CN104045837B

CN104045837B - A kind of three-arm star-shaped hydrophilic copolymers and synthetic method thereof and application

Info

Publication number: CN104045837B
Application number: CN201410267395.1A
Authority: CN
Inventors: 钱军民; 徐明辉; 胥伟军; 刘茸茸; 王红洁
Original assignee: Xian Jiaotong University
Current assignee: Xian Jiaotong University
Priority date: 2014-06-16
Filing date: 2014-06-16
Publication date: 2016-08-17
Anticipated expiration: 2034-06-16
Also published as: CN104045837A

Abstract

A kind of three-arm star-shaped hydrophilic copolymers and synthetic method thereof and application, tri-primary amine kernel is utilized to cause γ benzyl ester L glutamic acid N carboxyanhydrides ring-opening polymerization, carbodlimide method is utilized to be bonded on three Amino End Group of this star polymer by little molecule RAFT polymerizable chain transfer agents, it is thus achieved that macromole RAFT agent；Again with N (3 dimethylamine propyl) Methacrylamide, N n-methylolacrylamide as monomer, implement RAFT polymerization, the hydroxyl of N n-methylolacrylamide component in copolymer is finally utilized to react with isocyanation esterification terminal methyl Polyethylene Glycol, realize connecting Polyethylene Glycol through disulfide bond, then obtain required three-arm star-shaped hydrophilic copolymers after hydrazinolysis processes.The method can control each polymers compositions molecular size range flexibly and chain length, reaction condition gentleness, raw material are easy to get, and the polymer of synthesis can improve drug effect, reduces toxic and side effects, loads amycin and genomic medicine, it is achieved synergistic antitumor therapeutic effect simultaneously.

Description

A kind of three-arm star-shaped hydrophilic copolymers and synthetic method thereof and application

Technical field

The invention belongs to biomedical materials field, be specifically related to a kind of three-arm star-shaped hydrophilic copolymers and synthetic method thereof and application.

Background technology

Chemotherapy based on cell toxicity medicament is one of main policies treating malignant tumor at present.But, the usual cytotoxicity of cell toxicity medicament is big, poorly water-soluble and inanimate object selectivity, can kill tumor cell and normal cell simultaneously, and toxic and side effects is serious.Due to all strong with the drug dose positive correlation of chemotherapeutic efficacy and toxic and side effects, therefore it is difficult to improve therapeutic effect by raising drug level.More seriously, cell toxicity medicament is in chemotherapy process, and tumor cell nearly all there will be multidrug resistance.These become the restriction successful major obstacle of chemotherapy.In recent years many studies have shown that, the biomaterial such as biocompatibility and biodegradability macromolecular material is utilized to load chemotherapeutics, tumor tissues local drug concentration can be effectively increased, improve drug bioavailability, it is achieved strengthen therapeutic effect, reduce the purpose to normal cellulotoxic side effect.At present, drug carrier material most study is good biocompatibility, biodegradable polyester material, such as polylactide, poly (glycolide-lactide), polycaprolactone etc..These hydrophobic polyester materials can the hydrophobic cell toxicity medicament of efficient loading, but they mainly discharge medicine by hydrolytic degradation mode, and speed is relatively slow, affects drug effect performance, it is seen that they are not preferable drug carrier materials.Therefore, synthesizing new drug carrier material and exploitation newtype drug releasing mechanism always be study hotspot.In recent years, polyamino acid such as polyglutamic acid and polylysine, because having good biocompatibility and biodegradability, appealed at drug delivery field.Polyamino acid is class homopolymerization bonded by peptide, that be made up of aminoacid and derivant thereof or copolymerized macromolecule material.Different aminoacids presents different side base, charge characteristics and hydrophilic and hydrophobics, can flexible polyamino acid physicochemical property, such as degradation property, biocompatibility, self assembly behavior etc..Additionally, the catabolite of polyamino acid is the aminoacid of weakly acidic pH, the side effect such as the inflammatory reaction that conventional polyester Acid Materials Acidic catabolite brings can be avoided.Visible, polyamino acid and derivant thereof have wide DEVELOPMENT PROSPECT at medicine delivery side's mask.Utilizing Amino End Group Polyethylene Glycol to cause L-Trp polymerization to prepare the preparation method of amphipathic nature block polymer as the Chinese patent of Application No. 201110132965.2 discloses, gained copolymer can form micelle, for the loading of the medicines such as paclitaxel.For another example the Chinese patent of Application No. 201110200449.9 discloses the purine-Polyaspartimides prodrug of a kind of reduction-sensitive, the disulfide bond wherein contained can be degraded under tumor cell glutathion inside reduction, release medicine, has and reduces toxic and side effects and improve the effect of curative effect.

