条件苛刻、纯化方式繁琐等缺点，提供一种新型的聚醚-连接子-聚酯两亲性嵌段共聚物及其绿色合成工艺，并以该共聚物与难溶性药物自组装形成稳定的药物输送系统。
本发明通过采用含有芳香环的连接子(linker)对双亲性共聚物进行修饰，含有芳香环的连接子(linker)与难溶性药物特别是含有芳香环的药物之间存在强共轭作用(π-π堆积)，使得药物分子牢固地锁定在胶束的疏水性核中，不但提高了载药胶束的稳定性，而且极大地提高了共聚物对药物的载药量。
进一步，本发明通过对具有生物安全性的聚乙二醇或单保护聚乙二醇进行含有芳香环的小分子片段修饰，引入连接子(linker)，并以DBU、TBD或MTBD等为催化剂促进丙交酯的聚合，形成具有R 1-PEG-linker-PLA-R 2结构的两亲性共聚物，其中R 1、R 2独立地为羟基保护基或氢。当连接子(linker)部分为天然氨基酸片段时，该两亲性共聚物在体内产生的代谢产物均对人体无害，具有显著的生物安全性。进一步以DBU引发丙交酯聚合时，反应条件温和，易于得到分子量分布范围窄的共聚物；DBU催化剂本身危害小，并且可以通过简单的酸洗除去，不存在重金属锡残留的安全隐患；用甲基叔丁基醚代替乙醚对共聚物进行沉淀，也提高了工艺放大生产过程中的安全性。本发明提供的两亲性共聚物的新合成工艺条件温和、质量可控、适于工业化放大生产。
通过实验证明，本发明提供的纳米载药胶束系统冻干制剂中药物/两亲性共聚物的质量比例最高可达70:100，经生理盐水复溶后，在室温下形成略带蓝色乳光的澄清溶液，室温下存放的稳定性最高可达72h；另一方面还可以显著地提高含芳香基取代的难溶性药物的溶解度，并通过对肿瘤的高通透性和滞留效应(EPR效应)，极大地提高对肿瘤的治疗效果，降低药物的毒副作用。
本发明第一方面，提供一种两亲性嵌段共聚物，所述两亲性嵌段共聚物包含亲水性链段、疏水性链段以及用于连接亲水性链段和疏水性链段的linker，所述的linker为连接子，所述的linker的结构为含有芳香环、碳碳双键、碳碳三键、共轭双键和共轭三键中的一种或多种取代的小分子片段。
在推荐的实施例中，所述的linker结构中的芳香环、碳碳双键、碳碳三键、共轭双键或共轭三键可以位于所述的两亲性嵌段共聚物的直链中，也可以位于所述的两亲性嵌段共聚物的侧链上。
在推荐的实施例中，所述的连接子linker的结构为直链或者侧链上含有芳香环取代的C 1-C 30小分子片段。
在推荐的实施例中，所述的直链或者侧链上含有芳香环取代的C 1-C 30小分子片段中包含或者不包含杂原子取代，所述杂原子选自氧原子、氮原子、硫原子和磷原子中的一个或多个。
在推荐的实施例中，所述的linker的结构为C 1-C 30小分子片段，所述C 1-C 30小分子片段被芳香环取代；
所述芳香环为C 6-C 20芳基、被R a取代的C 6-C 20芳基、C 2-C 20杂芳基或被R b取代的C 2-C 20杂芳基，
所述R a的个数为一个或多个，当所述R a的个数为多个时，所述R a相同或不同；
所述R b的个数为一个或多个，当所述R b的个数为多个时，所述R b相同或不同；
R a和R b独立地为C 1～C 6烷基、C 1～C 6烷氧基、C 4～C 6环烷基、卤素、羟基或硝基；
所述C 2-C 20杂芳基或所述被R b取代的C 2-C 20杂芳基中的杂原子为O、S或N，所述杂原子的个数为一个或多个，当为多个时，所述杂原子相同或不同。
在推荐的实施例中，所述芳香环中，所述C 6-C 20芳基或所述被R a取代的C 6-C 20芳基中的C 6-C 20芳基为C 6-C 10芳基，进一步优选为苯基或萘基。
在推荐的实施例中，所述芳香环中，所述C 2-C 20杂芳基或所述被R b取代的C 2-C 20杂芳基中的C 2-C 20杂芳基为C 2-C 10杂芳基，进一步优选为C 3-C 8杂芳基，例如吲哚基或咪唑基。
在推荐的实施例中，R a或R b中，所述C 1～C 6烷基优选为C 1～C 3烷基。
在推荐的实施例中，R a或R b中，所述C 1～C 6烷氧基优选为C 1～C 3烷氧基。
在推荐的实施例中，R a和R b独立地为C 1～C 3烷基、C 1～C 3烷氧基、卤素、羟基或硝基。
在推荐的实施例中，所述芳香环为C 6-C 10芳基(例如苯基或萘基)、被R a取代的C 6-C 10芳基(例如苯基或萘基)、C 2-C 10杂芳基(例如吲哚基或咪唑基)或被R b取代的C 2-C 10杂芳基(例如吲哚基或咪唑基)，R a和R b独立地为C 1～C 3烷基、C 1～C 3烷氧基、卤素、羟基或硝基。
在推荐的实施例中，所述C 1-C 30小分子片段为C 2-C 10小分子片段。
在推荐的实施例中，所述C 1-C 30小分子片段被1～3个(例如1个或2个)芳香环取 代。
在推荐的实施例中，在所述C 1-C 30小分子片段包含或者不包含杂原子取代，所述杂原子选自氧原子、氮原子、硫原子和磷原子中的一个或多个。所述杂原子取代的个数为一个或多个，优选为1～4个(例如1个、2个、3个或4个)。
在推荐的实施例中，所述linker的结构选自如下任一结构：
Figure PCTCN2019074816-appb-000001
Ar为芳香环，所述芳香环的定义如前所述；
T 1为单键或
Figure PCTCN2019074816-appb-000002
p为0或1，q为1、2或3，X 1为-O-、-S-或-NH-；
T 2为单键或
Figure PCTCN2019074816-appb-000003
r为0、1、2、3、4或5，
T 3为单键或
Figure PCTCN2019074816-appb-000004
在推荐的实施例中，T 1为单键，T 2为单键。
在推荐的实施例中，T 1为
Figure PCTCN2019074816-appb-000005
p为0，q为2，X 1为-S-或-NH-，T 2为单键。
在推荐的实施例中，T 1为
Figure PCTCN2019074816-appb-000006
p为1，q为2，X 1为-O-，T 2为单键。
在推荐的实施例中，所述的linker的结构为含有芳香环的氨基酸、含有芳香环的氨 基醇或含有芳香环的多肽的C 1-C 30小分子片段，其中芳香环也可以来自于氨基酸、氨基醇或多肽上羟基、巯基、胺基或者羧基的保护基。较佳地，其中芳香环位于氨基酸、氨基醇或多肽的侧链，或者位于氨基酸、氨基醇或多肽的羟基、巯基、胺基或者羧基的保护基。
在推荐的实施例中，所述含有芳香环的氨基酸中的氨基酸可以是R构型、S构型或外消旋体。
在推荐的实施例中，所述含有芳香环的氨基醇中的氨基醇可以是R构型、S构型或外消旋体。
在推荐的实施例中，所述的含有芳香环的氨基酸选自苯丙氨酸、组氨酸、酪氨酸、色氨酸和3-(2-萘基)-丙氨酸中的一个或多个。
在推荐的实施例中，所述的含有芳香环的多肽中的一个或多个片段来自于苯丙氨酸、组氨酸、酪氨酸、色氨酸和3-(2-萘基)-丙氨酸中的一个或多个。
在推荐的实施例中，所述的苯丙氨酸、组氨酸、酪氨酸、色氨酸或3-(2-萘基)-丙氨酸可以是R构型、S构型或外消旋体。
在推荐的实施例中，所述的含有芳香环的氨基醇选自苯丙氨醇、组氨醇、酪氨醇、色氨醇和3-(2-萘基)-丙氨醇中的一个或多个；苯丙氨醇、组氨醇、酪氨醇、色氨醇、3-(2-萘基)-丙氨醇分别由苯丙氨酸、组氨酸、酪氨酸、色氨酸、3-(2-萘基)-丙氨酸还原得到。
在推荐的实施例中，所述的苯丙氨醇、组氨醇、酪氨醇、色氨醇或3-(2-萘基)-丙氨醇可以是R构型、S构型或外消旋体。
在推荐的实施例中，所述的直链或者侧链上含有芳香环取代的C 1-C 30小分子片段中含有芳香环的氨基酸、氨基醇或多肽，其中芳香环也可以来自于氨基酸、氨基醇或多肽上羟基、巯基、胺基或者羧基的保护基。较佳地，其中芳香环位于氨基酸、氨基醇或多肽的侧链，或者位于氨基酸、氨基醇或多肽的羟基、巯基、胺基或者羧基的保护基。
在推荐的实施例中，所述的亲水性链段为数均分子量在400～20000之间的聚乙二醇链段或单保护的聚乙二醇链段。所述单保护的聚乙二醇链段优选为单端基为羟基保护基的聚乙二醇链段。
在推荐的实施例中，所述疏水性链段选自数均分子量在400～20000之间的聚丙交酯链段、单保护的聚丙交酯链段、聚乙交酯链段、单保护的聚乙交酯链段、聚乙丙交酯链段、单保护的聚乙丙交酯链段、聚己内酯链段、单保护的聚己内酯链段、聚碳酸酯链段、单保护的聚碳酸酯链段、聚二氧环己酮链段、或者单保护的聚二氧环己酮链段中的一种。所述单保护的聚丙交酯链段、单保护的聚乙交酯链段、单保护的聚乙丙交酯链段、保护的聚己内酯链段、单保护的聚碳酸酯链段和单保护的聚二氧环己酮链段中的单保护各自 独立地优选为单端基为羟基保护基。
在推荐的实施例中，所述疏水性链段选自数均分子量在400～20000之间的聚丙交酯链段或单保护的聚丙交酯链段，所述单保护的聚丙交酯链段优选为单端基为羟基保护基的聚丙交酯链段。
在推荐的实施例中，所述的两亲性嵌段共聚物具有如下结构：R 1-PEG-linker-PLA-R 2，
其中R 1、R 2独立地选自羟基保护基或氢；
PEG为数均分子量在400～20000的聚乙二醇嵌段，linker为连接子，PLA为数均分子量在400～20000的聚丙交酯嵌段，聚乙二醇嵌段和聚丙交酯嵌段的数均分子量比例为1:(0.5～2)。
本发明的另一个目的在于提供上述两亲性嵌段共聚物的制备方法。
本发明提供的技术方案如下：
上述两亲性嵌段共聚物的制备方法，包括以下步骤：
1)对数均分子量为400～20000的聚乙二醇或单保护聚乙二醇进行linker修饰；
2)有机溶剂中，在催化剂的作用下，将步骤1)的产物与DL-丙交酯、L-丙交酯、D-丙交酯、乙交酯、DL-丙交酯和乙交酯的不同比例混合物、L-丙交酯和乙交酯的不同比例混合物、D-丙交酯和乙交酯的不同比例混合物、己内酯、双酚A和碳酸二苯酯的混合物或对二氧环己酮进行聚合，
3)可选地，对步骤2)得到的聚合物进行末端羟基保护，即可。
在推荐的实施例中，所述两亲性嵌段共聚物的制备方法，包括以下步骤：
1)对数均分子量为400～20000的聚乙二醇或单保护聚乙二醇进行含有芳香基取代的小分子片段修饰，得到R 1-PEG-linker；
2)将R 1-PEG-linker与DL-丙交酯或L-丙交酯或D-丙交酯溶于有机溶剂中，加入催化剂进行聚合，得到R 1-PEG-linker-PLA；
3)可选地，对R 1-PEG-linker-PLA进行PLA末端羟基保护，得到R 1-PEG-linker-PLA-R 2。
其中所得的PLA为数均分子量在400～20000的聚丙交酯；
R 1、R 2独立地为羟基保护基或氢。
在推荐的实施例中，所述两亲性嵌段共聚物的制备方法中，步骤2)中，所述催化剂为1,8-二氮杂二环十一碳-7-烯(DBU)，辛酸亚锡，2-乙基己酸镁，1,5,7-三氮杂二环[4.4.0]癸-5-烯(TBD)和7-甲基-1,5,7-三氮杂二环[4.4.0]癸-5-烯(MTBD)中的一种或多种。优选为1,8-二氮杂二环十一碳-7-烯(DBU)和/或辛酸亚锡。
在推荐的实施例中，所述两亲性嵌段共聚物的制备方法中，步骤2)后增加一个步骤： 将所得的产物(例如上述R 1-PEG-linker-PLA)进行纯化。
在推荐的实施例中，所述两亲性嵌段共聚物的制备方法中，步骤3)后增加一个步骤：将所得的产物(例如上述R 1-PEG-linker-PLA-R 2)进行纯化。
在推荐的实施例中，所述两亲性嵌段共聚物的制备方法中，步骤2)后增加一个步骤：将所得的产物(例如上述R 1-PEG-linker-PLA)进行纯化，并且，步骤3)后增加一个步骤：将所得的产物(例如上述R 1-PEG-linker-PLA-R 2)进行纯化。
在推荐的实施例中，所述的两亲性嵌段共聚物具有如下结构：
Figure PCTCN2019074816-appb-000007
其中，linker、R 1、R 2的定义如前所述，
n＝8～455(例如n＝8、9、400或455)；m＝3～160(例如m＝3、140或160)。
在推荐的实施例中，n＝9～455；m＝3～140。
在推荐的实施例中，n＝8～440；m＝3～160。
在推荐的实施例中，所述两亲性嵌段共聚物选自如下任一结构：
Figure PCTCN2019074816-appb-000008
其中，R 1、R 2、n和m的定义如上所述；
Ar为如前所述的芳香环；
T 1为单键或
Figure PCTCN2019074816-appb-000009
p为0或1，q为1、2或3(例如2)，X 1为-O-、-S-或-NH-；
T 2为单键或
Figure PCTCN2019074816-appb-000010
r为0、1、2、3、4或5(例如3)，
T 3为单键或
Figure PCTCN2019074816-appb-000011
在推荐的实施例中，T 1为单键，T 2为单键。
在推荐的实施例中，T 1为
Figure PCTCN2019074816-appb-000012
p为0，q为2，X 1为-S-或-NH-，T 2为单键。
在推荐的实施例中，T 1为
Figure PCTCN2019074816-appb-000013
p为1，q为2，X 1为-O-，T 2为单键。
在推荐的实施例中，所述两亲性共聚物具有如下结构：
Figure PCTCN2019074816-appb-000014
其中，R 1、R 2和Ar的定义如上所述；
n＝8～440；m＝3～160。
所述两亲性嵌段共聚物进一步优选为选自如下任一结构：
Figure PCTCN2019074816-appb-000015
Figure PCTCN2019074816-appb-000016
Figure PCTCN2019074816-appb-000017
其中，n和m的定义如前所述。
在推荐的实施例中，所述两亲性嵌段共聚物还可选自如下任一结构：
Figure PCTCN2019074816-appb-000018
Figure PCTCN2019074816-appb-000019
其中，n和m的定义如前所述。
本发明还提供了一种如式II所示的聚合物，
Figure PCTCN2019074816-appb-000020
其中，linker和n如式I中定义；
R 1为羟基保护基或氢.
