CN103059311B - ABA type amphiphilic triblock copolymer based on molecular glue and uses of the same - Google Patents

ABA type amphiphilic triblock copolymer based on molecular glue and uses of the same Download PDF

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CN103059311B
CN103059311B CN201210563824.0A CN201210563824A CN103059311B CN 103059311 B CN103059311 B CN 103059311B CN 201210563824 A CN201210563824 A CN 201210563824A CN 103059311 B CN103059311 B CN 103059311B
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pla
peg
compound
aba type
block copolymer
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CN103059311A (en
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杨晴来
龚兵
沈玉梅
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Shanghai Jiaotong University
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Shanghai Jiaotong University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/07—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media from polymer solutions
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2353/00—Characterised by the use of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives of such polymers

Abstract

The invention discloses an ABA type amphiphilic triblock copolymer based on molecular glue and uses of the same. The copolymer structure is as follows: the copolymer can be used for preparing a self-assembled loading drug micelle. The ABA type amphiphilic triblock copolymer based on molecular glue and uses of the same utilize a method of organic synthesis to modify polymer polyethylene glycol (PEG) and poly lactic acid (PLA) for the first time, introduce a molecular glue single chain with a hydrogen bond sequence selectivity into a polymer macromolecule, and enable the molecular glue single chain to form a molecular glue under certain conditions so as to selectively efficient synthesize the series amphiphilic triblock copolymer. The synthetic raw material of the compound is simple and easy to prepare, each synthesizing process is a conventional reaction, and suitable for mass production. The prepared block copolymer micelle has good stability, a blank micelle does no harm to normal cells, and the drug-loading micelle can effectively release encapsulated drugs under the reductants of dithiothreitol or reductible glutathione.

Description

ABA type amphipathic three block copolymer based on molecular glue and uses thereof
Technical field
The present invention relates to chemosynthesis, biological chemistry, pharmaceutics field, be specifically related to a kind of ABA type amphipathic three block copolymer based on molecular glue and uses thereof.
Background technology
Amphipathic nature block polymer has wide development potentiality as solid support material in study of pharmacy field, has stronger self-assembly ability, and conventionally taking polyoxyethylene glycol (PEG) etc. as hydrophilic section, polyester, polycaprolactone, poly-acid anhydrides etc. are hydrophobic section.Polyoxyethylene glycol (PEG) has good wetting ability, nontoxic, the residual advantages such as eliminating that are easy to, and be can be used for human body (Macromol Biosci, 2006,6:846-854) by the United States Federal's drugs administration approved.Poly(lactic acid) (PLA) is a kind of important biodegradable material, there is nontoxic aseptic, good biocompatibility, biodegradability and organize absorbability (Biomedical Science, Engineering and Technology, 2012,2:263-270).The segmented copolymer that poly(lactic acid) and polyoxyethylene glycol form, there is PLA and PEG advantage simultaneously, give again the performance that material is new simultaneously, be widely used in the bio-medical engineering field (Macromolecules such as controlled drug delivery system, bone inside-fixture, tissue engineering bracket material, cell cultures, 1996,29 (15): 5233-5235).
The method of current synthetic PLA-PEG-PLA segmented copolymer mainly concentrates in the direct melt condensation method of lactic acid and PEG and the research of rac-Lactide and PEG melt phase polycondensation, they respectively have relative merits, but directly melt condensation method generally adopts High Temperature High Pressure synthetic, condition time consumption and energy consumption, adopts rac-Lactide ring-opening polymerization generally to adopt ZnCl 2make in synthetic materials to have introduced and be with virose heavy metal Deng heavy metal catalysis, and require to have the rac-Lactide of polymerization-grade purity, purifying process complexity, cost is higher.The wetting ability of the present inventor based on polyoxyethylene glycol (PEG) and the hydrophobic thought of poly(lactic acid) (PLA), adopt the polymer-modified PEG of method of organic synthesis, PLA, in known high polymer, introduce respectively the molecular glue strand with the effect of hydrogen bond sequence selective, make it can effectively form under given conditions molecular glue, thereby can optionally efficiently synthesize the amphipathic nature block polymer of a series of different molecular weights, in previous work, contriver has synthesized a series of di-block copolymers and segmented copolymer by molecular glue (number of patent application has been respectively: 201110023046.1, 201110418589.3, 201210311658.X, 201210442360.8), in the present invention, contriver has synthesized a series of amphipathic three block copolymers with molecular glue group, the disulfide linkage that the molecular glue of introducing therein contains has been given multipolymer Redox-sensitive, under the reductive agent effects such as DTT, disulfide bonds make parcel drug release out, thereby play slowly-releasing, controlled-release function.Raw material required for the present invention, reagent are easy to get, mild condition, and building-up process is conventional chemical reaction, and is applicable to fairly large production.Adopt present method synthetic segmented copolymer PLA-PEG-PLA, PEG-PLA-PEG, thus can self-assembly be the micella encapsulation rate that effectively improves medicine, reduce the prominent release of releasing, control.
Summary of the invention
The object of the present invention is to provide a kind of ABA type amphipathic three block copolymer based on molecular glue and uses thereof.Amphipathic three block copolymer of the present invention can be used for preparing self-assembled micelle, and it is water-soluble and have an effect such as slowly-releasing, controlled release that this self-assembled micelle can be applicable to improve insoluble drug.The present invention is based on the wetting ability of polyoxyethylene glycol (PEG) and the hydrophobic thought of poly(lactic acid) (PLA), adopt first the polymer-modified PEG of method of organic synthesis, PLA, in known high polymer, introduce respectively the molecular glue strand with hydrogen bond matching effect, make it can form under given conditions molecular glue, thereby amphipathic three block copolymer PLA-PEG-PLA or the PEG-PLA-PEG of a series of different molecular weight ratios can be optionally efficiently synthesized, and the molecular glue of introducing therein contains disulfide linkage and makes multipolymer give Redox-sensitive, synthesis material reagent is easy to get, mild condition, building-up process is conventional green reaction, and applicable fairly large production.
The object of the invention is to be achieved through the following technical solutions:
First aspect, the present invention relates to a kind of ABA type amphipathic three block copolymer PEG-PLA-PEG based on molecular glue, and its structural formula is suc as formula shown in (I):
Wherein, n is any one integer in 2～225, and m is any one integer in 0～135.
Preferably, described multipolymer be prepare as follows and:
A, synthesis hydrophilic fragmentation compound PEG-A4: taking DMF as solvent, with NMM (N-methylmorpholine), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) be catalyzer, compd A 4 with compound PEG-NH 2 there is amidate action, obtain hydrophilic segment compound PEG-A4 described A4, NMM, HATU, PEG-NH 2mol ratio be 1: (1.0～2.0): (1.5～3): (1.0～2);
B, hydrophobic synthetic fragmentation compound Z1-PLA-Z1: with CH 2cl 2for solvent, taking DMAP as catalyzer, compound PLA and Succinic anhydried there is esterification, generate the PLA that is modified as end carboxyl the mol ratio of described PLA, DMAP, Succinic anhydried is 1: 2.0: 3; Continuing taking DMF as solvent, is activator with NMM (N-methylmorpholine), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester), described end carboxyl PLA and compound Z1 there is amidate action, obtain hydrophobic fragment compound Z1-PLA-Z1 the mol ratio of described PLA, NMM, HATU and Z1 is 1: 4.0: 4.0: (2.5～3.0);
C, synthetic ABA type amphipathic three block copolymer PEG-PLA-PEG: taking methylene dichloride as solvent, at I 2effect under, make hydrophilic segment compound PEG-A4 and hydrophobic fragment compound Z1-PLA-Z1 that oxidizing reaction occur, generate described ABA type amphipathic three block copolymer PEG-PLA-PEG; Described PEG-A4, hydrophobic fragment Z1-PLA-Z1 and I 2mol ratio be 2: 1.5: 24.
Second aspect, the present invention relates to a kind of above-mentioned ABA type amphipathic three block copolymer based on molecular glue in the purposes of preparing in carrier micelle.
Preferably, described ABA type amphipathic nature block polymer and poorly water soluble drugs are dissolved in polar solvent obtaining to mixed solution, described mixed solution is added dropwise in the aqueous phase solution of stirring and makes to form micro emulsion ball, pack the mixed solution that contains micro emulsion ball into dialysis tubing and appear described polar solvent, obtain described carrier micelle.
Preferably, described polar solvent is DMSO, DMF or THF; Described poorly water soluble drugs is Zorubicin, taxol, Elemenum, camptothecine or vitamin A acid; Described aqueous phase solution is PBS damping fluid; Described dialysis tubing molecular weight is 0.2KD.
The third aspect, the present invention relates to a kind of ABA type amphipathic three block copolymer PLA-PEG-PLA based on molecular glue, and its structural formula is suc as formula shown in (II):
Wherein, n is any one integer in 2～225, and m is any one integer in 1～135.