It is no matter polyester or time polyamino acid is used as chemotherapeutics carrier, it is necessary to it is formed amphipathic nature block polymer with hydrophilic polyglycol, in order to the nano-micelle with hydrophobic inner core and hydrophilic outer shell can be self-assembled in water.Wherein, hydrophobic cores is used for wrapping up hydrophobicity chemotherapeutics, and hydrophilic shell can make nano-carrier stablize, prevent micelle coalescence, from regulation of immune system effect, it is achieved internal long circulating.For traditional little molecular lipid body micelle, amphipathic nature block polymer has lower critical micelle concentration, stability in blood is more preferable, and passive target can be realized through ' infiltration of enhancing and the retention effect ' that tumor tissues is special, medicine is effectively enriched in inside tumor tissues, promotes the tumor cell picked-up to carrier-drug.But, the simple nano-micelle relying on amphipathic nature block polymer to be self-assembly of, when injection enter internal after due to dilution effect, still suffer from micelle and dissociate and discharge the risk of medicine in advance.

In recent years, gene therapy is considered to treat the most promising New Policy of malignant tumor, and it is by importing ectogenic therapeutic genes in tumor cell, with correcting defect gene or suppression/promote that certain genes/proteins matter is expressed, thus reaches the purpose for the treatment of disease.Meanwhile, gene therapy is also to overcome the effective way of tumor multidrug-resistance in chemotherapy.For overcoming the problems such as safety, delivered payload capability immunoreation limited, potential and carcinogenesis that viral vector in gene therapy exists, new focus is become for the research of non-viral vector.Non-viral vector has the advantages such as safety high, immunogenicity is low, carrying amount is big, easy batch production, mainly includes cationic-liposome and cationic polymer two class.Wherein, cationic polymer is study subject, can form stable complex through electrostatic interaction and genetic stew, be effectively compressed genetic stew, assists gene through after birth.Polymine is the most classical cationic polymer carrier, has that raw material is easy to get, compression ratio is high, buffer capacity strong and transfection efficiency advantages of higher, and research is concentrated the most.But, polymine is big due to non-degradable and cytotoxicity, governs its range of application.

At present, utilizing different mechanism of action and dissimilar treated with combined medication malignant tumor to become development trend, the therapeutic alliance being based especially on nano-carrier is more sent to great expectations.But, the bottleneck problem of therapeutic alliance based on nano-carrier maximum is the carrier material synthesizing and preferably can loading different pharmaceutical simultaneously.The Chinese patent of Application No. 201210114241.X discloses the triblock copolymer being made up of Polyethylene Glycol, polylactic acid and poly arginine, wherein polyester segments and poly arginine section are respectively used to load hydrophobic drug and genetic stew, have good biological safety and drug delivery capabilities.But the intersegmental of this block copolymer is connected by ester bond and ammonia ester bond, does not has the mechanism of dissociating of stimulating responsive, and drug releasing rate is slower, it is difficult to give full play to curative effect of medication.

Summary of the invention

It is an object of the invention to provide a kind of three-arm star-shaped water solubility copolymer and synthetic method thereof and application, the method can control each polymers compositions molecular size range flexibly and chain length, reaction condition gentleness, raw material are easy to get, the polymer of synthesis can improve drug effect, reduce toxic and side effects, load amycin and genomic medicine, it is achieved synergistic antitumor therapeutic effect simultaneously.