在推荐的实施例中，所述如式II所示的聚合物选自如下任一结构：
Figure PCTCN2019074816-appb-000021
其中，R 1、n、T 1、T 2、T 3和Ar的定义如前所述。
在推荐的实施例中，所述如式II所示的聚合物选自如下任一结构：
Figure PCTCN2019074816-appb-000022
其中，n和Ar的定义如前所述。
本发明还提供了一种如式II所示的聚合物的制备方法，式II所示的聚合物由如式III所示的聚合物经过小分子修饰制得，
Figure PCTCN2019074816-appb-000023
其中，linker和n如式I中定义；
R 1为羟基保护基或氢。
本发明还提供了一种如式II-1所示的聚合物的制备方法，如式II-1所示的聚合物由如式III-1所示的聚合物经过脱保护反应制得，
Figure PCTCN2019074816-appb-000024
其中，R 1、n、T 1、T 2和Ar的定义如前所述，R 4为胺基保护基。
本发明还提供了一种如式II-2所示的聚合物的制备方法，如式II-2所示的聚合物由 如式III-2所示的聚合物经过脱保护反应制得，
Figure PCTCN2019074816-appb-000025
其中，R 1、n、T 1、T 2和Ar的定义如前所述，R 3为羟基保护基。
在推荐的实施例中，如式III-2所示的聚合物由如式II-1所示的聚合物与式VI-1所示化合物经过缩合反应制得，
Figure PCTCN2019074816-appb-000026
其中，R 1、n、T 1、T 2、Ar和R 3的定义如前所述。
本发明还提供了一种如式II-3所示的聚合物的制备方法，如式II-3所示的聚合物由式III-3所示的聚合物与式IV-D所示的化合物发生缩合反应制得，
Figure PCTCN2019074816-appb-000027
其中，R 1、n、T 3和Ar的定义如前所述。
本发明还提供了一种如式I所示的两亲性嵌段共聚物的制备方法，其包括如下步骤：
1)如前所述的如式II所示的聚合物在催化剂的作用下引发丙交酯聚合，得式IA所示的共聚物，所述丙交酯为DL-丙交酯、L-丙交酯或D-丙交酯；所述催化剂如前所述；
Figure PCTCN2019074816-appb-000028
2)如式IA所示的共聚物经过羟基保护反应，得如式I所示的两亲性嵌段共聚物；
Figure PCTCN2019074816-appb-000029
其中，linker、R 1、R 2、m和n的定义如前所述，当R 2为氢时，无需进行步骤2)。
在推荐的实施例中，所述如式I所示的两亲性嵌段共聚物的制备方法中，如式II所示的聚合物由如下方法制得：如式III所示的聚合物经过小分子片段修饰，即可；
Figure PCTCN2019074816-appb-000030
其中，linker、R 1和n的定义如前所述。
在推荐的实施例中，本发明提供了一种如式I所示的两亲性嵌段共聚物的制备方法，
Figure PCTCN2019074816-appb-000031
其中，linker的结构为含有芳香环、碳碳双键、碳碳三键、共轭双键或共轭三键中的一种或多种取代的小分子片段。
R 1、R 2独立地为羟基保护基或氢；
n＝8～440；m＝3～160。
具体地来说，包括以下步骤：
1)式III所示的聚合物经过小分子片段修饰制得如式II所示的聚合物；
2)式II所示的聚合物在催化剂的作用下引发丙交酯聚合制得如式IA所示的共聚物；
3)可选地，式IA所示的共聚物经过羟基保护制得如式I所示的两亲性嵌段共聚物。
本发明还提供了一种如式IC’所示的两亲性嵌段共聚物，
Figure PCTCN2019074816-appb-000032
其中，n、m和Ar的定义如前所述；
R 5为取代或未取代的C 1-C 10烷基、C 6-C 20芳基或氨基酸残基。
在推荐的实施例中，R 5为取代或未取代的C 1-C 6烷基(例如甲基)、C 6-C 8芳基(例如苯基)或氨基酸残基(例如
Figure PCTCN2019074816-appb-000033
)，R 5优选为未取代的C 1-C 3烷基(例如甲基)、苯基或氨基酸残基(例如
Figure PCTCN2019074816-appb-000034
)。
本发明还提供了一种如式IC’所示的两亲性嵌段共聚物的制备方法，式IC’所示的两亲性嵌段共聚物由式IB所示的两亲性嵌段共聚物经过酰基保护制得，
Figure PCTCN2019074816-appb-000035
其中，Ar、R 5、n和m的定义如前所述。
在推荐的实施例中，本发明还提供了一种如式IC所示的两亲性嵌段共聚物，
Figure PCTCN2019074816-appb-000036
其中，n＝8～440；m＝3～160；
Ar为取代或未取代的芳基。
在推荐的实施例中，本发明还提供了一种如式IC所示的两亲性嵌段共聚物的制备方法，式IC两亲性嵌段共聚物由式IB两亲性嵌段共聚物经过乙酰基保护制得，
Figure PCTCN2019074816-appb-000037
其中，n＝8～440；m＝3～160；
Ar为取代或未取代的芳基。
本发明还提供了一种如式IB所示的两亲性嵌段共聚物，
Figure PCTCN2019074816-appb-000038
其中，n、m和Ar的定义如前所述。
本发明还提供了一种如式IB所示的两亲性嵌段共聚物的制备方法，式IB所示的两亲性嵌段共聚物由式IIA所示的聚合物在催化剂的作用下引发丙交酯聚合制得，
Figure PCTCN2019074816-appb-000039
其中，n、m和Ar的定义如前所述。
本发明还提供了一种如式IIA所示的聚合物，
Figure PCTCN2019074816-appb-000040
其中，n和Ar的定义如前所述。
本发明还提供了一种如式IIA所示的聚合物的制备方法，式IIA所示的聚合物由式IIIA所示的聚合物发生保护基水解反应制得，
Figure PCTCN2019074816-appb-000041
其中，R 3为羟基保护基；
n和Ar的定义如前所述。
本发明还提供了一种如式IIIA所示的聚合物，
Figure PCTCN2019074816-appb-000042
其中，R 3、n和Ar的定义如前所述。
本发明还提供一种如式IIIA所示的聚合物的制备方法，式IIIA所示的聚合物由式IVA所示的聚合物发生缩合反应制得，
Figure PCTCN2019074816-appb-000043
其中，R 3、n和Ar的定义如前所述。
本发明还提供了一种如式IVA所示的聚合物，
Figure PCTCN2019074816-appb-000044
其中，n和Ar的定义如前所述。
本发明还提供了一种如式IVA所示的聚合物的制备方法，式IVA所示的聚合物由式VA所示的聚合物发生胺基保护基水解反应制得，
Figure PCTCN2019074816-appb-000045
其中，R 4为胺基保护基；
n和Ar的定义如前所述。
本发明还提供了一种如式VA所示的聚合物，
Figure PCTCN2019074816-appb-000046
其中，R 4、n和Ar的定义如前所述。
本发明还提供了一种如式VA所示的聚合物的制备方法，式VA所示的聚合物由式VIA所示的聚合物与式VIIA所示的化合物经过缩合反应制得，
Figure PCTCN2019074816-appb-000047
其中，R 4、n和Ar的定义如前所述；
氨基酸化合物VIIA的构型可以是S构型、R构型或者外消旋体。
在推荐的实施例中，提供了如式IB或IC’所示的两亲性嵌段共聚物的制备方法，
Figure PCTCN2019074816-appb-000048
其中，n、m、R 3、R 4、R 5和Ar的定义如前所述。
氨基酸化合物VIIA的构型可以是S构型、R构型或者外消旋体。
具体地来说，包括以下步骤：
1)式VIA所示的聚合物与式VIIA所示的化合物经过缩合反应制得如式VA所示的 聚合物；
2)式VA所示的聚合物经过脱保护反应制得如式IVA所示的聚合物；
3)式IVA所示的聚合物经过缩合反应制得如式IIIA所示的聚合物；
4)式IIIA所示的聚合物经过脱保护反应制得如式IIA所示的聚合物；
5)式IIA所示的聚合物在催化剂的作用下引发丙交酯聚合制得如式IB所示的两亲性嵌段共聚物；
6)如式IB所示的两亲性嵌段聚合物在酰基化试剂的作用下经过酯化反应得到如式IC’所示的两亲性嵌段共聚物。
在推荐的实施例中，如式IB或IC’所示的两亲性嵌段共聚物的制备方法中，步骤5)后增加一个步骤：将如式IB所示的两亲性嵌段共聚物进行纯化。
本发明还提供了一种如式IB所示的两亲性嵌段共聚物的制备方法，式IB所示的两亲性嵌段共聚物由式IVA所示的聚合物在催化剂的作用下引发丙交酯聚合制得，
Figure PCTCN2019074816-appb-000049
其中，n、m和Ar的定义如前所述。
在另一个推荐的实施例中，提供了如式IB所示的两亲性嵌段共聚物的制备方法，
Figure PCTCN2019074816-appb-000050
其中，R 4、n、m和Ar的定义如前所述。
氨基酸化合物VIIA的构型可以是S构型、R构型或者外消旋体。
具体地来说，包括以下步骤：
1)式VIA所示的聚合物与式VIIA所示的化合物经过缩合反应制得如式VA所示的聚合物；
2)式VA所示的聚合物经过脱保护反应制得如式IVA所示的聚合物；
3)式IVA所示的聚合物在催化剂的作用下引发丙交酯聚合制得如式IB所示的两亲性嵌段共聚物；
4)可选地，对式IB所示的两亲性嵌段共聚物进行纯化。
本发明还提供了一种如式ID所示的两亲性嵌段聚合物，
Figure PCTCN2019074816-appb-000051
其中，n、m和Ar的定义如前所述。
本发明还提供了一种如式ID所示的两亲性嵌段共聚物的制备方法，式ID所示的两亲性嵌段共聚物由式IID所示的聚合物在催化剂的作用下引发丙交酯聚合制得，
Figure PCTCN2019074816-appb-000052
其中，n、m和Ar的定义如前所述。
本发明还提供了一种如式IID所示的聚合物，
Figure PCTCN2019074816-appb-000053
其中，n和Ar的定义如前所述。
本发明还提供了一种如式IID所示的聚合物的制备方法，式IID所示的聚合物由式IIID所示的聚合物与式IVD所示的化合物发生缩合反应制得，
Figure PCTCN2019074816-appb-000054
其中，n和Ar的定义如前所述；
氨基醇化合物IVD的构型可以是S构型、R构型或者外消旋体。
本发明还提供了一种如式IIID所示的聚合物，
Figure PCTCN2019074816-appb-000055
其中，n的定义如前所述。
本发明还提供了一种如式IIID所示的聚合物的制备方法，式IIID所示的聚合物由式VIA所示的聚合物与式VID所示的化合物经过开环缩合反应制得，
Figure PCTCN2019074816-appb-000056
其中，n的定义如前所述。
在另一推荐的实施例中，本发明提供了如式ID所示的两亲性嵌段共聚物的制备方法，
Figure PCTCN2019074816-appb-000057
其中，n、m和Ar的定义如前所述。
氨基醇化合物IVD的构型可以是S构型、R构型或者外消旋体。
具体地来说，包括以下步骤：
1)式VIA所示的聚合物与式VID所示的化合物发生开环缩合反应制得如式IIID所示的聚合物；
2)式IIID所示的聚合物与式IVD所示的化合物发生缩合反应制得如式IID所示的聚合物；
3)式IID所示的聚合物在催化剂的作用下引发丙交酯聚合制得如式ID所示的两亲性嵌段共聚物；
在推荐的实施例中，在步骤3)后增加一个步骤：将如式ID所示的两亲性嵌段共聚物进行纯化。
在推荐的实施例中，本发明中，引发丙交酯聚合的催化剂为1,8-二氮杂二环十一碳-7-烯(DBU)，辛酸亚锡，2-乙基己酸镁，1,5,7-三氮杂二环[4.4.0]癸-5-烯(TBD)和7-甲基-1,5,7-三氮杂二环[4.4.0]癸-5-烯(MTBD)中的一种或多种。优选为1,8-二氮杂二环十一碳-7-烯(DBU)和/或辛酸亚锡。