Preferably, described multipolymer be prepare as follows and:
A, synthesis hydrophilic fragmentation compound A4-PEG-A4: taking DMF as solvent, with NMM (N-methylmorpholine), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) be catalyzer, compd A 4 with compound N H 2-PEG-NH 2 there is amidate action, obtain hydrophilic segment compd A 4-PEG-A4 described A4, NMM, HATU, NH 2-PEG-NH 2mol ratio be 2.0: 4.0: 4.0: (0.3～0.5);
B, hydrophobic synthetic fragmentation compound PLA-Z1: taking DMF as solvent, with NMM (N-methylmorpholine), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) be activator, compound PLA with compound Z1 there is amidate action, obtain hydrophobic fragment compound PLA-Z1 the mol ratio of described PLA, NMM, HATU and Z1 is 1: (1.0～2.0): (1.5～3): (1.0～2);
C, synthetic ABA type amphipathic three block copolymer PLA-PEG-PLA: taking methylene dichloride as solvent, at I 2effect under, there is oxidizing reaction in hydrophilic segment compd A 4-PEG-A4 and hydrophobic fragment compound PLA-Z1, generates described ABA type amphipathic three block copolymer PLA-PEG-PLA; Described A4-PEG-A4, PLA-Z1 and I 2mol ratio be 1: 3: 24.
Fourth aspect, the present invention relates to a kind of above-mentioned ABA type amphipathic three block copolymer based on molecular glue in the purposes of preparing in carrier micelle.
Preferably, described ABA type amphipathic nature block polymer and poorly water soluble drugs are dissolved in polar solvent obtaining to mixed solution, described mixed solution is added dropwise in the aqueous phase solution of stirring and makes to form micro emulsion ball, pack the mixed solution that contains micro emulsion ball into dialysis tubing and appear described polar solvent, obtain described carrier micelle.
Preferably, described polar solvent is DMSO, DMF or THF; Described poorly water soluble drugs is Zorubicin, taxol, Elemenum, camptothecine or vitamin A acid; Described aqueous phase solution is PBS damping fluid; Described dialysis tubing molecular weight is 0.2KD.
Compared with prior art, the present invention has following beneficial effect:
1, adopt first the polymer-modified PEG of method of organic synthesis, PLA, in polymer macromolecule, introduce the molecular glue strand with hydrogen bond sequence selective, make it can form under given conditions molecular glue, thereby optionally efficient synthesizing series amphipathic three block copolymer, such compou nd synthesis raw material is simple and easy to get, and building-up process is popular response, is applicable to fairly large production.
2, the block copolymer micelle that prepared by the present invention has good stability, blank micella is to normal cell (NIH 313 cells) toxicological harmless effect, carrier micelle can effectively discharge wrapped up medicine under the effect of the reductive agent such as reducing agent dithiothreitol or reductive glutathione, thereby carrier micelle can effectively enter cancer cells and in cancer cells, discharge medicine and kills cancer cells (taking HeLa cell as example).
Brief description of the drawings
By reading the detailed description of non-limiting example being done with reference to the following drawings, it is more obvious that other features, objects and advantages of the present invention will become:
Fig. 1 is the synthetic route schematic diagram of hydrophilic segment compound PEG-A4;
Fig. 2 is the synthetic route schematic diagram of hydrophilic segment compd A 4-PEG-A4;
Fig. 3 is the synthetic route schematic diagram of hydrophobic fragment compound PLA-Z1;
Fig. 4 is the synthetic route schematic diagram of hydrophobic fragment compound Z1-PLA-Z1;
Fig. 5 is the synthetic route schematic diagram of amphipathic three block copolymer PEG-PLA-PEG;
Fig. 6 is the synthetic route schematic diagram of amphipathic three block copolymer PLA-PEG-PLA;
Fig. 7 is the GPC graph of molecular weight distribution of the amphipathic three block copolymer of embodiment 1;
Fig. 8 is the graph of a relation of micellar concentration to absorbance A;
Fig. 9 is the size distribution figure of the blank micella of PEG5000-PLA5000-PEG5000;
Figure 10 is the size distribution figure of PEG5000-PLA5000-PEG5000 carrier micelle;
Figure 11 is the stability test result of PEG5000-PLA5000-PEG5000 micella;
Figure 12 is that PEG5000-PLA5000-PEG5000 micella is through reductive agent DTT change of size figure after treatment;
Figure 13 is the rate of release figure of carrier micelle PEG5000-PLA5000-PEG5000 DOX under different concns DTT treatment condition;
Figure 14 is the vitro drug release graphic representation of carrier micelle PEG5000-PLA5000-PEG5000;
Figure 15 is that blank micella PEG5000-PLA5000-PEG5000 is to the Cytotoxic MTT experimental result of NIH 3T3;
Figure 16 is the two Coloration experiment results of blank micella PEG5000-PLA5000-PEG5000AO/EB;
Figure 17 is release graphics in carrier micelle PEG5000-PLA5000-PEG5000 cell;
Figure 18 is that carrier micelle PEG5000-PLA5000-PEG5000 is to Hela cell MTT experimental result.
Embodiment
Below in conjunction with the drawings and specific embodiments, the present invention is described in detail.Following examples will contribute to those skilled in the art further to understand the present invention, but not limit in any form the present invention.It should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, can also make some distortion and improvement.These all belong to protection scope of the present invention.
The present invention's raw material, reagent used is commercially available AR, CP level.
Gained intermediate product of the present invention and final product all adopt 1h-NMR, IR, GPC etc. characterize.
embodiment 1, amphipathic three block copolymer PEG-PLA-PEG and PLA-PEG-PLA's is synthetic
One, hydrophilic segment PEG-A4's is synthetic
(1) in the time of the n=2 of PEG, Mn=163;
Its synthetic route is as shown in Figure 1: under alkaline condition, getting compd A 4 and end is that amino PEG163 carries out amidate action, obtains compound PEG163-A4;
Described step is specially: take A4 (0.841g, 1mmol) be dissolved in 15ml DMF in the single port flask of 25ml, ice-water bath adds NMM (N-methylmorpholine) (112 μ L under stirring, 1.0mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (0.57g, 1.5mmol) after activation 30min (TLC monitoring priming reaction is complete), adding end is amino PEG163 (0.163g, 1mmol) after stirring 1h, be warming up to room temperature reaction 10h, stopped reaction (TLC monitoring reaction finishes), add suitable quantity of water, extract with methylene dichloride (DCM), organic phase washes with water respectively twice, twice of saturated NaCl solution washing, , anhydrous sodium sulfate drying, desolventizing is revolved in decompression, column chromatography obtains faint yellow solid 0.91g, the white solid 0.651g of column chromatography, productive rate 65.08%. 1H-NMR(CD 3OD，400MHz)δ7.94(m，2H，ArH)，7.66(s，1H，ArH)，7.12-7.37(m，30H，ArH)，3.53-3.65(m，12H，-OCH 2CH 2O-)，3.30(s，3H，CH 3O-)，2.36(t，4H，J＝8Hz，-SCH 2-)，2.24(t，4H，J＝8Hz，-CH 2-)，1.71-1.78(m，4H，-COCH 2-)。IR(KBr)2876，1756，1684，1602，1553，1450，1351，1290，1249，1185，1108，945，844，746，702，621，556。
(2) in the time of the n=44 of PEG, Mn=2000;
Its synthetic route is as shown in Figure 1: under alkaline condition, getting compd A 4 and end is that amino PEG2000 carries out amidate action, obtains compound PEG2000-A4;