For reaching above-mentioned purpose, the synthetic method of three-arm star-shaped hydrophilic copolymers of the present invention, it is characterised in that comprise the steps:

1) synthesis of three arms poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent:

To be dissolved in anhydrous organic solvent except three arms after water poly-(Pidolidone-γ-benzyl ester), the most in a nitrogen atmosphere in 0 DEG C～4 DEG C RAFT agent, DMAP and the dicyclohexylcarbodiimide added with a carboxyl, precipitate with cold diethyl ether after 24 hours～72 hours at room temperature reaction again, collect precipitation and be vacuum dried, obtaining three arms poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent；Wherein, it is 1:(6～20 except the mol ratio of poly-(Pidolidone-γ-benzyl ester) after water, RAFT agent, DMAP and the dicyclohexylcarbodiimide with a carboxyl): 3:(6～60)；

2) synthesis of three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide):

Poly-for three arms (Pidolidone-γ-benzyl ester) macromole RAFT agent, N-(3-dimethylamine propyl) Methacrylamide, N hydroxymethyl acrylamide are dissolved in anhydrous dioxane, then under oxygen-free environment, add initiator, react 36 hours～72 hours in 60 DEG C～65 DEG C, the reaction system that reaction is concentrated to give after terminating, precipitate in cold diethyl ether after dissolving with dichloromethane again, collect precipitation and be vacuum dried, obtaining three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)；Wherein, the mol ratio of three arms poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent, N-(3-dimethylamine propyl) Methacrylamide and N hydroxymethyl acrylamide is 1:(72～290): (3.6～14.4)；

3) three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer synthesis:

To be dissolved in anhydrous chloroform except the three-arm star-shaped after water poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide), it is subsequently adding 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified, react 36 hours～72 hours in 60 DEG C～65 DEG C, the reaction system that reaction is concentrated to give after terminating, and with ether sedimentation, then dialyse in distilled water, last lyophilizing, obtain three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer；Wherein, isocyanation esterification end methoxy poly (ethylene glycol) and except the mol ratio of three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide) after water is (9～36): 1；

4) synthesis of three-arm star-shaped hydrophilic copolymers: poly-for three-arm star-shaped (Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer hydrazinolysis is removed benzyl, obtains three-arm star-shaped hydrophilic copolymers.

Described step 1) in poly-(Pidolidone-γ-benzyl ester) be use following methods prepare: anhydrous three (2-amino-ethyl) amine is dissolved in anhydrous organic solvent, add γ-benzyl ester-Pidolidone-N-carboxyanhydrides in a nitrogen atmosphere, stirring forms homogeneous solution, then react 48 hours～72 hours in 25 DEG C～40 DEG C, the reactant liquor cold diethyl ether obtained is precipitated and washing with alcohol after terminating by reaction, obtains poly-(Pidolidone-γ-benzyl ester) after vacuum drying；Wherein, the mol ratio of anhydrous three (2-amino-ethyl) amine and γ-benzyl ester-Pidolidone-N-carboxyanhydrides is (1:30)～(1:120), and step 1) and step 4) in anhydrous organic solvent be anhydrous dimethyl formamide, anhydrous chloroform or anhydrous tetrahydro furan.

Described anhydrous three (2-amino-ethyl) amine is the backflow of hydrogenated calcium, and under nitrogen atmosphere, decompression distillation obtains.

Described γ-benzyl ester-Pidolidone-N-carboxyanhydrides is synthesized by following steps: Pidolidone-γ-benzyl ester added in anhydrous tetrahydro furan, add triphosgene the most under nitrogen atmosphere, concentrate after forming settled solution in 50 DEG C of reactions subsequently, the reaction system obtained after the most backward concentration adds anhydrous n-hexane and makes precipitation, the precipitation anhydrous n-hexane recrystallization that will obtain, obtains γ-benzyl ester-Pidolidone-N-carboxyanhydrides；Wherein, Pidolidone-γ-benzyl ester is 1:(0.35～0.4 with the mol ratio of triphosgene).