本发明还提供了一种两亲性嵌段共聚物的纯化方法如下：
依照本发明方案所制得的两亲性共聚物粗品溶于有机溶剂，分别用稀酸(例如稀盐酸)和饱和氯化钠洗涤，浓缩后，加入沉淀剂析出聚合物后过滤，得到纯的固体性状的两亲性嵌段共聚物。
在推荐的实施例中，所述两亲性嵌段共聚物的纯化方法中，所述有机溶剂为二氯甲烷。
在推荐的实施例中，所述沉淀剂为甲基叔丁基醚。
在推荐的实施例中，本发明所述的两亲性嵌段共聚物粗品溶于二氯甲烷，分别用稀盐酸和饱和氯化钠洗涤，无水硫酸钠干燥，过滤后浓缩滤液至剩余少量二氯甲烷，或浓缩干后用少量二氯甲烷溶解，再加入甲基叔丁基醚充分沉淀聚合物后过滤，固体通过真空干燥后，得到纯的固体性状的两亲性嵌段共聚物。
本发明的目的还在于提供上述两亲性嵌段共聚物与难溶性药物形成的纳米胶束载药系统。
本发明提供的技术方案如下：
一种纳米胶束载药系统，包含至少本发明所述的两亲性嵌段共聚物和药物。
在推荐的实施例中，所述药物优选为难溶性药物。
在推荐的实施例中，所述药物与所述两亲性嵌段共聚物的重量比为(0.5～100):100，优选(1～70):100。
在推荐的实施例中，所述的难溶性药物选自紫杉醇、多西他赛、卡巴他赛、7-表紫杉醇、t-乙酰基紫杉醇、10-脱乙酰基紫杉醇、10-脱乙酰基-7-表紫杉醇、7-木糖基紫杉醇、10-脱乙酰基-7-戊二酰紫杉醇、7-N,N-二甲基甘氨酰紫杉醇、7-L-丙氨酰紫杉醇、莱龙泰素、阿霉素、表阿霉素、SN-38、伊立替康、拓扑替康、环磷酰胺、异环磷酰胺、雌莫司汀、米托蒽醌、安吖啶、顺铂、卡铂、奥沙利铂、依托泊苷、替尼泊苷、长春碱、长春新碱、长春瑞滨、长春地辛、美登素、三尖杉酯碱、高三尖杉酯碱、丝裂霉素、博莱霉素、柔红霉素、伊达比星、多柔比星、表柔比星、吉西他滨、卡培他滨、氟达拉滨、克拉曲滨、硼替佐米、卡非佐米、艾莎佐米、卡莫司汀、氟尿嘧啶、阿糖胞苷、环孢菌素A、西罗莫 司、替西罗莫司、依维莫司、艾日布林、曲贝替定、氟维司群、来曲唑、替莫唑胺、雷洛昔芬、他莫昔芬、来那度胺、伊沙匹隆、甲氨蝶呤、培美曲塞、恩杂鲁胺、阿比特龙、苯达莫司汀、姜黄素、白藜芦醇、吲哚美辛、石杉碱甲、阿昔洛韦、别嘌醇、胺碘酮、硫唑嘌呤、贝那普利、骨化三醇、坎地沙坦、衣普罗沙坦、卡比多巴/左旋多巴、克拉霉素、氯氮平、醋酸去氨加压素、双氯芬酸、依那普利、法莫替丁、非洛地平、非诺贝特、芬太尼、非索非那定、福辛普利、呋塞米、格列本脲、莨菪碱、丙咪嗪、伊曲康唑、左甲状腺素、阿托伐他汀、洛伐他汀、美克洛嗪、甲地孕酮、巯嘌呤、美托拉宗、莫米松、萘丁美酮、奥美拉唑、帕罗西汀、普罗帕酮、喹那普利、辛伐他汀、西罗莫司、他克莫司、替扎尼定、利培酮、奥氮平、齐拉西酮、利斯的明、纳洛酮、环丙甲羟二羟吗啡酮、西罗莫司、他克莫司、卡莫司汀、黄体酮、雌激素、雌二醇、左炔诺孕酮、炔诺酮、伊沙匹隆、艾博霉素、雷帕霉素、普卡霉素、万古霉素、两性霉素B、足叶乙甙、强力霉素、伊曲康唑、氟康唑、伏立康唑、泊沙康唑、酮康唑、睾酮、孕酮、去炎松、地塞米松、替诺昔康、吡罗昔康、布洛芬、卡泊芬净、米卡芬净、奥拉帕尼、丁苯酞、康普瑞丁、GW6471、COX-II抑制剂、芳香化酶抑制剂、多肽药物以及它们的组合。
在推荐的实施例中，所述的纳米胶束载药系统还包含药学上可接受的药用辅料。
在推荐的实施例中，所述药用辅料占整个体系的重量比为0～99.9％，优选0～50％。
在推荐的实施例中，所述的药用辅料为冻干赋形剂。
在推荐的实施例中，所述的冻干赋形剂为乳糖、甘露糖、蔗糖、海藻糖、果糖、葡萄糖、海藻酸钠和明胶中的至少一种。
在推荐的实施例中，所述冻干赋形剂占整个体系的重量比为0～99.9％，优选0～50％。
在推荐的实施例中，所述纳米胶束载药系统至少包含本发明所述的两亲性嵌段共聚物、难溶性药物和药学上可接受的药用辅料。
本发明所述的纳米胶束载药系统可以用于制备治疗肿瘤、炎症、糖尿病、中枢神经疾病、心血管疾病、精神疾病等药物方面的用途。优选用于治疗癌症和中枢神经疾病。
或者，本发明所述的纳米胶束载药系统可以用于治疗肿瘤、炎症、糖尿病、中枢神经疾病、心血管疾病、精神疾病等，优选用于治疗癌症和中枢神经疾病。
本发明中提及的治疗有效量指的是上述纳米胶束载药系统含有的药物的量能有效地治疗疾病(具体地可以指癌症和中枢神经疾病等)。
本发明的纳米胶束载药系统可通过口服、吸入或注射途径给药，优选为通过注射途径给药，并一般制成冻干粉制剂，另外，本领域技术人员可参照现有药物的给药剂量确定给药剂量，并根据个体情况的不同上下调整。
本发明还提供了所述纳米胶束载药系统的制备方法，所述制备方法包括透析法、溶 剂挥发法或薄膜水化法，优选薄膜水化法。
本发明还提供了两亲性嵌段共聚物与含芳香环药物形成的纳米胶束载药系统的制备方法，包括透析法、溶剂挥发法、薄膜水化法，优选薄膜水化法。
薄膜水化法的具体步骤为：将一定比例的聚合物和药物溶解于有机溶剂中，经蒸发去除有机溶剂后，加入20℃～80℃注射用水溶解药膜得载药胶束溶液，可选地，加入冻干赋形剂，经过滤除菌冻干后得胶束冻干粉。
如附图21所示为无任何修饰基团下的胶束的核壳结构示意图(壳部舒展部分为PEG，核部分为PLA，圆点为难溶性药物)。当芳香环修饰基团位于PEG和PLA的链末端时(如专利CN103772686B、CN105287377A中所述)，共聚物中所有的芳香基官能团都拥挤在核结构的最中心，能够通过相互作用增溶药物的区域非常小(如附图22所示)，因而相对于未修饰的PEG-PLA，无法大幅度地提高载药量。本发明所采用的芳香官能团修饰位点位于PEG和PLA之间，在胶束结构上表现为均匀地分布在核壳的结合部，因而能与疏水性药物尤其是含芳香环的药物具有明显更大的相互作用表面积(如附图23所示)，最终体现为对载药量的大幅度提升，以及具有良好的胶束稳定性。
与现有技术相比，本发明具有以下的特点：
1)本发明通过采用含芳香环的小分子片段，尤其是含芳香环的氨基酸、氨基醇或多肽片段对聚乙二醇和聚丙交酯进行连接，所得的两亲性嵌段共聚物与含有难溶性药物尤其是含芳香环的药物在自组装形成胶束的过程中，由于额外引入的芳香环改善了共聚物的疏水性能，也增强了共聚物与药物之间的共轭作用，从而极大地促进了胶束对药物的负载能力，也提高了胶束药物的稳定性。本发明所得的胶束冻干粉中药物/共聚物质量比例最高可达70:100，用生理盐水复溶后可以稳定高达72h；如附图15所示，未经修饰的PEG-PLA(韩国三养共聚物材料)在载药量为20:100(药物：共聚物质量比例)时，复溶后6小时出现肉眼可辨浑浊，24小时产生明显颗粒沉淀。而本发明方案所采用的经过芳香环修饰的两亲性嵌段共聚物以20:100(药物：共聚物质量比例)的载药量负载紫杉醇时，72小时仍明显澄清。如附图16所示，在20:100、30:100、40:100、60:100的载药量下，本发明方案所采用的两亲性嵌段共聚物与紫杉醇所形成的胶束在72小时依然稳定。
2)本发明采用的含芳香环小分子片段作为连接子(linker)，尤其是采用含芳香环的氨基酸片段作为连接子(linker)的两亲性嵌段共聚物在体内产生的代谢产物均为具有很好的生物相容性的物质，是一种安全的生物医学材料；
3)本发明在引发丙交酯聚合过程中采用的催化剂特别是DBU，聚合温度在室温，不需要严格的无水无氧操作，可以得到分子量分布窄的共聚物。催化剂可以简单通过酸洗的方式去除，纯化方式简单，不存在重金属锡残留问题；
4)本发明在进行共聚物沉淀纯化时采用了比乙醚更加安全的沉淀剂，特别是甲基叔丁基醚，适合工业放大生产；
5)试验结果证明：本发明的两亲性嵌段共聚物制备得到的纳米胶束载药系统制成冻干制剂复溶后可迅速分散形成略带蓝色乳光的澄清溶液，该溶液在室温环境下稳定高达72h无明显药物沉淀析出，经注射后在体内具有显著的药物动力学性质和药效学性质，可有效发挥EPR效应，具有良好的产业化应用前景。
本发明所使用的术语，除有相反的表述外，具有如下的含义：
“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，更优选苯基、萘基、吲哚基、咪唑基，最优选苯基。芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基，优选为羟基。
本发明的羟基、巯基和羧基保护基是本领域已知的适当的用于羟基、巯基和羧基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例，优选地，所述的羟基保护基可以是C 1-10烷基或取代烷基，例如：甲基，叔丁基，烯丙基，苄基，甲氧基甲基，乙氧基乙基，2-四氢吡喃基(THP)等；可以是(C 1-10烷基或芳香基)酰基，例如：甲酰基，乙酰基，苯甲酰基等；可以是(C 1-6烷基或C 6-10芳基)磺酰基；也可以是(C 1-6烷氧基或C 6-10芳基氧基)羰基；也可以是(C 1-10烷基或芳基) 3硅烷基，例如：三乙基硅基，三异丙基硅基，叔丁基二甲基硅基，叔丁基二苯基硅基等。
本发明的胺基保护基是本领域已知的适当的用于胺基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的胺基保护基团。作为示例，优选地，所述的胺基保护基可以是酰胺保护基团，氨基甲酸酯保护基团等。例如：甲酰基，乙酰基，叔丁氧羰基，苄氧羰基，笏甲氧羰基，三氯乙氧基羰基等。
本发明的难溶性药物是指根据中国药典，在水溶液介质中的溶解度低于1g/1000mL的药物。
本发明中，通过核磁氢谱计算数均分子量。
附图说明
图1为共聚物Ia的凝胶渗透色谱图，PDI＝1.07；
图2为共聚物Ib的凝胶渗透色谱图，PDI＝1.05；
图3为共聚物Ic的凝胶渗透色谱图，PDI＝1.07；
图4为共聚物Id的凝胶渗透色谱图，PDI＝1.07；
图5为共聚物Ie的凝胶渗透色谱图，PDI＝1.06；
图6为共聚物Il的凝胶渗透色谱图，PDI＝1.07；
图7为共聚物Ia的核磁共振氢谱；
图8为共聚物Ib的核磁共振氢谱；
图9为共聚物Ic的核磁共振氢谱；
图10为共聚物Id的核磁共振氢谱；
图11为共聚物Ie的核磁共振氢谱；
图12为共聚物Il的核磁共振氢谱；
图13为共聚物Ia与紫杉醇形成胶束的透射电镜图；
图14为共聚物Ia与紫杉醇形成胶束的粒径图；
图15为未经修饰的PEG-PLA(韩国三养)与紫杉醇形成胶束的稳定性(紫杉醇与共聚物的重量比为20:100)和本发明共聚物Ia与紫杉醇形成胶束(紫杉醇与共聚物的重量比为20:100)的稳定性对照图；
图16为不同紫杉醇与共聚物Ia载药比例下的稳定性对照图；
图17为本发明紫杉醇胶束、Genexol-PM紫杉醇胶束和紫杉醇注射液对Colo-205细胞肿瘤体积的抑制作用图；
图18为本发明紫杉醇胶束、Genexol-PM紫杉醇胶束和紫杉醇注射液对裸鼠体重变化曲线图；
图19为本发明紫杉醇胶束、Genexol-PM紫杉醇胶束和紫杉醇注射液对MCF-7细胞肿瘤体积的抑制作用图；
图20为本发明紫杉醇胶束、Genexol-PM紫杉醇胶束和紫杉醇注射液对裸鼠体重变化曲线图；
图21为未修饰PEG-PLA胶束形态示意图；
图22为PLA末端修饰PEG-PLA胶束形态示意图；
图23为本发明PLA-linker-PLA胶束形态示意图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照 商品说明书选择。
实施例1：制备化合物VIa
将4.48g乳酸加入烧瓶中，再加入100mL二氯甲烷溶解，再加入咪唑(16.2g)，溶解后搅拌下加入TBSCl(18g)，室温反应16h后加水猝灭反应，后处理浓缩得到粗品中间体。用200mL甲醇溶解上述浓缩液，再加入100mL碳酸钾溶液，常温搅拌3h后，乙酸乙酯萃取，浓缩得到第二个粗品中间体。用50mL二氯甲烷溶解上述粗品，再加入DCC(7g),和NHS(5.4g),常温反应16h后过滤，滤液浓缩得到固液混合的粗品，柱层析纯化得到8.6g化合物VIa。
1H NMR(400MHz,Chloroform-d)δ4.64(q,J＝6.8Hz,1H),2.95–2.71(m,4H),1.63–1.49(m,3H),0.90(s,9H),0.12(d,J＝4.8Hz,6H).