Described step is specially: take A4 (0.841g, 1mmol) be dissolved in 15ml DMF in the single port flask of 25ml, ice-water bath adds NMM (N-methylmorpholine) (167 μ L under stirring, 1.5mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (0.76g, 2.0mmol) after activation 30min, adding end is amino PEG2000 (3.0g, 1.5mmol) after stirring 1h, be warming up to room temperature reaction 18h, stopped reaction, add appropriate dichloromethane extraction, wash twice, twice of saturated NaCl solution washing, organic phase underpressure distillation obtains faint yellow solid 2.4g, productive rate 85.01%. 1H-NMR(CD 3OD，400MHz)δ7.93(m，2H，ArH)，7.65(s，1H，ArH)，7.12-7.35(m，30H，ArH)，3.76(m，4H，-OCH 2CH 2O-)，3.54-3.58(m，200H，-OCH 2CH 2O-)，3.51(m，4H，-OCH 2CH 2O-)，3.33(s，3H，CH 3O-)，2.32(m，4H，-SCH 2-)，2.20(m，4H，-CH 2-)，1.70(m，4H，-COCH 2-)。GPC：Mn＝2783，Mw＝2903，D＝1.04。IR(KBr)2869，1757，1684，1602，1550，1447，1351，1295，1249，1189，1106，949，847，747，702，621，556。
(3) in the time of the n=112 of PEG, Mn=5000;
Its synthetic route is as shown in Figure 1: under alkaline condition, getting compd A 4 and end is that amino PEG5000 carries out amidate action, obtains compound PEG5000-A4;
Described step is specially: the synthetic schematic diagram of hydrophilic segment compound PEG-A4 is as shown in Scheme 1, take A4 (0.841g, 1mmol) be dissolved in 15ml DMF in the single port flask of 25ml, ice-water bath adds NMM (N-methylmorpholine) (223 μ L under stirring, 2.0mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (1.14g, 3mmol) after activation 30min, adding end is amino PEG5000 (10.0g, 2mmol) after stirring 1h, be warming up to room temperature reaction 24h, stopped reaction, add appropriate dichloromethane extraction, wash twice, twice of saturated NaCl solution washing, organic phase underpressure distillation obtains faint yellow solid 4.4g, productive rate 75.81%. 1H-NMR(CD 3OD，400MHz)δ7.93(m，2H，ArH)，7.65(s，1H，ArH)，7.12-7.35(m，30H，ArH)，3.76(m，4H，-OCH 2CH 2O-)，3.54-3.58(m，477H，-OCH 2CH 2O-)，3.51(m，4H，-OCH 2CH 2O-)，3.33(s，3H，CH 3O-)，2.32(m，4H，-SCH 2-)，2.20(m，4H，-CH 2-)，1.70(m，4H，-COCH 2-)。GPC：Mn＝5678，Mw＝6212，D＝1.09。IR(KBr)2882，1755，1664，1601，1553，1466，1350，1302，1280，1082，955，843，747，702，621，580。
(4) in the time of the n=225 of PEG, Mn=10000;
Its synthetic route is as shown in Figure 1: under alkaline condition, getting compd A 4 and end is that amino PEG10000 carries out amidate action, obtains compound PEG10000-A4;
Described step is specially: the synthetic schematic diagram of hydrophilic segment compound PEG-A4 is as shown in Scheme 1, take A4 (0.0841g, 0.1mmol) be dissolved in 15ml DMF in the single port flask of 25ml, ice-water bath adds NMM (N-methylmorpholine) (16.7 μ L under stirring, 0.15mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (0.057g, 0.15mmol) after activation 30min, adding end is amino PEG10000 (2.0g, 0.2mmol) after stirring 1h, be warming up to room temperature reaction 18h, stopped reaction, add appropriate dichloromethane extraction, wash twice, twice of saturated NaCl solution washing, organic phase underpressure distillation obtains faint yellow solid 0.87g, productive rate 81%. 1H-NMR(CD 3OD，400MHz)δ7.72(m，2H，ArH)，7.41(s，1H，ArH)，7.21-7.30(m，30H，ArH)，3.82(m，4H，-OCH 2CH 2O-)，3.57-3.72(m，1138H，-OCH 2CH 2O-)，3.48(m，4H，-OCH 2CH 2O-)，3.38(s，3H，CH 3O-)，2.37-2.41(m，4H，-SCH 2-)，2.24-2.28(m，4H，-CH 2-)，1.75-1.81(m，4H，-COCH 2-)。GPC：Mn＝9158，Mw＝9853，D＝1.07。IR(KBr)2882，1759，1665，1601，1553，1465，1355，1302，1280，1082，958，846，747，702，621。
Two, hydrophilic segment A4-PEG-A4's is synthetic
(1) in the time of the n=2 of PEG, Mn=163;
Its synthetic route is as shown in Figure 2: under alkaline condition, get compd A 4 and carry out amidate action with the PEG148 of two ends amino, obtain compd A 4-PEG148-A4;
Described step is specially: take A4 (0.841g, 1mmol) be dissolved in 15ml DMF in the single port flask of 25ml, ice-water bath adds NMM (N-methylmorpholine) (224 μ L under stirring, 2.0mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (0.76g, 2.0mmol) after activation 30min, add the PEG163 (0.045g of two ends amino, 0.3mmol) after stirring 1h, be warming up to room temperature reaction 8h, stopped reaction, add suitable quantity of water, extract with methylene dichloride (DCM), organic phase is water respectively, saturated common salt washing, anhydrous sodium sulfate drying, desolventizing is revolved in decompression, column chromatography obtains faint yellow solid 0.831g, the white solid 0.421g of column chromatography, productive rate 78.06%. 1H?NMR(400MHz，CDCl 3)δ＝8.78(s，2H，ArH)，8.12(brs，4H，NH)，8.09-7.91(m，3H，ArH)，7.43-7.19(m，60H，ArH)，6.29(s，1H，ArH)，3.81-3.64(m，4H，-OCH 2CH 2O-)，3.52(s，4H，-OCH 2CH 2O-)，3.41-3.20(m，4H，-OCH 2CH 2O-)，2.53(t，J＝11.2，8H，-SCH 2-)，2.39(t，J＝11.6，8H，-CH 2-)，2.20-1.92(m，8H，-COCH 2-)。IR(KBr)2916，1755，1684，1602，1544，1450，1351，1252，1185，1108，1099，951，845，746，702，668，556。
(2) in the time of the n=44 of PEG, Mn=2000;
Its synthetic route is as shown in Figure 2: under alkaline condition, get compd A 4 and two ends all amino PEG2000 carry out amidate action, obtain compd A 4-PEG2000-A4;
Described step is specially: take A4 (0.841g, 1mmol) be dissolved in 15ml DMF in the single port flask of 25ml, ice-water bath adds NMM (N-methylmorpholine) (224 μ L under stirring, 2.0mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (0.76g, 2.0mmol) after activation 30min, add the PEG2000 (0.8g of two ends amino, 0.4mmol) after stirring 1h, be warming up to room temperature reaction 14h, stopped reaction, add appropriate dichloromethane extraction, wash twice, twice of saturated NaCl solution washing, organic phase underpressure distillation obtains faint yellow solid 1.43g, the white solid 1.0g of column chromatography, productive rate 68.23%. 1HNMR(400MHz，CDCl 3)δ＝8.08(s，4H，ArH)，7.67(s，2H，ArH)，7.41-7.17(m，60H，ArH)，3.94-3.34(m，165H，-OCH 2CH 2O-)，2.37-2.18(m，16H，-SCH 2-，-CH 2-)，2.10(brs，5H)，1.83-1.67(m，8H，-COCH 2-)。GPC：Mn＝3446，Mw＝3514，D＝1.02。IR(KBr)2916，1755，1650，1602，1544，1451，1352，1252，1249，1192，1099，951，845，668，557。
(3) in the time of the n=112 of PEG, Mn=5000;
Its synthetic route is as shown in Figure 2: under alkaline condition, get compd A 4 and two ends all amino PEG5000 carry out amidate action, obtain compd A 4-PEG5000-A4;
Described step is specially: take A4 (0.841g, 1mmol) be dissolved in 15ml DMF in the single port flask of 25ml, ice-water bath adds NMM (N-methylmorpholine) (224 μ L under stirring, 2.0mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (0.76g, 2.0mmol) after activation 30min, add the PEG5000 (2.5g of two ends amino, 0.5mmol) after stirring 1h, be warming up to room temperature reaction 18h, stopped reaction, add appropriate dichloromethane extraction, wash twice, twice of saturated NaCl solution washing, organic phase underpressure distillation obtains faint yellow solid 3.2g, the white solid 1.97g of column chromatography, productive rate 59.07%. 1HNMR(400MHz，CDCl 3)δ＝8.09(s，4H，ArH)，7.65(s，2H，ArH)，7.42-7.16(m，60H，ArH)，3.95-3.34(m，440H，-OCH 2CH 2O-)，2.37-2.17(m，16H，-SCH 2-，-CH 2-)，2.12(brs，4H)，1.83-1.65(m，8H，-COCH 2-)。GPC：Mn＝6937，Mw＝8373，D＝1.06。IR(KBr)2915，1756，1650，1602，1544，1451，1351，1192，1252，1185，1108，951，845，702，621，556。
(4) in the time of the n=225 of PEG, Mn=10000;
In the time of the n=225 of PEG, Mn=10000, its synthetic route as shown in Figure 2: under alkaline condition, get compd A 4 and two ends all amino PEG2000 carry out amidate action, obtain compd A 4-PEG10000-A4;
Described step is specially: take A4 (0.841g, 1mmol) be dissolved in 15ml DMF in the single port flask of 25ml, ice-water bath adds NMM (N-methylmorpholine) (224 μ L under stirring, 2.0mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (0.76g, 2.0mmol) after activation 30min, add the PEG10000 (3.0g of two ends amino, 0.3mmol) after stirring 1h, be warming up to room temperature reaction 24h, stopped reaction, add appropriate dichloromethane extraction, wash twice, twice of saturated NaCl solution washing, organic phase underpressure distillation obtains faint yellow solid 3.28g, the white solid 1.68g of column chromatography, productive rate 43.13%. 1H?NMR(400MHz，CDCl 3)δ＝8.07(s，4H，ArH)，7.68(s，2H，ArH)，7.43-7.14(m，60H，ArH)，3.94-3.33(m，880H，-OCH 2CH 2O-)，2.37-2.16(m，16H，-SCH 2-，-CH 2-)，2.08(brs，5H)，1.83-1.65(m，8H，-COCH 2-)。GPC：Mn＝12143，Mw＝13235，D＝1.09。IR(KBr)2915，1755，1654，1602，1552，1351，1190，1085，945，845，702，668，556。