Described step 4) hydrazinolysis removing benzyl method be: poly-for three-arm star-shaped (Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is dissolved in anhydrous organic solvent, react 18 hours～48 hours in 30 DEG C～40 DEG C after dropping anhydrous hydrazine, the reaction system obtained is dialysed after terminating in the ammonia that mass concentration is 0.25% by reaction, last lyophilizing, obtains three-arm star-shaped hydrophilic copolymers；Wherein, anhydrous hydrazine is (3～20) with the mol ratio of benzyl protecting group in three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer: 1.

Described step 1) in RAFT agent with a carboxyl be S-1-dodecyl-S'-(α, α '-dimethyl-α "-acetic acid) trithiocarbonate, 4-cyano group-4-[(dodecyl sulfanyl thiocarbonyl group) sulfanyl] valeric acid, 4-cyano group-4-(thiobenzoyl) valeric acid or 4-cyanopentanoic acid dithiobenzoic acid.

Described step 2) in initiator be azodiisobutyronitrile or 4,4'-azo is double (cyanopentanoic acid), and the mol ratio of three arms poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent and initiator is 1:(0.36～1.44).

Described step 3) in 2, the isocyanate-modified terminal methyl Polyethylene Glycol of 2'-dithio diethyl is adopted and is synthesized with the following method: by end methoxy poly (ethylene glycol) that molecular weight is 800～4000Da, dibutyl tin laurate and 2,2'-dithio diethyl isocyanates is dissolved in dry toluene, react 48 hours under 85 DEG C of blanket of nitrogen, in the reaction system obtained, add anhydrous n-hexane make precipitation, collect precipitation and be vacuum dried, i.e. obtain 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified；Wherein, terminal methyl Polyethylene Glycol, dibutyl tin laurate and 2, the mol ratio of 2'-dithio diethyl isocyanates is 1:(0.02～0.08): (3～8).

A kind of three-arm star-shaped hydrophilic copolymers using described method to synthesize, its chemical name is three-arm star-shaped poly-(Pidolidone-γ-hydrazides)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer, and chemical constitution is:

Described three-arm star-shaped hydrophilic copolymers is as the application of the carrier loading amycin and genomic medicine.

Every 100 milliliters of anhydrous organic solvents dissolve poly-(Pidolidone-γ-benzyl ester) of 1g～6g；

Step 2) in, every 100 milliliters of anhydrous dioxane add three arms poly-(Pidolidone-γ-benzyl ester) the macromole RAFT agent of 2g～10g；

Step 3) in every 100 milliliters of anhydrous chloroforms dissolve 2g～5g except the tPBLG-b-PDMAPMA after water；

Every 100 milliliters of anhydrous tetrahydro furans dissolve the Pidolidone-γ-benzyl ester of 5g～15g.

Every 100 milliliters of anhydrous organic solvents dissolve the γ-benzyl ester-Pidolidone-N-carboxyanhydrides of 5g～15g；

Every 100 milliliters of dry toluenes dissolve the terminal methyl Polyethylene Glycol of 5g～30g.

Three described arms poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent is 1:(0.36～1.44 with the mol ratio of initiator)；

Described genomic medicine is Pgp siRNA, bcl-2siRNA or EGF siRNA, and its stowage is by genomic medicine and to load the mixing of the three-arm star-shaped water solubility copolymer after amycin, is mixed to form complex through turbula shaker, it is achieved the loading of genomic medicine.

Described step 5) in every 100 milliliters of anhydrous organic solvents dissolve 5g～30g three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer.

Compared with prior art, the beneficial effects of the present invention is:

(1) the three-arm star-shaped water solubility copolymer of present invention synthesis is formed by realizing the Polyethylene Glycol of internal recessive role, poly-(Pidolidone-γ-hydrazides) section by hydrazone key keyed jointing chemotherapeutic amycin and the synthetic cation poly-(N-(3-dimethylamine propyl) Methacrylamide) through electrostatic interaction load genetic stew, therefore, the three-arm star-shaped water solubility copolymer of present invention synthesis can load chemotherapeutic amycin and genetic stew simultaneously, it is achieved synergistic antitumor therapeutic effect.