实施例2：制备化合物Va
将10g聚乙二醇单甲醚(数均分子量2000)加入烧瓶中，加入50mL二氯甲烷溶解，搅拌下依次加入Boc保护的L-苯丙氨酸(3.6g)，EDCI(5.71g)和DMAP(1.52g)，室温反应24h后，有机相依次用1N盐酸，饱和碳酸氢钠洗涤，分液浓缩至剩余少量二氯甲烷溶液，用甲基叔丁基醚沉淀，布氏漏斗过滤，得9.5g化合物Va。
1H NMR(400MHz,Chloroform-d)δ7.26(m,5H),4.99(d,J＝8.3Hz,1H),4.59(m,1H),4.32–4.17(m,2H),3.62(s,197H),3.36(s,3H),3.08(m,2H),1.40(s,9H).
实施例3：制备化合物IVa
将8g化合物Va加入烧瓶中，用15mL二氯甲烷溶解，搅拌下加入10mL三氟乙酸，室温下反应18h后，调节pH至7-8，二氯甲烷萃取，用甲基叔丁基醚沉淀，布氏漏斗过滤得6g化合物IVa。
1H NMR(400MHz,Chloroform-d)δ7.26(m,5H),4.33–4.19(m,2H),4.01–3.41(m,195H),3.37(s,3H),3.18–2.97(m,2H).
实施例4：制备化合物IIIa
将1.8g化合物IVa加入烧瓶中，加入20mL二氯甲烷溶解，搅拌下加入VIa(0.4g),室温反应18h后，用甲基叔丁基醚沉淀，布氏漏斗过滤，得1.2g化合物IIIa。
1H NMR(400MHz,Chloroform-d)δ7.26(m,6H),4.87(m,J＝8.6,5.7Hz,1H),4.31–4.10(m,3H),3.62(m,188H),3.35(s,3H),3.19–3.04(m,2H),1.29(d,J＝6.7Hz,3H),0.81(s,9H),0.02(d,J＝14.2Hz,6H).
实施例5：制备化合物IIa
先用40mL水溶解氟化钾将(2g)，再加入乙酸(6g)，再将化合物IIIa(6g)加入到上述溶液中，室温反应24h后，调节pH至7-8，用二氯甲烷萃取，有机相用饱和食盐水洗涤，用甲基叔丁基醚沉淀，布氏漏斗过滤，得4g化合物IIa。
1H NMR(400MHz,Chloroform-d)δ7.26(m,6H),4.89(m,1H),4.41–4.08(m,3H),3.63(s,191H),3.36(s,3H),3.27–3.03(m,2H),1.31(d,J＝6.8Hz,3H).
实施例6：制备化合物Ia
将1.65g化合物IIa加入烧瓶中，加入DL-丙交酯(1.54g)，用8mL二氯甲烷搅拌溶解，加入DBU(46mg)室温反应1h后，加入50mL二氯甲烷稀释。有机相依次用1N盐酸，饱和食盐水洗涤，用甲基叔丁基醚沉淀，布氏漏斗过滤，得2.5g化合物Ia，核磁积分计算分子量3900，GPC测试PDI为1.07。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,22H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,3H),3.50(s,189H),3.24(s,3H),3.12–2.91(m,2H),1.57–1.17(m,76H).
实施例7：制备化合物Va’
将10g聚乙二醇单甲醚(数均分子量2000)加入烧瓶中，加入50mL二氯甲烷溶解，搅拌下依次加入Boc保护的苯丙氨酸(3.6g)，EDCI(5.71g)和DMAP(1.52g)，室温反应24h后，有机相依次用1N盐酸，饱和碳酸氢钠洗涤，分液浓缩至剩余少量二氯甲烷溶液，用甲基叔丁基醚沉淀，布氏漏斗过滤，得9.5g化合物Va’。
1H NMR(400MHz,Chloroform-d)δ7.26(m,5H),4.99(d,J＝8.3Hz,1H),4.59(m,1H),4.32–4.17(m,2H),3.62(s,197H),3.36(s,3H),3.08(m,2H),1.40(s,9H).
实施例8：制备化合物IVa’
将8g化合物Va’加入烧瓶中，用15mL二氯甲烷溶解，搅拌下加入10mL三氟乙酸，室温下反应18h后，调节pH至7-8，二氯甲烷萃取，用甲基叔丁基醚沉淀，布氏漏斗过滤得6g化合物IVa’。
1H NMR(400MHz,Chloroform-d)δ7.26(m,5H),4.33–4.19(m,2H),4.01–3.41(m,195H),3.37(s,3H),3.18–2.97(m,2H).
实施例9：制备化合物Ia’
将1.65g化合物IVa’加入烧瓶中，加入DL-丙交酯(1.54g)，用8mL甲苯搅拌溶解，加入辛酸亚锡(46mg)80℃反应5h后，加入50mL二氯甲烷稀释。有机相依次用1N盐酸，饱和食盐水洗涤，用甲基叔丁基醚沉淀，布氏漏斗过滤，得2.5g化合物Ia’，核磁积分计算分子量3900，GPC测试PDI为1.04。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,22H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,J＝27.5,12.4,6.1Hz,3H),3.50(s,189H),3.24(s,3H),3.12–2.91(m,2H),1.57–1.17(m,76H).
实施例10：制备化合物Vb
将3g聚乙二醇单甲醚(数均分子量2000)加入烧瓶中，加入20mL二氯甲烷溶解，搅拌下依次加入Boc保护的3-(2-萘基)-丙氨酸(1.4g)，EDCI(1.71g)，DMAP(0.55g)，室温反应18h后，有机相依次用1N盐酸，饱和碳酸氢钠，饱和食盐水洗涤，用甲基叔丁基醚沉淀，布氏漏斗过滤得2.5g化合物Vb。
1H NMR(400MHz,Chloroform-d)δ7.83–7.73(m,3H),7.63–7.58(m,1H),7.49–7.40(m,2H),7.26(d,2H),5.03(d,J＝8.2Hz,1H),4.67(dt,J＝8.1,5.9Hz,1H),4.35–4.17(m,2H),3.63(m,188H),3.37(s,3H),3.25(m,2H),1.39(s,9H).
实施例11：制备化合物IVb
将2.7g化合物Vb加入烧瓶中，用10mL二氯甲烷溶解，搅拌下加入8mL三氟乙酸，反应5h后调节pH至7-8，用二氯甲烷萃取，有机相用饱和食盐水洗，分液，用甲基叔丁基醚沉淀，布氏漏斗过滤，得2.5g化合物IVb。
1H NMR(400MHz,Chloroform-d)δ7.78(t,J＝8.0Hz,3H),7.66(s,1H),7.44(m,2H),7.33(m,1H),4.26(m,2H),3.85(m,1H),3.63(s,191H),3.36(s,3H),3.30–3.17(m,1H),3.05(dd,J＝13.5,7.7Hz,1H).
实施例12：制备化合物IIIb
将2.5g化合物IVb加入烧瓶中，用10mL二氯甲烷溶解，搅拌下加入化合物VIa(0.5g)，室温反应12h后用甲基叔丁基醚沉淀，布氏漏斗过滤，得2.4g化合物IIIb。
1H NMR(400MHz,Chloroform-d)δ7.77(m,3H),7.58(s,1H),7.44(m,2H),7.19(d,J＝8.4Hz,1H),4.96(m,1H),4.38–4.11(m,3H),3.63(s,186H),3.37(s,3H),3.35–3.25(m,2H),1.31(d,J＝6.7Hz,3H),0.74(s,9H),0.04–-0.04(m,6H).
实施例13：制备化合物IIb
先用20mL水溶解氟化钾(0.8g)，再加入乙酸(2.4g)，再将化合物IIIb(2.4g)加入到上述溶液中，室温反应6h后调节pH至7-8，用二氯甲烷萃取，有机相用饱和食盐水洗，用甲基叔丁基醚沉淀，布氏漏斗过滤，得1.2g化合物IIb。
1H NMR(400MHz,Chloroform-d)δ7.84–7.70(m,3H),7.60(d,J＝1.6Hz,1H),7.50–7.37(m,2H),7.12(d,J＝8.3Hz,1H),4.97(m,1H),4.33–4.12(m,3H),3.63(s,189H),3.36(s,5H),1.31(d,J＝6.8Hz,3H).
实施例14：制备化合物Ib
将1g化合物IIb和DL-丙交酯(0.73g)加入烧瓶中，用10mL甲苯溶解，再加入2-乙基己酸镁(24mg)，90℃反应3h，加入二氯甲烷稀释。依次用1N盐酸，饱和食盐水洗涤，用甲基叔丁基醚沉淀，布氏漏斗过滤得1.2g化合物Ib，核磁积分计算分子量4200，GPC测试PDI为1.05。
1H NMR(400MHz,Chloroform-d)δ7.77(m,3H),7.60(d,J＝4.3Hz,1H),7.44(m,2H),7.26(s,1H),6.69–6.50(m,1H),5.28–4.82(m,22H),4.30(m,3H),3.63(s,185H),3.37(s,5H),2.74(d,J＝14.1Hz,1H),1.66–1.33(m,67H).
实施例15：制备化合物IIIc
将10g聚乙二醇单甲醚(数均分子量2000)加入烧瓶中，再加入50mL二氯甲烷溶解，搅拌下依次加入琥珀酸酐(1g)和DMAP(0.6g)，反应5h后用甲基叔丁基醚沉淀，布氏漏斗过滤，得7g化合物IIIc。
1H NMR(400MHz,Chloroform-d)δ4.25(q,J＝4.1Hz,2H),3.63(m,186H),3.37(s,J＝2.9Hz,3H),2.63(m,4H).