Three, hydrophobic fragment PLA-Z1's is synthetic
(1) in the time of the m=0 of PLA;
Its synthetic route is as shown in Figure 3: under alkaline condition, get compound Z1 and PLA162 and carry out amidate action, obtain amide compound PLA162-Z1;
Described step is specially: take PLA162 (0.162g, 1mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (0.57g, 1.5mmol), Z1 (0.783, 1mmol) in the dry single port flask of 25ml, under ice-water bath, under nitrogen protection, add NMM (N-methylmorpholine) (112 μ L, 1.0mmol), dry DMF 15ml is warming up to 35 DEG C of reaction 14h after stirring 45min, stopped reaction, add suitable quantity of water, extract with methylene dichloride DCM, organic phase is water respectively, saturated common salt washing, anhydrous sodium sulfate drying, desolventizing is revolved in decompression, column chromatography obtains faint yellow solid 1.020g, the product 0.67g of column chromatography, productive rate 73%. 1H-NMR(CDCl 3，400MHz)δ8.17(s，1H，NH)7.91(s，2H，ArH)，7.70(s，1H，ArH)，7.19-7.70(m，30H，ArH)，6.62-6.64(m，2H，NH)，5.29～5.31(m，1H，CH 3-CH-O-)，4.42-4.44(m，1H，CH 3-CH-OH)，3.77(brs，1H，-OH)，3.26-3.27(m，4H，-NH-CH 2-)，2.50-2.53(t，4H，J＝8.0Hz，-SCH 2-)，1.49-1.57(m，6H，CH 3-)。IR(KBr)3396，2986，2944，1760，1660，1604，1533，1450，1380，1271，1185，1126，1090，1048，952，866，747，702，626，508。
(2) in the time of the m=38 of PLA, Mn=3000;
Its synthetic route is as shown in Figure 3: under amidation reaction condition, get compound Z1 and PLA3000 and carry out amidate action, obtain compound PLA3000-Z1;
Described step is specially: take PLA3000 (3.0g, 1mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (1.14g, 3.0mmol), Z1 (1.566, 2mmol) in the dry single port flask of 25ml, under ice-water bath, under nitrogen protection, add NMM (N-methylmorpholine) (223 μ L, 2.0mmol), dry DMF 15ml is warming up to 30 DEG C of reaction 8h after stirring 45min, stopped reaction, add appropriate dichloromethane extraction, wash twice, twice of saturated NaCl solution washing, organic phase underpressure distillation obtains faint yellow solid 4.4g, column chromatography obtains white solid product 2.86g, productive rate 76%. 1H-NMR(CDCl 3，400MHz)δ8.12(m，2H，ArH)，7.80(s，1H，ArH)，7.19-7.43(m，30H，ArH)，6.34(brs，2H，NH)，5.16～5.30(m，18H，PLA-CH-)，4.36(m，1H，PLA-CH-)，3.27(m，4H，-NCH 2-)，2.51(m，4H，-SCH 2-)，1.48-1.59(m，59H，PLA-CH 3-)。GPC：Mn＝3978，Mw＝4853，D＝1.22。IR(KBr)3385，2994，2941，1757，1657，1599，1536，1449，1379，1359，1266，1189，1129，1092，1047，951，866，803，746，702，622，507。
(3) in the time of the m=66 of PLA, Mn=5000;
Its synthetic route is as shown in Figure 3: under amidation reaction condition, get compound Z1 and PLA5000 and carry out amidate action, obtain compound PLA5000-Z1;
Described step is specially: take PLA5000 (5.0g, 1mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (0.76g, 2.0mmol), Z1 (1.174, 1.5mmol) in the dry single port flask of 25ml, under ice-water bath, under nitrogen protection, add NMM (N-methylmorpholine) (167 μ L, 1.5mmol), dry DMF 15ml is warming up to 35 DEG C of reaction 14h after stirring 45min, stopped reaction, add appropriate dichloromethane extraction, wash twice, twice of saturated NaCl solution washing, organic phase underpressure distillation obtains faint yellow solid 5.8g, the product 4.1g of column chromatography, productive rate 71%. 1H-NMR(CDCl 3，400MHz)δ8.12(m，2H，ArH)，7.80(s，1H，ArH)，7.19-7.43(m，30H，ArH)，6.34(brs，2H，NH)，5.16～5.30(m，73H，PLA-CH-)，4.36(m，1H，PLA-CH-)，3.27(m，4H，-NCH 2-)，2.51(m，4H，-SCH 2-)，1.48-1.59(m，219H，PLA-CH 3-)。GPC：Mn＝6937，Mw＝8373，D＝1.20。IR(KBr)3392，2994，2943，1756，1662，1600，1533，1451，1379，1268，1189，1129，1092，1048，952，866，743，702，623，508。
(4) in the time of the m=135 of PLA, Mn=10000;
Its synthetic route is as shown in Figure 3: under amidation reaction condition, get compound Z1 and PLA10000 and carry out amidate action, obtain compound PLA10000-Z1;
Described step is specially: take PLA10000 (1.0g, 0.1mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (0.057g, 0.15mmol), Z1 (0.0783, 0.1mmol) in the dry single port flask of 25ml, under ice-water bath, under nitrogen protection, add NMM (N-methylmorpholine) (17 μ L, 0.1mmol), dry DMF 15ml is warming up to 35 DEG C of reaction 18h after stirring 45min, stopped reaction, add appropriate dichloromethane extraction, wash twice, twice of saturated NaCl solution washing, organic phase underpressure distillation obtains faint yellow solid 1.2g, the white solid product 0.92g of column chromatography, productive rate 81%. 1H-NMR(CDCl 3，400MHz)δ8.17(m，2H，ArH)，7.83(s，1H，ArH)，7.20-7.45(m，30H，ArH)，6.39(brs，2H，NH)，4.98～5.38(m，135H，PLA-CH-)，4.38(m，1H，PLA-CH-)，3.28-3.30(m，4H，-NCH 2-)，2.52-2.55(m，4H，-SCH 2-)，1.43-1.77(m，409H，PLA-CH 3-)。GPC：Mn＝9113，Mw＝12533，D＝1.37。IR(KBr)3391，2990，2948，1758，1662，1600，1543，1450，1380，1268，1185，1129，1092，1053，952，865，745，700，621，508。
Four, hydrophobic fragment Z1-PLA-Z1's is synthetic
(1) in the time of the m=0 of PLA;
Its synthetic route is as shown in Figure 4: modification PLA162 obtains holding carboxyl PLA, and under amidation reaction condition, the PLA162 that gets compound Z1 and modification carries out amidate action, obtains compound Z1-PLA162-Z1;
Described step is specially: take PLA162 (1.62g, 10mmol) and be dissolved in 20ml CH 2cl 2in, under ice-water bath, adding and once add DMAP (2.44g, 20mmol), stirring at room temperature 18h after Succinic anhydried (3.0g, 30mmol) stirring 1h, after reaction finishes, adds suitable quantity of water, and with DCM extraction, organic phase is used respectively saturated NaHCO 3the aqueous solution, saturated common salt washing, anhydrous sodium sulfate drying, pressure reducing and steaming solvent obtains the PLA that is modified as end carboxyl.
Take the end carboxyl PLA162 (0.262g after above modification, 1mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (1.52g, 4mmol), Z1 (1.96, 2.5mmol) in the dry single port flask of 25ml, under ice-water bath, under nitrogen protection, add NMM (N-methylmorpholine) (448 μ L, 4.0mmol), dry DMF 15ml is warming up to 35 DEG C of reaction 10h after stirring 30min, stopped reaction, add appropriate dichloromethane extraction, wash twice, twice of saturated NaCl solution washing, organic phase underpressure distillation obtains faint yellow solid 1.8g, the product 1.58g of column chromatography, productive rate 88.31%. 1H?NMR(CDCl 3，400MHz)δ＝8.22(m，4H，ArH)，7.54(s，2H，ArH)，7.35-7.14(m，60H，ArH)5.31(q，J＝11.6，1H，CH 3-CH-O-)，5.20(q，J＝11.9，1H，CH 3-CH-O-)，3.45-3.38(m，8H，-NH-CH 2-)，2.76-2.72(m，2H，-CH 2CH 2-)，2.65-2.62(m，2H，-CH 2CH 2-)，2.37-2.33(m，8H，-SCH 2-)，1.49-1.46(m，6H，CH 3-).IR(KBr)3396，2986，2944，1755，1655，1601，1533，1450，1380，1364，1185，1268，1187，1131，1090，，952，865，739，702，636，508。
(2) in the time of the m=38 of PLA, Mn=3000;
Its synthetic route is as shown in Figure 4: modification PLA3000 obtains holding carboxyl PLA, and under amidation reaction condition, the PLA3000 that gets compound Z1 and modification carries out amidate action, obtains compound Z1-PLA3000-Z1;
Described step is specially: take PLA3000 (3.0g, 1mmol) and be dissolved in 20ml CH 2cl 2in, under ice-water bath, adding and once add DMAP (0.244g, 2mmol), stirring at room temperature 15h after Succinic anhydried (0.3g, 3mmol) stirring 1h, after reaction finishes, adds suitable quantity of water, and with DCM extraction, organic phase is used respectively saturated NaHCO 3the aqueous solution, saturated common salt washing, anhydrous sodium sulfate drying, pressure reducing and steaming solvent obtains the PLA that is modified as end carboxyl.