Wherein, connect the functional bridged bond of Polyethylene Glycol containing disulfide bond, so it is loaded with carrier one end of amycin and genomic medicine to enter in tumor cell and just can respond reproducibility environment in tumor cell and rupture, after sloughing Polyethylene Glycol, the cationic layer carrying genomic medicine is exposed, the cationic layer exposed can promote that drug-carrier is escaped to Cytoplasm from endosome, discharges contained medicine, avoids lysosomal zymolysis simultaneously, thus improve drug effect, reduce toxic and side effects.Poly-(Pidolidone-γ-hydrazides) section of the present invention is prepared by ring-opening polymerisation method, and its final catabolite is glutamic acid, and can be absorbed by the body utilization, is not result in the adverse effect of polyester material acid degradation products.And nondegradable cation poly-(N-(3-dimethylamine propyl) Methacrylamide) section is synthesized by RAFT polymerization; narrow molecular weight distribution and molecular size range are controlled; by effectively controlling its molecular weight; the loading effect of genetic stew can either be guaranteed; ensure that again and excreted by Excretory system, it is to avoid its accumulation in vivo.

(2) synthetic method of the present invention can control each polymers compositions molecular size range flexibly and chain length, reaction condition gentleness, raw material are easy to get, the three-arm star-shaped water solubility copolymer of synthesis has water solublity, unimolecule nano-micelle can be self-assembly of in aqueous after loading chemotherapeutic amycin, unimolecule nano-micelle is enriched in tumor tissues through tumor tissues ' infiltration of enhancing and retention effect ' passive target, promote tumor cell picked-up carrier-drug, improve drug bioavailability, thus improve curative effect and reduce toxic and side effects.

Simultaneously, the unimolecule nano-micelle being self-assembled into has star structure, the nano-micelle formed will have the linear higher stability of amphipathic copolymer of ratio, lower critical micelle concentration, longer circulation time in vivo, therefore, after three-arm star-shaped water solubility copolymer medicine carrying, stability is higher in vivo, there is passive target effect, curative effect of medication can be improved and reduce toxic and side effects.

(3) quantity of the Polyethylene Glycol section on three-arm star-shaped water solubility copolymer can be by N hydroxymethyl acrylamide quantity flexible in cation section polymer, a Polyethylene Glycol section can be connected on single arm and present triblock copolymer molecular structure, also can connect several Polyethylene Glycol section and present block and the molecular structure of comb shaped structure combination, make the regulation of nano-micelle hydrophilic shell physicochemical property the most flexible.

Accompanying drawing explanation

Fig. 1 is the synthetic route schematic diagram of the three-arm star-shaped hydrophilic copolymers of the present invention；

Fig. 2 is three-arm star-shaped poly-(Pidolidone-γ-hydrazides)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-Polyethylene Glycol water solubility copolymer of embodiment 1 synthesis¹H-NMR spectrum.

Fig. 3 be embodiment 1 synthesis carrier load amycin after the grain size distribution of self-assembled nanometer grain.

Fig. 4 is the laser co-focusing fluorescence photo that the three-arm star-shaped hydrophilic copolymers that embodiment 1 synthesizes carries in the nanoparticle entrance breast cancer cell MCF-7 of amycin and FAM labelling siRNA altogether；Wherein, a is the nuclear fluorescence photo of DAPI dyeing, and b is the doxorubicin fluorescence photo at nucleus, and c is the fluorescence photo after the siRNA entrance cell of FAM labelling, and d is the constitutional diagram of a-c.

Detailed description of the invention

Seeing Fig. 1, the present invention is that kernel causes γ-benzyl ester-Pidolidone-N-carboxyanhydrides ring-opening polymerisation with three (2-amino-ethyl) amine, forms three arms poly-(Pidolidone-γ-benzyl ester) molecule；Then, utilize carbodlimide method to connect the RAFT agent with a carboxyl on its Amino End Group, implement RAFT and be polymerized synthetic cationic polymers section；Finally, the terminal methyl Polyethylene Glycol of keyed jointing isocyanation esterification, and obtain required three-arm star-shaped hydrophilic copolymers after hydrazinolysis processes, load while can be used for chemotherapeutic drugs Doxorubicin and genetic stew and deliver.