实施例16：制备化合物IIc
将3.5g化合物IIIc加入烧瓶中，用15mL DMF溶解，搅拌下依次加入苯丙胺醇(0.8g)，EDCI(1.9g)和HOBT(1.34g)，室温反应18h后有机相依次用1N盐酸，饱和食盐水洗涤，用甲基叔丁基醚沉淀，布氏漏斗过滤，得2.5g化合物IIc。
1H NMR(400MHz,Chloroform-d)δ7.26(s,5H),6.24(d,J＝8.0Hz,1H),4.28–4.19(m,2H),4.14(m,1H),3.63(m,195H),3.37(s,3H),3.02(s,1H),2.86(d,J＝7.4Hz,2H),2.79–2.56(m,2H),2.50–2.38(m,2H).
实施例17：制备化合物Ic
将1g化合物IIc加入烧瓶中，再加入D-丙交酯(0.42g)和L-丙交酯(0.42g)，用10mL二氯甲烷搅拌溶解，加入DBU(30mg)，在50℃反应10min后，依次用1N盐酸和饱和食盐水洗涤，用甲基叔丁基醚沉淀，布氏漏斗过滤，得1.2g化合物Ic，核磁积分计算分子量4000，GPC测试PDI为1.07。
1H NMR(400MHz,Chloroform-d)δ7.26(s,5H),6.19–5.96(m,1H),5.17(m,23H),4.36(td,2H),4.27–4.05(m,4H),3.64(s,197H),3.38(s,3H),2.93–2.68(m,2H),2.64(t,J＝6.9Hz,2H),2.48–2.38(m,2H),1.66–1.43(m,73H).
实施例18：制备化合物IId
将2.5g化合物IIIc加入烧瓶中，用15mL DMF溶解，搅拌下依次加入3-(2-萘基)-丙氨醇(0.8g)，EDCI(0.9g)和HOBT(0.5g)，室温反应24h后依次用1N盐酸，饱和碳酸氢钠，饱和食盐水洗涤，用甲基叔丁基醚沉淀，布氏漏斗过滤，得2g化合物IId。
1H NMR(400MHz,Chloroform-d)δ7.83–7.71(m,3H),7.67(d,J＝1.6Hz,1H),7.51–7.33(m,3H),6.29(d,J＝7.9Hz,1H),4.31–4.13(m,3H),3.63(s,193H),3.37(s,3H),3.03(d,J＝7.5Hz,3H),2.80–2.57(m,2H),2.44(m,2H).
实施例19：制备化合物Id
将1g化合物IId加入烧瓶中，再加入D-丙交酯(0.41g)和L-丙交酯(0.41g)，用10mL二氯甲烷搅拌溶解，加入DBU(28mg)，25℃反应1h后依次用1N盐酸，饱和食盐水洗涤，用甲基叔丁基醚沉淀，布氏漏斗过滤，得1.2g化合物Id，核磁积分计算分子量4000，GPC测试PDI为1.07。
1H NMR(400MHz,Chloroform-d)δ7.79(t,J＝8.7Hz,3H),7.63(s,1H),7.45(m,2H),7.37–7.30(m,1H),6.32–6.08(m,1H),5.31–5.06(m,23H),4.52(s,1H),4.35(p,J＝6.8Hz,1H),4.15(ddd,J＝17.4,6.6,5.6Hz,4H),3.63(d,J＝3.0Hz,200H),3.37(s,3H),3.11–2.89(m,2H),2.75(s,1H),2.64(t,J＝6.9Hz,2H),2.44(dd,J＝6.8,3.1Hz,2H),1.67–1.43(m,73H).
实施例20：制备化合物IIIe
将8g聚乙二醇单甲醚(数均分子量2000)加入烧瓶中，用100mL二氯甲烷溶解，搅拌下依次加入对羧基苯甲醛(2.5g)，DCC(6.56g)和DMAP(2.18g)，室温反应10h后， 用甲基叔丁基醚沉淀后，固体用油泵常温抽干得5.5g化合物IIIe。
1H NMR(400MHz,Chloroform-d)δ10.08(s,1H),8.26–8.14(m,2H),8.00–7.88(m,2H),4.52–4.45(m,2H),3.62(s,189H),3.36(s,3H).
实施例21：制备化合物IIe
将2.5g化合物IIIe加入烧瓶中，用50mL乙醇溶解，搅拌下加入硼氢化钠(100mg)，反应1h后依次用1N盐酸，饱和食盐水洗涤，用甲基叔丁基醚沉淀后，固体用油泵常温抽干得0.8g化合物IIe。
1H NMR(400MHz,Chloroform-d)δ8.02(d,J＝8.2Hz,2H),7.42(d,J＝8.0Hz,2H),4.74(d,J＝5.7Hz,2H),4.45(m,2H),3.62(m,203H),3.36(s,3H),2.65(t,J＝6.1Hz,1H).
实施例22：制备化合物Ie
将0.8g化合物IIe加入烧瓶中，再加入DL-丙交酯(0.7g)，用10mL二氯甲烷溶解，加入DBU(16mg)，10℃反应30min，有机相依次用1N盐酸，饱和食盐水洗洗涤用甲基叔丁基醚沉淀后，固体用油泵常温抽干得0.8g化合物Ie，核磁积分计算分子量3800，GPC测试PDI为1.06。
1H NMR(400MHz,Chloroform-d)δ8.14–7.95(m,2H),7.37(d,J＝8.0Hz,2H),5.31–5.09(m,20H),4.53–4.41(m,2H),4.34(p,J＝6.8Hz,1H),3.63(m,200H),3.37(s,3H),2.73(d,J＝14.5Hz,1H),1.68–1.41(m,60H).
实施例23：制备化合物If
按照化合物Ia的合成路线，以数均分子量为4000的聚乙二醇单甲醚、外消旋色氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，获得化合物If，数均分子量为7900，PDI为1.07。
1H NMR(400MHz,DMSO-d 6)δ10.5(s,1H),7.62(d,1H),7.30(d,1H),7.18(s,1H),7.12(m,2H),5.48(d,J＝5.9Hz,1H),5.18(m,54H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,3H),3.50(s,364H),3.24(s,3H),3.30–3.12(m,2H),1.57–1.17(m,160H).
实施例24：制备化合物Ig
按照化合物Ia的合成路线，以数均分子量为5000的聚乙二醇单甲醚、酪氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，获得化合物Ig，数均分子量为10000，PDI为1.09。
1H NMR(400MHz,DMSO-d 6)δ7.15(d,2H),6.8(d,2H),5.48(d,J＝5.9Hz,1H),5.33(s,1H),5.18(m,68H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,3H),3.50(s,455H),3.24(s,3H),3.42–3.20(m,2H),1.57–1.17(m,208H).
实施例25：制备化合物Ih
按照化合物Ia的合成路线，以数均分子量为2000的聚乙二醇单甲醚、组氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，获得化合物Ih，数均分子量为5000，PDI为1.05。
1H NMR(400MHz,DMSO-d 6)δ12.0(s,1H),8.77(s,1H),7.63(s,1H),5.48(d,J＝5.9Hz,1H),5.18(m,42H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,3H),3.50(s,180H),3.24(s,3H),3.82–3.56(m,2H),1.57–1.17(m,126H).
实施例26：制备化合物Ii
按照化合物Ia的合成路线，以数均分子量为2000的聚乙二醇单苄醚、苯丙氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，获得化合物Ii，数均分子量为4000，PDI为1.06。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.45(d,2H),7.38–7.14(m,8H),5.48(d,J＝5.9Hz,1H),5.18(m,23H),5.01(m,1H),4.82(s,2H),4.53–4.42(m,1H),4.16(m,J＝27.5,12.4,6.1Hz,3H),3.50(s,189H),3.12–2.91(m,2H),1.57–1.17(m,68H).
实施例27：制备化合物Ij
按照化合物Ia的合成路线，以数均分子量为10000的聚乙二醇单苄醚、苯丙氨酸、甘氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，获得化合物Ij，数均分子量为20000，PDI为1.08。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,138H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,J＝27.5,12.4,6.1Hz,3H),4.03(s,2H),3.50(s,910H),3.24(s,3H),3.12–2.91(m,2H),1.57–1.17(m,421H).
实施例28：制备化合物Ik
按照化合物Ia的合成路线，以数均分子量为6000的聚乙二醇单甲醚、苯丙氨酸、甘氨酸、D-酪氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，获得化合物Ik，数均分子量为14000，PDI为1.07。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),7.10(d,2H),6.75(d,2H),5.48(d,J＝5.9Hz,1H),5.18(m,108H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,3H),3.50(s,545H),3.24(s,3H),3.08-2.88(m,2H),3.12–2.91(m,2H),1.57–1.17(m,320H).
实施例29：制备化合物Il
按照化合物Ia的合成路线，以数均分子量为2000的聚乙二醇单甲醚、苯丙氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，并用乙酰基保护PLA末端，获得化合物Il，数均分子量为7000，PDI为1.06。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,66H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,J＝27.5,12.4,6.1Hz,3H),3.50(s,189H),3.24(s,3H),3.12–2.91(m,2H),2.03(s,3H),1.57–1.17(m,200H).
实施例30：制备化合物Im
按照化合物Ia的合成路线，以数均分子量为2000的聚乙二醇单甲醚、苯丙氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，并用苯甲酰基保护PLA末端，获得化合物Im，数均分子量为4500，PDI为1.06。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),8.00(d,2H),7.63(d,1H),7.58(dd,2H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,30H),5.01(m,1H),4.53–4.42(m,3H),4.16(m,J＝27.5,12.4,6.1Hz,3H),3.50(s,181H),3.24(s,3H),3.12–2.91(m,2H),2.56(t,2H),1.57–1.17(m,91H).
实施例31：制备化合物In
按照化合物Ia的合成路线，以数均分子量为2000的聚乙二醇单甲醚、苯丙氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，并用Boc保护的苯丙氨酸保护PLA末端，获得化合物In，数均分子量为5000，PDI为1.04。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,10H),5.48(d,J＝5.9Hz,1H),5.18(m,37H),5.01(m,2H),4.53–4.42(m,3H),4.16(m,J＝27.5,12.4,6.1Hz,3H),3.50(s,180H),3.24(s,3H),3.12–2.91(m,4H),2.56(t,2H),1.57–1.17(m,112H).
实施例32：制备化合物Io
按照化合物Ia的合成路线，以数均分子量为2000的聚乙二醇单甲醚、苯甲酰基保 护的赖氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，获得化合物Io，数均分子量为4000，PDI为1.08。
1H NMR(400MHz,DMSO-d 6)δ8.50(m,1H),8.05(d,2H),7.72(d,1H),7.58(dd,2H),5.48(d,J＝5.9Hz,1H),5.18(m,22H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,3H),3.50(s,182H),3.32(t,2H),3.24(s,3H),3.12–2.91(m,2H),1.78(m,2H),1.57–1.17(m,78H).
实施例33：制备化合物Ip
按照化合物Ia的合成路线，以数均分子量为2000的聚乙二醇单甲醚、二硫代二丙酸、苯丙氨醇、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，获得化合物Ip，数均分子量为4300，PDI为1.09。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,25H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,3H),3.50(s,180H),3.24(s,3H),3.12–2.91(m,4H),2.80(t,2H),2.58(t,2H),2.44(t,2H),1.57–1.17(m,76H).
实施例34：制备化合物Iq
按照化合物Ia的合成路线，以数均分子量为2000的聚乙二醇单甲醚、邻苯二甲酰亚胺、叔丁氧羰基保护的苯丙氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，获得化合物Iq，数均分子量为5000，PDI为1.07。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,39H),5.01(m,1H),4.53–4.42(m,3H),4.16(m,J＝27.5,12.4,6.1Hz,3H),3.57(t,2H),3.50(s,180H),3.24(s,3H),3.12–2.91(m,2H),2.64(t,2H),2.56(t,2H),1.57–1.17(m,118H).
实施例35：制备化合物Ir
按照化合物Ia的合成路线，以数均分子量为2000的聚乙二醇单甲醚、巯基乙酸、叔丁氧羰基保护的苯丙氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，获得化合物Ir，数均分子量为6000，PDI为1.07。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,53H),5.01(m,1H),4.53–4.42(m,3H),4.16(m,J＝27.5,12.4,6.1Hz,3H),3.50(s,180H),3.28(t,2H),3.24(s,3H),3.12–2.91(m,2H),2.88(t,2H),2.56(t,2H),1.57–1.17(m,160H).
实施例36：制备化合物Is
按照化合物Ia的合成路线，以数均分子量为4000的聚乙二醇单甲醚、丁内酯、叔丁氧羰基保护的苯丙氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，获得化合物Is，数均分子量为8000，PDI为1.07。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,54H),5.01(m,1H),4.53–4.42(m,3H),4.16(m,J＝27.5,12.4,6.1Hz,3H),3.50(s,364H),3.24(s,3H),3.12–2.91(m,2H),2.56(t,2H),1.57–1.17(m,162H).