Take the end carboxyl PLA3000 (0.31g after above modification, 0.1mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (0.152g, 0.4mmol), Z1 (0.235, 0.3mmol) in the dry single port flask of 25ml, under ice-water bath, under nitrogen protection, add NMM (N-methylmorpholine) (44.8 μ L, 0.4mmol), dry DMF 15ml is warming up to 35 DEG C of reaction 12h after stirring 30min, stopped reaction, add appropriate dichloromethane extraction, wash twice, twice of saturated NaCl solution washing, organic phase underpressure distillation obtains faint yellow solid 0.42g, the product 0.35g of column chromatography, productive rate 75.21%. 1H?NMR(400MHz，CDCl 3)δ＝8.23-7.94(m，4H，ArH)，7.76(m，2H，ArH)，7.42-7.18(m，60H，ArH)，6.48(brs，4H，NH)，5.25-5.01(m，35H，PLA-CH-)，3.28-3.25(m，8H，-NCH 2-)，2.80(m，4H，-CH 2CH 2-)，2.52-2.49(s，8H，-SCH 2-)，1.71(m，3H，CH 3CH 2-)，1.68-1.45(s，102H，PLA-CH 3-)。GPC：Mn＝4002，Mw＝4205，D＝1.05。IR(KBr)3303，3058，2992，2927，1755，1657，1596，1557，1538，1489，1445，1379，1362，1268，1187，1131，1092，1046，892，742，701，621，505。
(3) in the time of the m=66 of PLA, Mn=5000;
Its synthetic route is as shown in Figure 4: modification PLA5000 obtains holding carboxyl PLA, and under amidation reaction condition, the PLA5000 that gets compound Z1 and modification carries out amidate action, obtains compound Z1-PLA5000-Z1.
Described step is specially: take PLA5000 (5.0g, 1mmol) and be dissolved in 20ml CH 2cl 2in, under ice-water bath, adding and once add DMAP (0.244g, 20mmol), stirring at room temperature 22h after Succinic anhydried (0.3g, 30mmol) stirring 1h, after reaction finishes, adds suitable quantity of water, and with DCM extraction, organic phase is used respectively saturated NaHCO 3the aqueous solution, saturated common salt washing, anhydrous sodium sulfate drying, pressure reducing and steaming solvent obtains the PLA that is modified as end carboxyl.
Take the end carboxyl PLA5000 (0.51g after above modification, 0.1mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (0.152g, 0.4mmol), Z1 (0.195, 0.25mmol) in the dry single port flask of 25ml, under ice-water bath, under nitrogen protection, add NMM (N-methylmorpholine) (44.8 μ L, 0.4mmol), dry DMF 15ml is warming up to 35 DEG C of reaction 18h after stirring 30min, stopped reaction, add appropriate dichloromethane extraction, wash twice, twice of saturated NaCl solution washing, organic phase underpressure distillation obtains faint yellow solid 0.65g, the product 0.53g of column chromatography, productive rate 80.11%. 1H?NMR(400MHz，CDCl 3)δ＝8.20-7.94(m，4H，ArH)，7.75(m，2H，ArH)，7.42-7.16(m，60H，ArH)，6.48(brs，4H，NH)，5.25-5.01(m，64H，PLA-CH-)，3.28-3.23(m，8H，-NCH 2-)，2.78(m，4H，-CH 2CH 2-)，2.52-2.49(m，8H，-SCH 2-)，1.66-1.46(m，192H，PLA-CH 3-)。GPC：Mn＝6738，Mw＝8018，D＝1.19。IR(KBr)3417，2993，2943，1755，1650，1597，1533，1449，1381，1268，1187，1131，1090，865，739，702，639，506。
(4) in the time of the m=135 of PLA, Mn=10000;
Its synthetic route is as shown in Figure 4: modification PLA10000 obtains holding carboxyl PLA, and under amidation reaction condition, the PLA10000 that gets compound Z1 and modification carries out amidate action, obtains compound Z1-PLA10000-Z1.
Described step is specially: take PLA10000 (10.0g, 1mmol) and be dissolved in 20ml CH 2cl 2in, under ice-water bath, adding and once add DMAP (0.244g, 2mmol), stirring at room temperature 22h after Succinic anhydried (0.3g, 3mmol) stirring 1h, after reaction finishes, adds suitable quantity of water, and with DCM extraction, organic phase is used respectively saturated NaHCO 3the aqueous solution, saturated common salt washing, anhydrous sodium sulfate drying, pressure reducing and steaming solvent obtains the PLA that is modified as end carboxyl.
Take the end carboxyl PLA10000 (1.01g after above modification, 0.1mmol), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) (0.152g, 0.4mmol), Z1 (0.235g, 0.3mmol) in the dry single port flask of 25ml, under ice-water bath, under nitrogen protection, add NMM (N-methylmorpholine) (44.8 μ L, 0.4mmol), dry DMF 15ml is warming up to 35 DEG C of reaction 36h after stirring 30min, stopped reaction, add appropriate dichloromethane extraction, wash twice, twice of saturated NaCl solution washing, organic phase underpressure distillation obtains faint yellow solid 1.168g, the product 0.73g of column chromatography, productive rate 63.00%. 1H?NMR(400MHz，CDCl 3)δ＝8.17-7.93(m，4H，ArH)，7.76(m，2H，ArH)，7.42-7.17(m，60H，ArH)，6.43(brs，4H，NH)，5.25-5.01(m，133H，PLA-CH-)，3.28-3.24(m，8H，-NCH 2-)，2.78(m，4H，-CH 2CH 2-)，2.52-2.48(m，8H，-SCH 2-)，1.66-1.46(m，399H，PLA-CH 3-)。GPC：Mn＝10946，Mw＝13463，D＝1.23。IR(KBr)3316，3057，2931，1755，1660，1696，1538，1445，1382，1268，1187，1093，1034，855，742，701，621，506。
Five, triblock copolymer PEG-PLA-PEG's is synthetic
(1) PEG163-PLA162-PEG163's is synthetic;
As the n=2 of PEG; When the m=0 of PLA, its synthetic route as shown in Figure 5: under oxidation reaction condition, get compound Z1-PLA162-Z1 and PEG163-A4 and carry out oxidizing reaction, obtain segmented copolymer PEG163-PLA162-PEG163;
Described step is specially: take respectively Z1-PLA162-Z1 (27mg, 0.015mmol) and PEG163-A4 (19mg, 0.02mmol) dissolve in 20ml methylene dichloride in 500ml single port bottle, stirring and dissolving mixes rear underpressure distillation dry (revolving except DCM), and residue adds 60ml methylene dichloride I 2solution (wherein I 2for 6.0mM) dissolve, after stirring at normal temperature 1h, reaction solution is cooled to 0 DEG C, add Na 2s 2o 3(3.0mM) until I 2color disappear.Saturated NaCl for organic layer (aq) washing, anhydrous Na 2sO 4dry, after underpressure distillation, obtaining crude product is faint yellow solid 18.2mg, and thin-layer chromatography separates to obtain product 9.2mg, productive rate 51%.IR(KBr)3440，2885，1763，1645，1560，1450，1380，1273，1180，1104，953，799，619；
(2) PEG2000-PLA3000-PEG2000's is synthetic;
As the n=44 of PEG, when the m=38 of PLA, its synthetic route as shown in Figure 5: under oxidation reaction condition, get compound Z1-PLA3000-Z1 and PEG2000-A4 and carry out oxidizing reaction, obtain segmented copolymer PEG2000-PLA3000-PEG2000.
Described step is specially: take respectively Z1-PLA3000-Z1 (46.30mg, 0.015mmol) and PEG2000-A4 (56.46mg, 0.02mmol) dissolve in 20ml methylene dichloride in 250ml single port bottle, it is dry that stirring and dissolving mixes rear underpressure distillation, and residue adds 60ml methylene dichloride I 2solution (wherein I 2for 6.0mM) dissolve, after stirring at normal temperature 1h, reaction solution is cooled to 0 DEG C, add Na 2s 2o 3(3.0mM) until I 2color disappear.Saturated NaCl for organic layer (aq) washing, anhydrous Na 2sO 4dry, underpressure distillation obtains faint yellow solid 89mg, and thin layer plate chromatographic separation obtains faint yellow solid 35mg, productive rate 42%. 1H?NMR(400MHz，CDCl 3)δ8.97(m，4H，NH)，8.27-7.40(m，12H，ArH)，5.21-5.12(m，34H)，3.81-3.40(m，344H，-OCH 2CH 2O-)，3.35(s，6H，CH 3O-)，2.93-2.77(m，14H，-NCH 2-，-SCH 2-)，2.55-1.98(m，24H，-SCH 2-，-CH 2-，-COCH 2-)，1.70-1.39(m，102H，PLA-CH 3-)。GPC：Mn＝5703，Mw＝7059，D＝1.24。IR(KBr)3458，2873，1757，1655，1603，1544，1450，1380，1352，1255，1189，1098，950，863，759，704。
(3) PEG5000-PLA5000-PEG5000's is synthetic;
In the time of the n=112 of PEG, Mn=5000; When the m=66 of PLA, Mn=5000, its synthetic route as shown in Figure 5: under oxidation reaction condition, get compound Z1-PLA5000-Z1 and PEG5000-A4 and carry out oxidizing reaction, obtain segmented copolymer PEG5000-PLA5000-PEG5000.