Below by embodiment, the invention will be further described, but the present invention is not limited to this.

Embodiment 1:

1) γ-benzyl ester-Pidolidone-N-carboxyanhydrides (BLG-NCA) synthesis:

Pidolidone-γ-benzyl ester is added in anhydrous tetrahydro furan, add triphosgene the most under nitrogen atmosphere, concentrating under reduced pressure is reacted to formation settled solution to remove major part solvent with concentrated solvent subsequently in 50 DEG C, the reaction system obtained after the most backward concentration adds anhydrous n-hexane and makes precipitation, the precipitation anhydrous n-hexane recrystallization that will obtain, obtains γ-benzyl ester-Pidolidone-N-carboxyanhydrides (BLG-NCA)；Wherein, Pidolidone-γ-benzyl ester is 1:0.35 with the mol ratio of triphosgene, dissolves the Pidolidone-γ-benzyl ester of 10g in every 100 milliliters of anhydrous tetrahydro furans；

2) synthesis of three arms poly-(Pidolidone-γ-benzyl ester) (tPBLG):

Distillation of reducing pressure under three (2-amino-ethyl) amine hydrogenated calcium backflow 12 hours, nitrogen atmosphere is obtained anhydrous three (2-amino-ethyl) amine, then anhydrous three (2-amino-ethyl) amine is dissolved in anhydrous dimethyl formamide, add BLG-NCA in a nitrogen atmosphere, stirring forms homogeneous solution, then reacts 72 hours in 25 DEG C；The reactant liquor cold diethyl ether obtained is precipitated and washing with alcohol after terminating by reaction, obtains three arms poly-(Pidolidone-γ-benzyl ester) (tPBLG) of white powder after vacuum drying；Wherein, the mol ratio of anhydrous three (2-amino-ethyl) amine and BLG-NCA is 1:30, dissolves the BLG-NCA of 15g in every 100 milliliters of anhydrous dimethyl formamides；

3) synthesis of three arms poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent:

By tPBLG under a nitrogen through toluene azeotropic water removing, tPBLG after obtaining except water, to be dissolved in anhydrous chloroform except three arms after water poly-(Pidolidone-γ-benzyl ester), S-1-dodecyl-S'-(α is added the most in a nitrogen atmosphere in 0 DEG C, α '-dimethyl-α "-acetic acid) trithiocarbonate (DDACT), DMAP (DMAP) and dicyclohexylcarbodiimide (DCC), precipitate with cold diethyl ether after 48 hours at room temperature reaction again, collect precipitation and be vacuum dried, obtain yellow solid product three arm poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent, i.e. tPBLG-CTA；Wherein, except the mol ratio of tPBLG, DDACT, DMAP and DCC after water is 1:6:3:12, dissolving the tPBLG after 3g removes water in every 100 milliliters of anhydrous chloroforms, during azeotropic water removing, reflux temperature is 120 DEG C, except water time 2 h；

4) synthesis of three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide) (tPBLG-b-PDMAPMA):

TPBLG-CTA, N-(3-dimethylamine propyl) Methacrylamide (DMAPMA), N hydroxymethyl acrylamide are dissolved in anhydrous dioxane, then azodiisobutyronitrile is added after utilizing nitrogen deoxygenation, react 48 hours in 60 DEG C, the reaction system that reaction is concentrated under reduced pressure to give after terminating is to remove solvent, precipitate in cold diethyl ether after dissolving with dichloromethane again, collect precipitation and be vacuum dried, obtain arm star poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide), i.e. tPBLG-b-PDMAPMA；Wherein, the mol ratio of tPBLG-CTA, DMAPMA, N hydroxymethyl acrylamide and azodiisobutyronitrile is 1:72:3.6:0.36, dissolves the tPBLG-CTA of 20g in every 100 milliliters of anhydrous dioxane；

5) synthesis of the terminal methyl Polyethylene Glycol that 2,2'-dithio diethyl is isocyanate-modified:

By end methoxy poly (ethylene glycol) that dry molecular weight is 800Da, dibutyl tin laurate and 2,2'-dithio diethyl isocyanates is dissolved in dry toluene, react 48 hours under 85 DEG C of blanket of nitrogen, in the reaction system obtained, add anhydrous n-hexane make precipitation, obtain 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified；Wherein, terminal methyl Polyethylene Glycol, dibutyl tin laurate and 2, the mol ratio of 2'-dithio diethyl isocyanates is 1:0.03:5, dissolves the end methoxy poly (ethylene glycol) of 5g in every 100 milliliters of dry toluenes；

6) three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer synthesis:

Toluene azeotropic method is utilized to remove trace water contained by tPBLG-b-PDMAPMA in a nitrogen atmosphere, tPBLG-b-PDMAPMA after obtaining except water, to be dissolved in anhydrous chloroform except the tPBLG-b-PDMAPMA after water, it is subsequently adding 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified, react 36 hours in 60 DEG C, the reaction system that reaction is concentrated to give after terminating, and with ether sedimentation, then dialyse 48 hours in distilled water, three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is obtained after lyophilizing；Wherein, 2, terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified and except the mol ratio of three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide) after water is 9:1, every 100 milliliters of anhydrous chloroforms dissolve 2g except the tPBLG-b-PDMAPMA after water, reflux temperature during azeotropic water removing is 110 DEG C, except the water time is 6 hours；

7) synthesis of three-arm star-shaped hydrophilic copolymers:

Dry three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is dissolved in anhydrous dimethyl formamide, react 24 hours in 40 DEG C after dropping anhydrous hydrazine, the reaction system obtained is dialysed 2 days after terminating in the ammonia that mass concentration is 0.25% by reaction, last lyophilizing, obtains three-arm star-shaped hydrophilic copolymers；Wherein, anhydrous hydrazine is 5:1 with the mol ratio of benzyl protecting group in three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer；Every 100 milliliters of anhydrous dimethyl formamides dissolve 10g three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer.

The chemical name of the three-arm star-shaped hydrophilic copolymers of the present embodiment synthesis is three-arm star-shaped poly-(Pidolidone-γ-hydrazides)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-Polyethylene Glycol hydrophilic copolymers, and its structural formula is

¹H-NMR spectrum is shown in Fig. 2.Figure it is seen that the chemical shift of each copolymer component proton has all obtained good qualification, show that the synthesis of this copolymer is successful.

After the three-arm star-shaped hydrophilic copolymers carrier load amycin of the present embodiment synthesis, presenting amphipathic character, can be self-assembled into as nanoparticle in water, the grain size distribution that dynamic light scattering method records is shown in Fig. 3.As seen from Figure 3, particle size distribution range is 50 nanometers～110 nanometers, and particle size distribution range is narrow, more satisfactory.

The nanoparticle that the three-arm star-shaped hydrophilic copolymers of the present embodiment synthesis is formed after loading the siRNA of amycin and green fluorescence agent FAM labelling altogether can be efficiently entering intracellular through endocytosis, and it sees Fig. 4 in intracellular distribution.B in Fig. 4 a is the fluorescence that the nucleus that DAPI dyes sends, R in Fig. 4 b is the fluorescence that the amycin at nucleus sends, G in Fig. 4 c is the fluorescence sent after the bcl-2siRNA entrance breast cancer cell MCF-7 of FAM labelling, after Fig. 4 a-4c is combined, obtain Fig. 4 d, by Fig. 4 d it can be seen that amycin and bcl-2siRNA all can be efficiently entering in breast cancer cell MCF-7, it is distributed in around nucleus, it is seen that the carrier of synthesis can be used for amycin and the common of bcl-2siRNA loads and deliver.

Embodiment 2:

1) with the step 1 in embodiment 1) identical.