实施例37：制备化合物It
按照化合物Ia’的合成路线，以数均分子量为5000的聚乙二醇单甲醚、叔丁氧羰基保护的苯丙氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，获得化合物It，数均分子量为9000，PDI为1.07。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,54H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,J＝27.5,12.4,6.1Hz,3H),3.50(s,454H),3.24(s,3H),3.12–2.91(m,2H),1.57–1.17(m,160H).
实施例38：制备化合物Iu
按照化合物Ia’的合成路线，以数均分子量为3000的聚乙二醇单甲醚、叔丁氧羰基保护的D-苯丙氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，获得化合物Iu，数均分子量为8000，PDI为1.07。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,68H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,J＝27.5,12.4,6.1Hz,3H),3.50(s,274H),3.24(s,3H),3.12–2.91(m,2H),1.57–1.17(m,208H).
实施例39：制备化合物Iv
按照化合物Ia’的合成路线，以数均分子量为10000的聚乙二醇单甲醚、叔丁氧羰基保护的L-色氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，获得化合物Iv，数均分子量为30000，PDI为1.07。
1H NMR(400MHz,DMSO-d 6)δ10.5(s,1H),7.62(d,1H),7.30(d,1H),7.18(s,1H),7.12(m,2H),5.48(d,J＝5.9Hz,1H),5.18(m,278H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,3H),3.50(s,908H),3.24(s,3H),3.30–3.12(m,2H),1.57–1.17(m,840H).
实施例40：制备化合物Iw
按照化合物Ia’的合成路线，以数均分子量为20000的聚乙二醇单甲醚、Fmoc保护的L-苯丙氨酸、甘氨酸、DL-丙交酯为原料，通过引入连接子(linker)并引发聚合，获得化合物Iw，数均分子量为40000，PDI为1.07。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,275H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,J＝27.5,12.4,6.1Hz,3H),3.50(s,1818H),3.24(s,3H),3.12–2.91(m,2H),1.57–1.17(m,842H).
实施例41：制备化合物Ix
按照化合物Ia’的合成路线，以数均分子量为2000的聚乙二醇单甲醚(1g)、Boc保护的L-苯丙氨酸(132mg)、DL-丙交酯(970mg)为原料，通过引入连接子(linker)并引发聚合，获得化合物Ix，数均分子量为4200，PDI为1.07。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,26H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,J＝27.5,12.4,6.1Hz,3H),3.50(s,189H),3.24(s,3H),3.12–2.91(m,2H),1.57–1.17(m,79H).
实施例42：制备化合物Iy
按照化合物Ia的合成路线，以数均分子量为2000的聚乙二醇单甲醚(1g)、Boc保护的L-苯丙氨酸(132mg)、DL-丙交酯(1.22g)为原料，通过引入连接子(linker)并引发聚合，获得化合物Iy，数均分子量为4700，PDI为1.07。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,33H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,J＝27.5,12.4,6.1Hz,3H),3.50(s,189H),3.24(s,3H),3.12–2.91(m,2H),1.57–1.17(m,99H).
实施例43：制备化合物Iz
按照化合物Ia的合成路线，以数均分子量为2000的聚乙二醇单甲醚(1g)、Boc保护的L-苯丙氨酸(132mg)、DL-丙交酯(2.73g)为原料，通过引入连接子(linker)并引发聚合，获得化合物Iz，数均分子量为5000，PDI为1.07。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,37H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,J＝27.5,12.4,6.1Hz,3H),3.50(s,189H),3.24(s,3H),3.12–2.91(m,2H),1.57–1.17(m,110H).
实施例44：制备化合物Iaa
按照化合物Ia的合成路线，以数均分子量为2000的聚乙二醇单甲醚(1g)、Boc保护的L-苯丙氨酸(132mg)、DL-丙交酯(1.47g)为原料，通过引入连接子(linker)并引发聚合，获得化合物Iaa，数均分子量为5200，PDI为1.07。
1H NMR(400MHz,DMSO-d 6)δ8.54–8.37(m,1H),7.35–7.14(m,5H),5.48(d,J＝5.9Hz,1H),5.18(m,40H),5.01(m,1H),4.53–4.42(m,1H),4.16(m,J＝27.5,12.4,6.1Hz,3H),3.50(s,189H),3.24(s,3H),3.12–2.91(m,2H),1.57–1.17(m,123H).
实施例45：紫杉醇胶束冻干粉剂的制备
取500mg两亲性嵌段共聚物Ia和100mg紫杉醇放入500mL烧瓶中，加入100mL乙腈溶解；室温下置于摇床中震荡30min；旋蒸除去乙腈，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入150mL 30℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的紫杉醇含量为16％。
该冻干粉用生理盐水复溶成5mg/mL浓度的溶液后，在室温下稳定时间大于72h。
实施例46：紫杉醇胶束冻干粉剂的制备
取500mg两亲性嵌段共聚物Ia和150mg紫杉醇放入500mL烧瓶中，加入100mL乙腈溶解；室温下置于摇床中震荡30min；旋蒸除去乙腈，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入150mL 30℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的紫杉醇含量为23％。
该冻干粉用生理盐水复溶成5mg/mL浓度的溶液后，在室温下稳定时间大于72h。
实施例47：紫杉醇胶束冻干粉剂的制备
取500mg两亲性嵌段共聚物Ia和200mg紫杉醇放入500mL烧瓶中，加入100mL乙腈溶解；室温下置于摇床中震荡2h；旋蒸除去乙腈，在烧瓶壁形成透明薄膜；
迅速向烧瓶中导入150mL 60℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的紫杉醇含量为28％，其粒径测定结果如附图14所示，取三次测试平均值，平均粒径为20.2nm。透射电镜照片如附图13所示。
该冻干粉用生理盐水复溶成5mg/mL浓度的溶液后，在室温下稳定时间大于72h。
实施例48：紫杉醇胶束冻干粉剂的制备
取500mg两亲性嵌段共聚物Ia和300mg紫杉醇放入500mL烧瓶中，加入100mL乙腈溶解；室温下置于摇床中震荡30min；旋蒸除去乙腈，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入150mL 30℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的紫杉醇含量为37％。
该冻干粉用生理盐水复溶成5mg/mL浓度的溶液后，在室温下稳定时间大于72h。
实施例49：紫杉醇胶束冻干粉剂的制备
取500mg两亲性嵌段共聚物Ib和300mg紫杉醇放入500mL烧瓶中，加入100mL乙腈溶解；室温下置于摇床中震荡1h；旋蒸除去乙腈，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入150mL 50℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的紫杉醇含量为37％。
该冻干粉用生理盐水复溶成5mg/mL浓度的溶液后，在室温下稳定时间大于72h。
实施例50：紫杉醇胶束冻干粉剂的制备
取500mg两亲性嵌段共聚物Ib和50mg紫杉醇放入500mL烧瓶中，加入100mL乙腈溶解；室温下置于摇床中震荡1h；旋蒸除去乙腈，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入150mL 50℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的紫杉醇含量为9％。
该冻干粉用生理盐水复溶成3mg/mL浓度的溶液后，在室温下稳定时间大于72h。
实施例51：紫杉醇胶束冻干粉剂的制备
取500mg两亲性嵌段共聚物Ic和150mg紫杉醇放入500mL烧瓶中，加入100mL乙腈溶解；室温下置于摇床中震荡30min；旋蒸除去乙腈，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入150mL 30℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的紫杉醇含量为23％。
该冻干粉用生理盐水复溶成5mg/mL浓度的溶液后，在室温下稳定时间大于72h。
实施例52：多西他赛胶束冻干粉剂的制备
取200mg两亲性嵌段共聚物Ib和80mg多西他赛放入250mL烧瓶中，加入50mL乙腈溶解；室温下置于摇床中震荡2h；旋蒸除去乙腈，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入50mL 20℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的多西他赛含量为28％。
该冻干粉用生理盐水复溶成5mg/mL浓度的溶液后，在室温下稳定时间大于48h。
实施例53：艾日布林胶束冻干粉剂的制备
取200mg两亲性嵌段共聚物Ic和40mg艾日布林放入250mL烧瓶中，加入50mL乙腈溶解；室温下置于摇床中震荡2h；旋蒸除去乙腈，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入50mL 40℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的艾日布林含量为17％。
该冻干粉用生理盐水复溶成5mg/mL浓度的溶液后，在室温下稳定时间大于48h。
实施例54：伊立替康胶束冻干粉剂的制备
取200mg两亲性嵌段共聚物Id和40mg伊立替康放入250mL烧瓶中，加入50mL乙腈溶解；室温下置于摇床中震荡2h；旋蒸除去乙腈，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入50mL 60℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的伊立替康含量为16％。
该冻干粉用生理盐水复溶成3mg/mL浓度的溶液后，在室温下稳定时间大于24h。
实施例55：SN-38胶束冻干粉剂的制备
取200mg两亲性嵌段共聚物Ih和20mg SN-38放入250mL烧瓶中，加入50mL乙腈溶解；室温下置于摇床中震荡2h；旋蒸除去乙腈，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入50mL 40℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的SN-38含量为9％。
该冻干粉用生理盐水复溶成1.5mg/mL浓度的溶液后，在室温下稳定时间大于24h。
实施例56：氟维司群胶束冻干粉剂的制备
取200mg两亲性嵌段共聚物Ih和70mg氟维司群放入250mL烧瓶中，加入50mL乙腈溶解；室温下置于摇床中震荡2h；旋蒸除去乙腈，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入50mL 40℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的氟维司群含量为25％。
该冻干粉用生理盐水复溶成2mg/mL浓度的溶液后，在室温下稳定时间大于72h。
实施例57：硼替佐米胶束冻干粉剂的制备
取200mg两亲性嵌段共聚物Iu和70mg硼替佐米放入250mL烧瓶中，加入50mL 二氯甲烷溶解；室温下置于摇床中震荡2h；旋蒸除去二氯甲烷，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入50mL 40℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的硼替佐米含量为25％。