Described step is specially: take respectively Z1-PLA5000-Z1 (99.45mg, 0.015mmol) and PEG5000-A4 (116.46mg, 0.02mmol) dissolve in 20ml methylene dichloride in 250ml single port bottle, it is dry that stirring and dissolving mixes rear underpressure distillation, and residue adds 60ml methylene dichloride I 2solution (wherein I 2for 6.0mM) dissolve, after stirring at normal temperature 1h, reaction solution is cooled to 0 DEG C, add Na 2s 2o 3(3.0mM) until I 2color disappear.Saturated NaCl for organic layer (aq) washing, anhydrous Na 2sO 4dry, underpressure distillation obtains faint yellow solid 206mg, and thin layer plate chromatographic separation obtains faint yellow solid 55mg, productive rate 36%. 1H?NMR(400MHz，CDCl 3)δ8.96(m，4H，NH)，8.26-7.38(m，12H，ArH)，5.21-5.12(m，68H，PLA-CH-)，3.82-3.42(m，903H，-OCH 2CH 2O-)，3.33(s，6H，CH 3O-)，2.94-2.78(m，14H，-NCH 2-，-SCH 2-)，2.56-1.98(m，24H，-SCH 2-，-CH 2-，-COCH 2-)，1.70-1.39(m，204H，PLA-CH 3-)。GPC：Mn＝23758，Mw＝28301，D＝1.20。IR(KBr)3458，2873，1757，1655，1603，1544，1450，1380，1352，1255，1189，1098，950，863，759，704。
(4) PEG10000-PLA10000-PEG10000's is synthetic;
In the time of the n=225 of PEG, Mn=10000; In the time of the m=135 of PLA, Mn=10000, its synthetic route as shown in Figure 5: under oxidation reaction condition, get compound Z1-PLA10000-Z1 and PEG10000-A4 and carry out oxidizing reaction, obtain segmented copolymer PEG10000-PLA10000-PEG10000.
Described step is specially: take respectively Z1-PLA10000-Z1 (174.45mg, 0.015mmol) and PEG10000-A4 (216.46mg, 0.02mmol) dissolve in 20ml methylene dichloride in 250ml single port bottle, it is dry that stirring and dissolving mixes rear underpressure distillation, and residue adds 60ml methylene dichloride I 2solution (wherein I 2for 6.0mM) dissolve, after stirring at normal temperature 1h, reaction solution is cooled to 0 DEG C, add N a2S 2o 3(3.0mM) until I 2color disappear.Saturated NaCl for organic layer (aq) washing, anhydrous Na 2sO 4dry, underpressure distillation obtains faint yellow solid 206mg, and thin layer plate chromatographic separation obtains faint yellow solid 55mg, productive rate 36%. 1H?NMR(400MHz，CDCl 3)δ8.98(m，4H，NH)，8.27-7.38(m，12H，ArH)，5.23-5.12(m，133H，PLA-CH-)，3.82-3.41(m，1920H，-OCH 2CH 2O-)，3.33(s，6H，CH 3O-)，2.94-2.76(m，14H，-NCH 2-，-SCH 2-)，2.56-1.96(m，24H，-SCH 2-，-CH 2-，-COCH 2-)，1.72-1.39(m，399H，PLA-CH 3-)。GPC：Mn＝34553，Mw＝43191，D＝1.25。IR(KBr)3458，2873，1757，1655，1603，1544，1450，1380，1352，1255，1189，1098，950，863，759，704。
Six, triblock copolymer PLA-PEG-PLA's is synthetic
(1) PLA162-PEG148-PLA162's is synthetic;
As the n=2 of PEG, when the m=0 of PLA, its synthetic route as shown in Figure 6: under oxidation reaction condition, get compound PLA162-Z1 and A4-PEG148-A4 and carry out oxidizing reaction, obtain segmented copolymer PLA162-PEG148-PLA162;
Described step is specially: take respectively PLA162-Z1 (28mg, 0.03mmol) and A4-PEG148-A4 (18mg, 0.01mmol) dissolve in 20ml methylene dichloride in 250ml single port bottle, it is dry that stirring and dissolving mixes rear underpressure distillation, and residue adds 60ml methylene dichloride I 2solution (wherein I 2for 6.0mM) dissolve, after stirring at normal temperature 1h, reaction solution is cooled to 0 DEG C, add Na 2s 2o 3(3.0mM) until I 2color disappear.Saturated NaCl for organic layer (aq) washing, anhydrous Na 2sO 4dry, underpressure distillation obtains faint yellow solid 18mg, and thin layer plate chromatographic separation obtains faint yellow solid 9.4mg, productive rate 55%.IR(KBr)3449，2882，1754，1639，1558，1447，1383，1265，1187，1109，957，841，799，619.
(2) PLA3000-PEG2000-PLA3000's is synthetic;
In the time of the n=44 of PEG, Mn=2000; In the time of the m=38 of PLA, Mn=3000; Its synthetic route is as shown in Figure 6: under oxidation reaction condition, get compound PLA3000-Z1 and A4-PEG2000-A4 and carry out oxidizing reaction, obtain segmented copolymer PLA3000-PEG2000-PLA3000.
Described step is specially: take respectively PLA3000-Z1 (113mg, 0.03mmol) and A4-PEG2000-A4 (36.46mg, 0.01mmol) dissolve in 20ml methylene dichloride in 250ml single port bottle, it is dry that stirring and dissolving mixes rear underpressure distillation, and residue adds 60ml methylene dichloride I 2solution (wherein I 2for 6.0mM) dissolve, after stirring at normal temperature 1h, reaction solution is cooled to 0 DEG C, add Na 2s 2o 3(3.0mM) until I 2color disappear.Saturated NaCl for organic layer (aq) washing, anhydrous Na 2sO 4dry, underpressure distillation obtains faint yellow solid 100mg, and thin layer plate chromatographic separation obtains faint yellow solid 35g, productive rate 37%. 1H?NMR(400MHz，CDCl 3)δ8.30-7.35(m，12H，ArH)，6.78(brs，4H，NH)，5.25-5.16(m，77H，PLA-CH-)，3.80-3.34(m，168H，-OCH 2CH 2O-)，3.36(s，6H，CH 3O-)，2.91-2.74(m，14H，-NCH 2-，-SCH 2-)，2.53-2.01(m，24H，-SCH 2-，-CH 2-，-COCH 2-)，1.71-1.35(m，231H，PLA-CH 3-)。GPC：Mn＝9956，Mw＝12046，D＝1.21。IR(KBr)3455，2878，1755，1650，1602，1544，1450，1380，1350，1256，1180，1098，956，863，759，704，667，648。
(3) PLA5000-PEG5000-PLA5000's is synthetic;
In the time of the n=113 of PEG, Mn=5000; In the time of the m=66 of PLA, Mn=5000; Its synthetic route is as shown in Figure 6: under oxidation reaction condition, get compound PLA5000-Z1 and A4-PEG5000-A4 and carry out oxidizing reaction, obtain segmented copolymer PLA5000-PEG5000-PLA5000.
Described step is specially: take respectively PLA5000-Z1 (173mg, 0.03mmol) and A4-PEG5000-A4 (66.46mg, 0.01mmol) dissolve in 20ml methylene dichloride in 250ml single port bottle, it is dry that stirring and dissolving mixes rear underpressure distillation, and residue adds 60ml methylene dichloride I 2solution (wherein I 2for 6.0mM) dissolve, after stirring at normal temperature 1h, reaction solution is cooled to 0 DEG C, add Na 2s 2o 3(3.0mM) until I 2color disappear.Saturated NaCl for organic layer (aq) washing, anhydrous Na 2sO 4dry, underpressure distillation obtains faint yellow solid 185mg, and thin layer plate chromatographic separation obtains faint yellow solid 74mg, productive rate 45%. 1H?NMR(400MHz，CDCl 3)δ8.30-7.34(m，12H，ArH)，6.78(brs，4H，NH)，5.25-5.14(m，130H，PLA-CH-)，3.80-3.36(m，452H，-OCH 2CH 2O-)，3.33(s，6H，CH 3O-)，2.91-2.72(m，14H，-NCH 2-，-SCH 2-)，2.53-2.02(m，24H，-SCH 2-，-CH 2-，-COCH 2-)，1.71-1.35(m，390H，PLA-CH 3-)。GPC：Mn＝17336，Mw＝21496，D＝1.24。IR(KBr)3440，2872，1756，1715，1659，1601，1539，1453，1382，1353，1268，1188，1097，952，863，753，701，667。
(4) PLA10000-PEG10000-PLA10000's is synthetic
In the time of the n=225 of PEG, Mn=10000; In the time of the m=135 of PLA, Mn=10000; Its synthetic route is as shown in Figure 6: under oxidation reaction condition, get compound PLA10000-Z1 and A4-PEG10000-A4 and carry out oxidizing reaction, obtain segmented copolymer PLA10000-PEG10000-PLA10000.