该冻干粉用生理盐水复溶成2mg/mL浓度的溶液后，在室温下稳定时间大于72h。
实施例58：GW6471胶束冻干粉剂的制备
取200mg两亲性嵌段共聚物Is和50mg GW6471放入250mL烧瓶中，加入50mL丙酮溶解；室温下置于摇床中震荡2h；旋蒸除去丙酮，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入50mL 40℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的GW6471含量为20％。
该冻干粉用生理盐水复溶成2mg/mL浓度的溶液后，在室温下稳定时间大于72h。
实施例59：伏立康唑胶束冻干粉剂的制备
取200mg两亲性嵌段共聚物Ix和70mg伏立康唑放入250mL烧瓶中，加入50mL乙腈溶解；室温下置于摇床中震荡2h；旋蒸除去乙腈，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入50mL 40℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的伏立康唑含量为25％。
该冻干粉用生理盐水复溶成2mg/mL浓度的溶液后，在室温下稳定时间大于72h。
实施例60：地塞米松胶束冻干粉剂的制备
取200mg两亲性嵌段共聚物Iy和90mg地塞米松放入250mL烧瓶中，加入50mL乙腈溶解；室温下置于摇床中震荡2h；旋蒸除去乙腈，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入50mL 40℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的地塞米松含量为30％。
该冻干粉用生理盐水复溶成2mg/mL浓度的溶液后，在室温下稳定时间大于72h。
实施例61：奥拉帕尼胶束冻干粉剂的制备
取200mg两亲性嵌段共聚物Iz和100mg奥拉帕尼放入250mL烧瓶中，加入50mL乙腈溶解；室温下置于摇床中震荡2h；旋蒸除去乙腈，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入50mL 40℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的奥拉帕尼含量为33％。
该冻干粉用生理盐水复溶成2mg/mL浓度的溶液后，在室温下稳定时间大于72h。
实施例62：康普瑞丁胶束冻干粉剂的制备
取200mg两亲性嵌段共聚物Iaa和70mg康普瑞丁放入250mL烧瓶中，加入50mL二氯甲烷溶解；室温下置于摇床中震荡2h；旋蒸除去二氯甲烷，在烧瓶壁形成透明薄膜；迅速向烧瓶中导入50mL 40℃的纯水；震荡成具有明显蓝色乳光的均一溶液；过0.22μm滤膜；在冻干机上冻干成白色粉末状固体；HPLC检测冻干后固体的康普瑞丁含量为25％。
该冻干粉用生理盐水复溶成2mg/mL浓度的溶液后，在室温下稳定时间大于72h。
实施例63大鼠药代动力学研究
1.1实验动物
健康成年SD大鼠，雄性，6-8周龄，体重200-250g，由上海西普尔-必凯实验动物有限公司提供，动物合格证号：2008001682093。
1.2供试样品配制
1)紫杉醇胶束：由本发明实施例46制得的紫杉醇冻干粉，紫杉醇与共聚物(PEG-linker-PLA)Ia的重量比为30:100；
2)Genexol-PM胶束:韩国三养紫杉醇胶束冻干粉，紫杉醇与共聚物(PEG-PLA)的重量比为20:100；
3)紫杉醇注射液：购自北京双鹭药业股份有限公司的紫杉醇注射液，30mg/5ml*10包装，产品批号：20170501。
紫杉醇胶束冻干粉或者Genexol-PM：称取适量样品，加入适量的生理盐水，摇床200r/min的速度振荡约20min直至澄清，供静脉注射给药。
1.3供试药品给药
静脉注射给药：每个供试化合物3只雄性SD大鼠，禁食一夜后分别静脉注射给药，剂量3mg/kg，给药体积3mL/kg。
1.4实验方法
在给药前及给药后0.0833、0.25、0.5、1、2、4、6、8、24小时后，将每只动物的颈静脉穿刺(每个时间点约0.15mL)进行聚丙烯管的采血，将所有血样转移到预冷的EDTA-K2试管或预冷的塑料微量离心管中，所述试管含有3μL 0.5M EDTA-K2作为抗凝剂并置于湿冰上直至离心。每个收集的血液在4℃离心15分钟，收集血浆，所有的血浆将被储存在约-80℃的冷冻箱中，直至LCMS/MS检测。
1.5药代动力学数据结果
各组药代动力学参数比较见表1。
表1
Figure PCTCN2019074816-appb-000058
1.6实验结论
1)等剂量(10mg/kg)单次静脉注射给予SD大鼠，本发明的紫杉醇胶束中的紫杉醇在血浆中的药物暴露量显著低于紫杉醇注射液组，而且也低于韩国三养的Genexol-PM，显示本发明的紫杉醇胶束在体内的稳定性明显优于韩国三养的Genexol-PM组和紫杉醇注射液组，显示本发明的紫杉醇胶束可能具有更好的安全性。
2)本发明的紫杉醇胶束中的紫杉醇半衰期明显高于紫杉醇注射液组和韩国三养的Genexol-PM，显示本发明的紫杉醇胶束可能具有更好的疗效。
实施例64本发明紫杉醇胶束在小鼠Colo-205模型上的药效学研究
2.1实验动物
BALB/c裸小鼠，5周龄，体重14-16克，雌性，由上海西普尔-必凯实验动物有限公司提供，动物合格证号：20130016001491。
2.2饲养条件
动物到达后在实验环境饲养7天后方开始实验。动物在SPF级动物房以IVC(独立送风系统)笼具饲养(每笼4只)。每笼动物信息卡注明笼内动物数目，性别，品系，接收日期，给药方案，实验编号，组别以及实验开始日期。所有笼具、垫料及饮水在使用前均灭菌。笼具、饲料及饮水每周更换两次。
2.3肿瘤细胞接种方法
人结直肠癌Colo-205细胞(ATCC-CCL-222)体外单层培养，培养条件为RPMI 1640培养基中加10％胎牛血清，100U/mL青霉素和100μg/mL链霉素，37℃5％CO2孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％，数量到达要求时，收取细胞，计数，接种。将0.2mL(5×106个)Colo-205细胞皮下接种于 每只小鼠的右后背。肿瘤平均体积达到163mm 3时，开始将动物随机分组给药。
2.4供试样品配制
1)紫杉醇胶束：由本发明实施例46制得的紫杉醇冻干粉，紫杉醇与共聚物(PEG-linker-PLA)Ia的重量比为30:100；
2)Genexol-PM胶束:韩国三养紫杉醇胶束冻干粉，紫杉醇与共聚物(PEG-PLA)的重量比为20:100；
3)紫杉醇注射液：购自北京双鹭药业股份有限公司的紫杉醇注射液，30mg/5ml*10包装，产品批号：20170501。
紫杉醇胶束冻干粉或者Genexol-PM：称取适量样品，加入适量的生理盐水，摇床200r/min的速度振荡约20min直至澄清，供静脉注射给药。
2.5供试药品给药
给药剂量和给药方案见表2。每周测2-3次裸小鼠皮下的瘤体积，称量鼠重，记录数据。
给药方案如表2。
表2
Figure PCTCN2019074816-appb-000059
注：按照体重计算给药体积，给药体积为10μl/g。
2.6分析评价
实验评价指标：采用肿瘤生长抑制率TGI(％)或相对肿瘤增殖率T/C(％)进行评价，其中T为实验组，C为对照组。
相对肿瘤增殖率T/C(％)的计算：若T>T 0，T/C(％)＝(T-T 0)/(C-C 0)×100％，若T<T 0，T/C(％)＝(T-T 0)/T 0×100％其中T、C为实验结束时的肿瘤体积；T 0、C 0为实验开始时的肿瘤体积。
肿瘤生长抑制率TGI(％)的计算：TGI(％)＝(1-T/C)×100％。
评价标准：T/C(％)>40(即TGI(％)<60％)为无效；T/C(％)≤40(即TGI(％)≥60％)为有效，并经过统计学处理P<0.05为有效。
2.7药效实验结果
紫杉醇胶束、Genexol-PM和紫杉醇注射液对Colo-205细胞肿瘤体积的抑制作用如表 3、图17所示，裸鼠体重变化曲线见图18所示。
表3、各组药物对Colo-205细胞肿瘤体积的抑制作用
Figure PCTCN2019074816-appb-000060
结果表明：
1)本发明的紫杉醇胶束、Genexol-PM胶束和紫杉醇注射液对Colo-205裸鼠肿瘤生长抑制作用都非常明显，其中本发明的紫杉醇胶束组的疗效优于Genexol-PM组和紫杉醇注射液组；
2)紫杉醇注射液组动物出现排尿困难现象，并有动物死亡，解剖后发现膀胱破裂；本发明的紫杉醇胶束组动物一切正常，表明本发明的紫杉醇胶束的安全性优于紫杉醇注射液。
实施例65本发明紫杉醇胶束在小鼠MCF-7模型上的药效学研究
3.1实验动物
BALB/c裸小鼠，6-8周龄，体重18-20克，雌性，由上海灵畅生物科技有限公司提供，动物合格证号：2013001829943。
3.2饲养条件
同实施例2.2
3.3肿瘤细胞接种方法
人乳腺癌MCF-7细胞(ECACC,货号：86012803)体外单层培养，培养条件为EMEM(EBSS)+2mM Glutamine+1％Non Essential Amino Acids(NEAA)培养基中加10％胎牛血清，100U/mL青霉素和100μg/mL链霉素，37℃5％CO 2孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％，数量到达要求时，收取细胞，计数，接种。将0.2mL(1×107个)MCF-7细胞(加基质胶，体积比为1:1)皮下接种于 每只小鼠的右后背，肿瘤平均体积达到209mm 3时开始随机分组给药。
3.4供试样品配制
1)紫杉醇胶束：由本发明实施例36制得的紫杉醇冻干粉，紫杉醇与两亲性嵌段共聚物(PEG-linker-PLA)Ia的重量比为30:100；
2)Genexol-PM胶束:韩国三养紫杉醇胶束冻干粉，紫杉醇与共聚物(PEG-PLA)的重量比为20:100；
3)紫杉醇注射液：购自北京双鹭药业股份有限公司的紫杉醇注射液，30mg/5ml*10包装，产品批号：20170501。
紫杉醇胶束冻干粉或者Genexol-PM：称取适量样品，加入适量的生理盐水，摇床200r/min的速度振荡约20min直至澄清，供静脉注射给药。
3.5供试药品给药
给药剂量和给药方案见表4。每周测2-3次裸小鼠皮下的瘤体积，称量鼠重，记录数据。
给药方案如下表4。
表4
Figure PCTCN2019074816-appb-000061
注：按照体重计算给药体积，给药体积为10μl/g。
3.6分析评价
实验评价指标：采用肿瘤生长抑制率TGI(％)或相对肿瘤增殖率T/C(％)进行评价，其中T为实验组，C为对照组。
相对肿瘤增殖率T/C(％)的计算：若T>T 0，T/C(％)＝(T-T 0)/(C-C 0)×100％，若T<T 0，T/C(％)＝(T-T 0)/T 0×100％其中T、C为实验结束时的肿瘤体积；T 0、C 0为实验开始时的肿瘤体积。
肿瘤生长抑制率TGI(％)的计算：TGI(％)＝(1-T/C)×100％。
评价标准：T/C(％)>40(即TGI(％)<60％)为无效；T/C(％)≤40(即TGI(％)≥60％)为有效，并经过统计学处理P<0.05为有效。
3.7药效实验结果
本发明的紫杉醇胶束、Genexol-P胶束和紫杉醇注射液对MCF-7细胞肿瘤体积的抑 制作用如表5、图19所示，裸鼠体重变化曲线见图20所示。
表5、各组药物对MCF-7细胞肿瘤体积的抑制作用的比较
Figure PCTCN2019074816-appb-000062
结果表明：
1)本发明紫杉醇胶束、Genexol-PM组和紫杉醇注射液都对MCF-7裸鼠肿瘤生长抑制作用非常明显，其中本发明的紫杉醇胶束疗效优于其它两组。
2)紫杉醇注射液组动物出现排尿困难现象，并有动物死亡，解剖后发现膀胱破裂；本发明的紫杉醇胶束组动物一切正常，表明本发明的紫杉醇胶束的安全性优于紫杉醇注射液。
本发明中使用到的缩写如表6所示。
表6
缩写 全称
DBU 1,8-二氮杂二环十一碳-7-烯
Me-PEG 聚乙二醇单甲醚
PLA 聚乳酸/聚丙交酯
linker 连接子
Boc 叔丁氧羰基
Fmoc 芴甲氧羧基
TBSCl 叔丁基二甲基氯硅烷
DCC 二环己基碳二亚胺
NHS N-羟基丁二酰亚胺
EDCI 1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐
DMAP N,N-二甲基氨基吡啶
Mn 数均分子量
实施例中所涉及的化合物的结构式如下表7所示。
表7
Figure PCTCN2019074816-appb-000063
Figure PCTCN2019074816-appb-000064
Figure PCTCN2019074816-appb-000065
上表中，带“*”碳原子为手性碳原子，该手性碳原子的构型为R构型、S构型或外消旋体。
由于已根据其特殊的实施方案描述了本发明，某些修饰和等价变化对于本领域普通技术人员是显而易见的且包括在本发明的范围内。

Claims (26)

  1. 一种两亲性嵌段共聚物，其特征在于，所述两亲性嵌段共聚物包含亲水性链段、疏水性链段以及用于连接亲水性链段和疏水性链段的linker，所述的linker为连接子，所述的linker的结构为C 1-C 30小分子片段，所述C 1-C 30小分子片段被一个或多个芳香环取代；
    所述芳香环为C 6-C 20芳基、被R a取代的C 6-C 20芳基、C 2-C 20杂芳基或被R b取代的C 2-C 20杂芳基；
    R a和R b独立地为C 1～C 6烷基、C 1～C 6烷氧基、C 4～C 6环烷基、卤素、羟基或硝基；
    所述R a的个数为一个或多个，当所述R a的个数为多个时，所述R a相同或不同；
    所述R b的个数为一个或多个，当所述R b的个数为多个时，所述R b相同或不同；
    所述C 2-C 20杂芳基或所述被R b取代的C 2-C 20杂芳基中的杂原子为O、S或N，所述杂原子的个数为一个或多个，当为多个时，所述杂原子相同或不同；
    所述亲水性链段为数均分子量在400～20000之间的聚乙二醇链段或单保护的聚乙二醇链段；
    所述疏水性链段选自数均分子量在400～20000之间的聚丙交酯链段、单保护的聚丙交酯链段、聚乙交酯链段、单保护的聚乙交酯链段、聚乙丙交酯链段、单保护的聚乙丙交酯链段、聚己内酯链段、单保护的聚己内酯链段、聚碳酸酯链段、单保护的聚碳酸酯链段、聚二氧环己酮链段、或者单保护的聚二氧环己酮链段中的一种。
  2. 根据权利要求1所述的两亲性嵌段共聚物，其特征在于，所述芳香环中，所述C 6-C 20芳基或所述被R a取代的C 6-C 20芳基中的C 6-C 20芳基为C 6-C 10芳基，优选为苯基或萘基；
    和/或，所述芳香环中，所述C 2-C 20杂芳基或所述被R b取代的C 2-C 20杂芳基中的C 2-C 20杂芳基为C 2-C 10杂芳基，优选为C 3-C 8杂芳基；
    和/或，R a或R b中，所述C 1～C 6烷基优选为C 1～C 3烷基；
    和/或，R a或R b中，所述C 1～C 6烷氧基优选为C 1～C 3烷氧基；
    和/或，所述C 1-C 30小分子片段为C 2-C 10小分子片段；
    和/或，所述C 1-C 30小分子片段被1～3个芳香环取代；
    和/或，所述C 1-C 30小分子片段包含或者不包含杂原子取代，所述杂原子选自氧原子、氮原子、硫原子和磷原子中的一个或多个；所述杂原子取代的个数为一个或多个，优选为1～4个；
    和/或，所述疏水性链段选自数均分子量在400～20000之间的聚丙交酯链段或单保护 的聚丙交酯链段，所述单保护的聚丙交酯链段优选为单端基为羟基保护基的聚丙交酯链段。
  3. 根据权利要求1或2所述的两亲性嵌段共聚物，其特征在于，所述芳香环为C 6-C 10芳基、被R a取代的C 6-C 10芳基、C 2-C 10杂芳基或被R b取代的C 2-C 10杂芳基，R a和R b独立地为C 1～C 3烷基、C 1～C 3烷氧基、卤素、羟基或硝基。
  4. 根据权利要求1所述的两亲性嵌段共聚物，其特征在于，所述linker的结构选自如下任一结构：
    Figure PCTCN2019074816-appb-100001
    Ar为芳香环，所述芳香环的定义如权利要求1～3任一项所述；
    T 1为单键或
    Figure PCTCN2019074816-appb-100002
    p为0或1，q为1、2或3，X 1为-O-、-S-或-NH-；
    T 2为单键或
    Figure PCTCN2019074816-appb-100003
    r为0、1、2、3、4或5，
    T 3为单键或
    Figure PCTCN2019074816-appb-100004
  5. 根据权利要求4所述的两亲性嵌段共聚物，其特征在于，T 1为单键，T 2为单键；
    或，T 1为
    Figure PCTCN2019074816-appb-100005
    p为0，q为2，X 1为-S-或-NH-，T 2为单键；
    或，T 1为
    Figure PCTCN2019074816-appb-100006
    p为1，q为2，X 1为-O-，T 2为单键。
  6. 根据权利要求1所述的两亲性嵌段共聚物，其特征在于，所述的linker的结构包 为含有芳香环的氨基酸、含有芳香环的氨基醇或含有芳香环的多肽的C 1-C 30小分子片段，其中，所述芳香环位于氨基酸、氨基醇或多肽的侧链，或者位于氨基酸、氨基醇或多肽的羟基、巯基、胺基或者羧基的保护基；
    所述含有芳香环的氨基酸中的氨基酸优选为R构型、S构型或外消旋体；
    所述含有芳香环的氨基醇中的氨基醇优选为R构型、S构型或外消旋体。
  7. 根据权利要求6所述的两亲性嵌段共聚物，其特征在于，所述的含有芳香环的氨基酸选自苯丙氨酸、组氨酸、酪氨酸、色氨酸和3-(2-萘基)-丙氨酸中的一个或多个；
    和/或，所述的含有芳香环的氨基醇选自苯丙氨醇、组氨醇、酪氨醇、色氨醇和3-(2-萘基)-丙氨醇中的一个或多个；
    和/或，所述的含有芳香环的多肽中的一个或多个片段来自于苯丙氨酸、组氨酸、酪氨酸、色氨酸和3-(2-萘基)-丙氨酸中的一个或多个。
  8. 根据权利要求1所述的两亲性嵌段共聚物，其特征在于，所述的两亲性嵌段共聚物具有如下结构：R 1-PEG-linker-PLA-R 2，
    其中R 1和R 2独立地选自羟基保护基或氢；
    PEG为数均分子量在400～20000的聚乙二醇嵌段，PLA为数均分子量在400～20000的聚丙交酯嵌段，聚乙二醇嵌段和聚丙交酯嵌段的数均分子量比例为1:(0.5～2)；
    linker的定义如权利要求1～7任一项所述。
  9. 根据权利要求1所述的两亲性嵌段共聚物，其特征在于，所述的两亲性嵌段共聚物具有如下结构：
    Figure PCTCN2019074816-appb-100007
    其中，其中R 1和R 2独立地选自羟基保护基或氢；
    linker的定义如权利要求1～7任一项所述；
    n＝8～455；m＝3～160。
  10. 根据权利要求9所述的两亲性嵌段共聚物，其特征在于，所述两亲性嵌段共聚物选自如下任一结构：
    Figure PCTCN2019074816-appb-100008
    Figure PCTCN2019074816-appb-100009
    其中，R 1、R 2、n和m的定义如权利要求9所述；
    Ar、T 1、T 2和T 3的定义如权利要求4或5所述.
  11. 根据权利要求1～10至少一项所述的两亲性嵌段共聚物，其特征在于，所述两亲性嵌段共聚物进一步优选为选自如下任一结构：
    Figure PCTCN2019074816-appb-100010
    Figure PCTCN2019074816-appb-100011
    Figure PCTCN2019074816-appb-100012
    n和m的定义如权利要求9所述。
  12. 根据权利要求1～10至少一项所述的两亲性嵌段共聚物，其特征在于，所述两亲性嵌段共聚物选自如下任一结构：
    Figure PCTCN2019074816-appb-100013
    n和m的定义如权利要求9所述。
  13. 根据权利要求1～12至少一项所述的两亲性嵌段共聚物的制备方法，其特征在于，所述制备方法包括以下步骤：
    1)对数均分子量为400～20000的聚乙二醇或单保护聚乙二醇进行linker修饰；
    2)有机溶剂中，在催化剂的作用下，将步骤1)的产物与DL-丙交酯、L-丙交酯、D-丙交酯、乙交酯、DL-丙交酯和乙交酯的不同比例混合物、L-丙交酯和乙交酯的不同比 例混合物、D-丙交酯和乙交酯的不同比例混合物、己内酯、双酚A和碳酸二苯酯的混合物或对二氧环己酮进行聚合，
    3)可选地，对步骤2)得到的聚合物进行末端羟基保护，即可。
  14. 根据权利要求13所述的两亲性嵌段共聚物的制备方法，其特征在于，如式I所示的两亲性嵌段共聚物的制备方法包括如下步骤：
    1)如式II所示的聚合物在催化剂的作用下引发丙交酯聚合，得式IA所示的共聚物，所述丙交酯为DL-丙交酯、L-丙交酯或D-丙交酯；
    Figure PCTCN2019074816-appb-100014
    2)如式IA所示的共聚物经过羟基保护反应，得如式I所示的两亲性嵌段共聚物；
    Figure PCTCN2019074816-appb-100015
    其中，linker、R 1、R 2、m和n的定义如权利要求9所述，当R 2为氢时，无需进行步骤2)。
  15. 根据权利要求14所述的两亲性嵌段共聚物的制备方法，其特征在于，如式II所示的聚合物由如下方法制得：如式III所示的聚合物经过小分子片段修饰，即可；
    Figure PCTCN2019074816-appb-100016
    其中，linker、R 1和n的定义如权利要求14所述。
  16. 根据权利要求13～15至少一项所述的两亲性嵌段共聚物的制备方法，其特征在于，步骤2)中，所述催化剂为1,8-二氮杂二环十一碳-7-烯，辛酸亚锡，2-乙基己酸镁，1,5,7-三氮杂二环[4.4.0]癸-5-烯和7-甲基-1,5,7-三氮杂二环[4.4.0]癸-5-烯中的一种或多种；优选为1,8-二氮杂二环十一碳-7-烯和/或辛酸亚锡。
  17. 一种如式II所示的聚合物，
    Figure PCTCN2019074816-appb-100017
    其中，R 1、n和linker的定义如权利要求9所述。
  18. 如权利要求17所述的如式II所示的聚合物，其特征在于，所述如式II所示的聚合物选自如下任一结构：
    Figure PCTCN2019074816-appb-100018
    其中，R 1和n的定义如权利要求9所述；
    Ar、T 1、T 2和T 3的定义如权利要求4或5所述。
  19. 如权利要求17所述的如式II所示的聚合物的制备方法，其特征在于，式II所示的聚合物由式III所示的聚合物经过小分子修饰制得，
    Figure PCTCN2019074816-appb-100019
    其中，R 1、n和linker的定义如权利要求17所述。
  20. 一种如式II-1所示的聚合物的制备方法，其特征在于，如式II-1所示的聚合物由式III-1所示的聚合物经过脱保护反应制得，
    Figure PCTCN2019074816-appb-100020
    其中，其中，R 1和n的定义如权利要求9所述；
    Ar、T 1和T 2的定义如权利要求4或5所述；
    R 4为胺基保护基。
  21. 一种如式II-2所示的聚合物的制备方法，其特征在于，如式II-2所示的聚合物由式III-2所示的聚合物经过脱保护反应制得，
    Figure PCTCN2019074816-appb-100021
    其中，其中，R 1和n的定义如权利要求9所述；
    Ar、T 1和T 2的定义如权利要求4或5所述；
    R 3为羟基保护基。
  22. 一种如式II-3所示的聚合物的制备方法，其特征在于，如式II-3所示的聚合物由式III-3所示的聚合物与式IV-D所示的化合物发生缩合反应制得，
    Figure PCTCN2019074816-appb-100022
    其中，其中，R 1和n的定义如权利要求9所述；
    Ar和T 3的定义如权利要求4或5所述。
  23. 一种纳米胶束载药系统，其特征在于，包含如权利要求1～12至少一项所述的两亲性嵌段共聚物和药物。
  24. 根据权利要求23所述的纳米胶束载药系统，其特征在于，所述药物与所述两亲性嵌段共聚物的重量比为(0.5～100):100，优选(1～70):100；
    和/或，所述药物为难溶性药物，所述的难溶性药物优选为选自紫杉醇、多西他赛、卡巴他赛、7-表紫杉醇、t-乙酰基紫杉醇、10-脱乙酰基紫杉醇、10-脱乙酰基-7-表紫杉醇、7-木糖基紫杉醇、10-脱乙酰基-7-戊二酰紫杉醇、7-N,N-二甲基甘氨酰紫杉醇、7-L-丙氨酰紫杉醇、莱龙泰素、阿霉素、表阿霉素、SN-38、伊立替康、拓扑替康、环磷酰胺、异环磷酰胺、雌莫司汀、米托蒽醌、安吖啶、顺铂、卡铂、奥沙利铂、依托泊苷、替尼泊苷、长春碱、长春新碱、长春瑞滨、长春地辛、美登素、三尖杉酯碱、高三尖杉酯碱、丝裂霉素、博莱霉素、柔红霉素、伊达比星、多柔比星、表柔比星、吉西他滨、卡培他滨、氟达拉滨、克拉曲滨、硼替佐米、卡非佐米、艾莎佐米、卡莫司汀、氟尿嘧啶、阿糖胞苷、环孢菌素A、西罗莫司、替西罗莫司、依维莫司、艾日布林、曲贝替定、氟维司群、来曲唑、替莫唑胺、雷洛昔芬、他莫昔芬、来那度胺、伊沙匹隆、甲氨蝶呤、培美曲塞、恩杂鲁胺、阿比特龙、苯达莫司汀、姜黄素、白藜芦醇、吲哚美辛、石杉碱甲、阿昔洛韦、别嘌醇、胺碘酮、硫唑嘌呤、贝那普利、骨化三醇、坎地沙坦、衣普罗沙坦、卡比多巴/左旋多巴、克拉霉素、氯氮平、醋酸去氨加压素、双氯芬酸、依那普利、法莫替丁、非洛地平、非诺贝特、芬太尼、非索非那定、福辛普利、呋塞米、格列本脲、莨菪碱、丙咪嗪、伊曲康唑、左甲状腺素、阿托伐他汀、洛伐他汀、美克洛嗪、甲地孕酮、巯嘌呤、美托拉宗、莫米松、萘丁美酮、奥美拉唑、帕罗西汀、普罗帕酮、喹那普利、辛伐他汀、西罗莫司、他克莫司、替扎尼定、利培酮、奥氮平、齐拉西酮、利斯的明、纳洛酮、环丙甲羟二羟吗啡酮、西罗莫司、他克莫司、卡莫司汀、黄体酮、雌激素、雌二醇、左炔诺孕酮、炔诺酮、伊沙匹隆、艾博霉素、雷帕霉素、普卡霉素、万古霉素、两性霉素B、足叶乙甙、强力霉素、伊曲康唑、氟康唑、伏立康唑、泊沙康唑、酮康唑、睾酮、孕酮、去炎松、地塞米松、替诺昔康、吡罗昔康、布洛芬、卡泊芬净、米卡芬净、奥拉帕尼、丁苯酞、康普瑞丁、GW6471、COX-II抑制剂、芳香化酶抑制剂、多肽药物以及它们的组合。
  25. 根据权利要求23～24至少一项所述的纳米胶束载药系统，其特征在于，所述的纳米胶束载药系统还包含药学上可接受的药用辅料，所述的药用辅料优选为冻干赋形剂，所述的冻干赋形剂优选为乳糖、甘露糖、蔗糖、海藻糖、果糖、葡萄糖、海藻酸钠和明胶中的至少一种。
  26. 根据权利要求23～25至少一项所述的纳米胶束载药系统的制备方法，其特征在于，所述制备方法包括透析法、溶剂挥发法或薄膜水化法，优选薄膜水化法。
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