Described step is specially: take respectively PLA10000-Z1 (323mg, 0.03mmol) and A4-PEG10000-A4 (116.46mg, 0.01mmol) dissolve in 20ml methylene dichloride in 250ml single port bottle, it is dry that stirring and dissolving mixes rear underpressure distillation, and residue adds 60ml methylene dichloride I 2solution (wherein I 2for 6.0mM) dissolve, after stirring at normal temperature 1h, reaction solution is cooled to 0 DEG C, add Na 2s 2o 3(3.0mM) until I 2color disappear.Saturated NaCl for organic layer (aq) washing, anhydrous Na 2sO 4dry, underpressure distillation obtains faint yellow solid 302mg, and thin layer plate chromatographic separation obtains faint yellow solid 150mg, productive rate 48%. 1H?NMR(400MHz，CDCl 3)δ8.30-7.33(m，12H，ArH)，6.76(brs，4H，NH)，5.25-5.14(m，265H，PLA-CH-)，3.79-3.36(m，918H，-OCH 2CH 2O-)，3.33(s，6H，CH 3O-)，2.90-2.72(m，14H，-NCH 2-，-SCH 2-)，2.53-2.01(m，24H，-SCH 2-，-CH 2-，-COCH 2-)，1.73-1.35(m，795H，PLA-CH 3-)。GPC：Mn＝36311，Mw＝45751，D＝1.26。IR(KBr)3439，2870，1755，1710，1650，1601，1540，1450，1380，1353，1265，1187，1089，951，863，753，701，667。
the mensuration of embodiment 2, block copolymer amount
Adopt GPC method to measure the molecular weight of the polymkeric substance making in embodiment 1; Instrument: Agilent1260 type gel permeation chromatograph, the gel chromatographic columns of GPC post: 7.5 × 300mm, 10 μ m, solvent: tetrahydrofuran (THF), flow velocity: 1.0mL/min, column temperature: 35 DEG C, standard specimen: polystyrene.The GPC graph of molecular weight distribution of each polymkeric substance as shown in Figure 7.
the preparation of embodiment 3, micella and sign (taking PEG5000-PLA5000-PEG5000 as embodiment)
1, the preparation of blank micella
Accurately take the segmented copolymer of 10mg synthesized, be dissolved in 2mL DMF (also can be DMSO or THF), segmented copolymer DMF solution slowly splash into 10ml stir PBS buffered soln (also can be pure water or physiological saline) in (10min/ml), stirring 30min makes it form micro emulsion ball, proceed in dialysis tubing, with PBS damping fluid dialysis 48 hours, 4h changed water once, give DMF, obtain self-assembled micelle.
2, the preparation of carrier micelle
Accurately taking the segmented copolymer of 10mg synthesized and 1mg DOX.HCI and dissolve in 2mL DMF (also can be DMSO or THF), (can be Azythromycin, taxol, Elemenum or camptothecine containing medicine after adding 20 μ l triethylamines to stir 30min; What in the present embodiment, adopt is Azythromycin) the segmented copolymer DMF solution of synthesized slowly splash into (10min/ml) in the middle of the PBS buffered soln (also can be pure water or physiological saline) that 10ml stirs, stirring 30min makes it form micro emulsion ball, proceed in dialysis tubing, with PBS damping fluid dialysis 48 hours, 4h changes water once, give DMF, obtain self-assembly carrier micelle.
3, the mensuration of minimum aggregate concentration CMC
With 1,6-phenylbenzene-1,3,5-hexatriene (DPH) is ultraviolet molecular probe (maximum absorption wavelength is 313nm) mensuration CMC value, get the EP pipe of 10 10ml, in every arm, add the DPH acetone soln of 20 μ l 1mM, after acetone volatilization is dry, in every arm, add respectively different concns (concentration range: 0.5mg/mL, 0.25mg/mL, 0.1mg/mL, 0.05mg/mL, 0.025mg/mL, 5 × 10 -3mg/mL, 1 × 10 -3mg/mL, 0.25 × 10 -3mg/mL, 0.05 × 10 -3mg/mL, 0 × 10 -3mg/mL) micellar solution 4ml, stirs 4h and measures respectively absorbancy under room temperature, taking micellar concentration as X-coordinate, absorbancy is that ordinate zou does graphic representation, and the hop point increasing progressively by absorbancy is determined minimum aggregate concentration CMC.To the graph of a relation of absorbance A as shown in Figure 8, the CMC value of micella PEG5000-PLA5000-PEG5000 is 0.012mg/mL to micellar concentration.
4, the mensuration of micella size distribution
Get 1mL micella, insert laser particle analyzer and measure particle diameter, measure temperature: 25 DEG C of starting time 3min, LASER Light Source: He-Ne laser, wavelength is 633nm.As shown in Figure 9, the size distribution figure of carrier micelle as shown in figure 10 for the size distribution figure of blank micella.
5, the stability test of blank micella
Get blank micella that 2mL prepares in the centrifuge tube of 5mL, the variation of compartment timing micella particle diameter, until particle diameter generation considerable change illustrates that micella changes.PEG5000-PLA5000-PEG5000 micella change of size is in the test result in a week as shown in figure 11: from scheming, can find out this micella stable existence for a long time.
6, the variation of particle diameter after reductive agent DTT processing micella
DTT processes blank micella, the micellar solution 10ml of preparation 0.5mg/ml, and adding the DTT (dithiothreitol (DTT)) of 15.4mg to make DTT strength of solution is 10mM, 37 DEG C of stirrings of constant temperature, at 1h, 3h, 6h, change of size when 8h.Change of size figure as shown in figure 12; As shown in Figure 12: under the processing of reductive agent DTT; disulfide linkage in micella is destroyed; micella particle diameter is changed, can find out that particle diameter slightly diminishes, make part particle diameter become large because post-rift fragment also exists particles that Hyarogen-bonding can make to diminish again to pile up.
7, reductive agent DTT processes the drug release experiment of carrier micelle
Get respectively the carrier micelle of above preparation, being mixed with containing DTT concentration is 0.1mM, 1.0mM, the each 3mL of polypeptide drug-loaded micelle solution of 10mM, insert in the water-bath of 37 DEG C, on time segment spectrophotofluorometer with excitation wavelength 485nm, the fluorescent absorption value of measuring emission wavelength 590nm changes, draw fluorescence absorbancy change curve as shown in figure 13: along with the lengthening in treatment time, the increase of DTT concentration, the fluorescent absorption value of micellar solution increases, hence one can see that carrier micelle is under the treatment condition of reductive agent DTT, micella disulfide bonds, the DOX of micella parcel discharges.
Get respectively the each 2mL of carrier micelle of above preparation, pack in the dialysis tubing that molecular weight is 2.0KD, inserting respectively DTT concentration is 1.0mM, in the PBS solution 100mL of 0.0mM, be controlled at 37 DEG C of dialysis, interval section take out 5mL PBS solution with spectrophotofluorometer at excitation wavelength 485nm place, mensuration emission wavelength is that the absorption value at 590nm place is calculated the drug level and the content that discharge, adds the DTT solution of same concentrations simultaneously.Calculate the Cumulative release amount of medicine.Calculation formula is as follows:
E r = V e Σ 1 n - 1 C i + V 0 C n m drug
Er in formula: the cumulative release amount of medicine DOX, %; The displaced volume (5mL) of Ve:PBS; V0: the volume (100mL) that discharges liquid PBS; Ci: the concentration (μ g/mL) that discharges liquid Chinese medicine when the i time displacement sampling; Mdrug: (μ g) for the quality of the carrier micelle DOX that discharges; N: the number of times of displacement PBS.Shown in drug release curve Figure 14; Carrier micelle can discharge the medicine of parcel slowly, can accelerate the rate of release of medicine and the burst size of increase medicine simultaneously under the treatment condition of reductive agent DTT.
the cell experiment (taking micella PEG5000-PLA5000-PEG5000 as embodiment) of embodiment 4, micella
One, the cytotoxicity experiment of blank micella
1, mtt assay
The NIH 3T3 cell of taking the logarithm vegetative period, in 96 Zhong Banmei holes, hole, planting into cell count is 1 × 10 4individual, add 200 μ lDMEM to cultivate 24h, removing substratum adds the blank micellar solution of DMEM (every group of concentration is established 4 holes) of 200 μ l different concns to cultivate 24h, remove the blank micellar solution of DMEM, PBS damping fluid is careful to be cleaned three times, adds the MTT water culture 4h of 100 μ l DMEM and 20 μ l 5mg.mL-1 to form crystallization, then removes solution, add 200 μ l DMSO dissolving crystallized, sentence microplate reader at absorbing wavelength 490nm and measure its absorbancy.Experimental result is as shown in figure 15: more than 90%, illustrate that polymer micelle is to normal cell toxicological harmless effect in the survival rate major part of tested micellar concentration scope inner cell.
2, the two Coloration experiments of A0/EB
In each hole of 6 orifice plates, plant into 5 × 10 5individual NIH 3T3 cell, adds 1mL DMEM to cultivate 24h, removes substratum and adds 1mL to contain polymer concentration 1000 μ g.mL -1dMEM micellar solution, cultivate 24h, remove substratum PBS clean three times, then add 100 μ l PBS and two staining reagent AO/EB staining agent (5 μ g.mL -1) cultivation 10min, fluorescence microscopy Microscopic observation dead cell and viable cell situation.Observations is as shown in figure 16: as can be seen from the figure the survival rate of cell more than 90% with above 1 in MTT experimental result mutually confirm.
Two, carrier micelle cell experiment
1, fluorescence microscopy is measured cell endocytic and the interior release experiment of cell of carrier micelle
The Hela cell of taking the logarithm vegetative period is planted into cell count 2 × 10 in each hole of six hollow plates 6individual, cultivate 24h, add GSH-OEt (effect of glutathione ethyl ester) to cultivate 2h, using the hole that do not add GSH-OEt as blank, then in each hole, add the DOX micella substratum of 9ug/mL, respectively process 0.5h, the fixing 30min of 4% formaldehyde solution after 1.0h, the DAPI 10min that dyes, fluorescence microscopy Microscopic observation (excitation wavelength 486nm, emission wavelength 596nm).Result is as shown in figure 17: under the identical treatment time, add GSH-OEt and be conducive to promote that micella enters cell interior, and reach nucleus, along with entering nuclear carrier micelle, the prolongation of time increases, cancer cells micella under reductive glutathione effect is destroyed makes medicine start to discharge, the adding of GSH-OEt can further promote micella to destroy and the drug release that makes parcel out.
3, mtt assay
The Hela cell of taking the logarithm vegetative period, in 96 Zhong Banmei holes, hole, planting into cell count is 1 × 10 4individual, add 200 μ L DMEM to cultivate 24h, remove substratum and cultivate 2h with the GSH-OEt DMEM of 10mM concentration respectively, the DMEM of 0.1mMBSO (fourth methyllanthionine-sulphoxide imine) cultivates 12h, to add DMEM as blank, then add the DMEM polypeptide drug-loaded micelle solution (every group of concentration is established 4 holes) of 200 μ l different concns to cultivate 48h, remove DMEM polypeptide drug-loaded micelle solution, PBS damping fluid is careful to be cleaned three times, add the MTT water culture 4h of 100 μ l DMEM and 20 μ l5mg.mL-1 to form crystallization, then remove solution, add 200 μ l DMSO dissolving crystallized, sentence microplate reader at absorbing wavelength 490nm and measure its absorbancy.
Experimental result is as shown in figure 18: compared with control group, under the effect of BSO, make cancer cells survival rate increase, in the effect of GSH-OEt, the survival rate of cancer cells is reduced, wherein the effect of BSO is the generation of reductive glutathione in anticancer, the effect of GSH-OEt is the increase that impels reductive glutathione content in cell, this explanation carrier micelle has reduced form susceptibility, under the synergy of GSH-OEt, make carrier micelle strengthen the effect of murdering of cancer cells, to be wherein presented at DOX concentration in carrier micelle be 0.0001 μ g.mL to result -1when above, carrier micelle to the inhibiting rate of cancer cells more than 50%.
Above specific embodiments of the invention are described.It will be appreciated that, the present invention is not limited to above-mentioned specific implementations, and those skilled in the art can make various distortion or amendment within the scope of the claims, and this does not affect flesh and blood of the present invention.

Claims (10)

1. the ABA type amphipathic three block copolymer based on molecular glue, its structural formula is suc as formula shown in (I):
Wherein, n is any one integer in 2～225, and m is any one integer in 0～135.
2. the ABA type amphipathic three block copolymer based on molecular glue according to claim 1, is characterized in that, described multipolymer be prepare as follows and:
A, synthesis hydrophilic fragmentation compound PEG-A4: taking DMF as solvent, with NMM (N-methylmorpholine), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) be catalyzer, compd A 4 with compound PEG-NH 2 there is amidate action, obtain hydrophilic segment compound PEG-A4 described A4, NMM, HATU, PEG-NH 2mol ratio be 1: (1.0～2.0): (1.5～3): (1.0～2);
B, hydrophobic synthetic fragmentation compound Z1-PLA-Z1: with CH 2cl 2for solvent, taking DMAP as catalyzer, compound PLA and Succinic anhydried there is esterification, generate the PLA that is modified as end carboxyl the mol ratio of described PLA, DMAP, Succinic anhydried is 1: 2.0: 3; Continuing taking DMF as solvent, is activator with NMM (N-methylmorpholine), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester), described end carboxyl PLA and compound Z1 there is amidate action, obtain hydrophobic fragment compound Z1-PLA-Z1 the mol ratio of described PLA, NMM, HATU and Z1 is 1: 4.0: 4.0: (2.5～3.0);
C, synthesizing amphipathic triblock copolymer PEG-PLA-PEG: taking methylene dichloride as solvent, at I 2effect under, make hydrophilic segment compound PEG-A4 and hydrophobic fragment compound Z1-PLA-Z1 that oxidizing reaction occur, generate amphipathic three block copolymer PEG-PLA-PEG, i.e. described ABA type amphipathic three block copolymer; Described PEG-A4, hydrophobic fragment Z1-PLA-Z1 and I 2mol ratio be 2: 1.5: 24.
3. the ABA type amphipathic three block copolymer based on molecular glue as claimed in claim 1 is in the purposes of preparing in carrier micelle.
4. purposes according to claim 3, it is characterized in that, described ABA type amphipathic nature block polymer and poorly water soluble drugs are dissolved in polar solvent obtaining to mixed solution, described mixed solution is added dropwise in the aqueous phase solution of stirring and makes to form micro emulsion ball, pack the mixed solution that contains micro emulsion ball into dialysis tubing and appear described polar solvent, obtain described carrier micelle.
5. purposes according to claim 4, is characterized in that, described polar solvent is DMSO, DMF or THF; Described poorly water soluble drugs is Zorubicin, taxol, Elemenum, camptothecine or vitamin A acid; Described aqueous phase solution is PBS damping fluid; Described dialysis tubing molecular weight is 0.2KD.
6. the ABA type amphipathic three block copolymer based on molecular glue, its structural formula is suc as formula shown in (II):
Wherein, n is any one integer in 2～225, and m is any one integer in 1～135.
7. the ABA type amphipathic three block copolymer based on molecular glue according to claim 6, is characterized in that, described multipolymer be prepare as follows and:
A, synthesis hydrophilic fragmentation compound A4-PEG-A4: taking DMF as solvent, with NMM (N-methylmorpholine), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) be catalyzer, compd A 4 with compound N H 2-PEG-NH 2 there is amidate action, obtain hydrophilic segment compd A 4-PEG-A4 described A4, NMM, HATU, NH 2-PEG-NH 2mol ratio be 2.0: 4.0: 4.0: (0.3～0.5);
B, hydrophobic synthetic fragmentation compound PLA-Z1: taking DMF as solvent, with NMM (N-methylmorpholine), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) be activator, compound PLA with compound Z1 there is amidate action, obtain hydrophobic fragment compound PLA-Z1 the mol ratio of described PLA, NMM, HATU and Z1 is 1: (1.0～2.0): (1.5～3): (1.0～2);
C, synthesizing amphipathic triblock copolymer PLA-PEG-PLA: taking methylene dichloride as solvent, at I 2effect under, there is oxidizing reaction in hydrophilic segment compd A 4-PEG-A4 and hydrophobic fragment compound PLA-Z1, generates amphipathic three block copolymer PLA-PEG-PLA, i.e. described ABA type amphipathic three block copolymer; Described A4-PEG-A4, PLA-Z1 and I 2mol ratio be 1: 3: 24.
8. the ABA type amphipathic three block copolymer based on molecular glue as claimed in claim 6 is in the purposes of preparing in carrier micelle.
9. purposes according to claim 8, it is characterized in that, described ABA type amphipathic nature block polymer and poorly water soluble drugs are dissolved in polar solvent obtaining to mixed solution, described mixed solution is added dropwise in the aqueous phase solution of stirring and makes to form micro emulsion ball, pack the mixed solution that contains micro emulsion ball into dialysis tubing and appear described polar solvent, obtain described carrier micelle.
10. purposes according to claim 9, is characterized in that, described polar solvent is DMSO, DMF or THF; Described poorly water soluble drugs is Zorubicin, taxol, Elemenum, camptothecine or vitamin A acid; Described aqueous phase solution is PBS damping fluid; Described dialysis tubing molecular weight is 0.2KD.
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