2) synthesis of three arms poly-(Pidolidone-γ-benzyl ester) (tPBLG):

Distillation of reducing pressure under three (2-amino-ethyl) amine hydrogenated calcium backflow 12 hours, nitrogen atmosphere is obtained anhydrous three (2-amino-ethyl) amine, then anhydrous three (2-amino-ethyl) amine is dissolved in anhydrous chloroform, add BLG-NCA in a nitrogen atmosphere, stirring forms homogeneous solution, reacts 60 hours in 40 DEG C；The reactant liquor cold diethyl ether obtained is precipitated and washing with alcohol after terminating by reaction, obtains white powder tPBLG after vacuum drying；Wherein, the mol ratio of anhydrous three (2-amino-ethyl) amine and BLG-NCA is 1:60, dissolves the BLG-NCA of 5g in every 100 milliliters of anhydrous chloroforms；

By tPBLG under a nitrogen through toluene azeotropic water removing, tPBLG after obtaining except water, to be dissolved in anhydrous dimethyl formamide except the tPBLG after water, S-1-dodecyl-S'-(α is added the most in a nitrogen atmosphere in 0 DEG C, α '-dimethyl-α "-acetic acid) trithiocarbonate (DDACT), DMAP (DMAP) and dicyclohexylcarbodiimide (DCC), precipitate with cold diethyl ether after 48 hours at room temperature reaction again, collect precipitation and be vacuum dried, obtain yellow solid product three arm poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent, i.e. tPBLG-CTA.Wherein, except the mol ratio of tPBLG, DDACT, DMAP and DCC after water is 1:12:3:30, every 100 milliliters of anhydrous dimethyl formamides dissolve 6g except the tPBLG after water；During azeotropic water removing, reflux temperature is 120 DEG C, except water time 2 h；

By tPBLG-CTA, N-(3-dimethylamine propyl) Methacrylamide (DMAPMA), N hydroxymethyl acrylamide is dissolved in anhydrous dioxane, then 4 are added after utilizing nitrogen deoxygenation, 4'-azo is double (cyanopentanoic acid), react 48 hours in 60 DEG C, the reaction system that reaction is concentrated under reduced pressure to give after terminating is to remove solvent, precipitate in cold diethyl ether after dissolving with dichloromethane again, collect precipitation and be vacuum dried, obtain three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide), i.e. tPBLG-b-PDMAPMA；Wherein, tPBLG-CTA, DMAPMA, N hydroxymethyl acrylamide and 4, the mol ratio of 4'-azo double (cyanopentanoic acid) is 1:290:14.4:0.36, dissolves the tPBLG-CTA of 10g in every 100 milliliters of anhydrous dioxane；

5) 2, the synthesis of the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified: by end methoxy poly (ethylene glycol) that dry molecular weight is 4000Da, dibutyl tin laurate and 2,2'-dithio diethyl isocyanates is dissolved in dry toluene, react 48 hours under 85 DEG C of blanket of nitrogen, in the reaction system obtained, add anhydrous n-hexane make precipitation, obtain 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified；Wherein, terminal methyl Polyethylene Glycol, dibutyl tin laurate and 2, the mol ratio of 2'-dithio diethyl isocyanates is 1:0.02:6, dissolves the end methoxy poly (ethylene glycol) of 10g in every 100 milliliters of dry toluenes；

Toluene azeotropic method is utilized to remove trace water contained by tPBLG-b-PDMAPMA in a nitrogen atmosphere, tPBLG-b-PDMAPMA after obtaining except water, to be dissolved in anhydrous chloroform except the tPBLG-b-PDMAPMA after water, it is subsequently adding 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified, react 72 hours in 60 DEG C, the reaction system that reaction is concentrated to give after terminating, and with ether sedimentation, then dialyse 48 hours in distilled water, three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is obtained after lyophilizing；Wherein, terminal methyl Polyethylene Glycol that 2,2'-dithio diethyl are isocyanate-modified and except the mol ratio of three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide) after water is 12:1；Every 100 milliliters of anhydrous chloroforms dissolve 2g except the tPBLG-b-PDMAPMA after water；Reflux temperature during azeotropic water removing is 115 DEG C, except the water time is 4 hours；

7) synthesis of three-arm star-shaped hydrophilic copolymers:

Dry three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is dissolved in anhydrous dimethyl formamide, react 24 hours in 40 DEG C after dropping anhydrous hydrazine, the reaction system obtained is dialysed 2 days after terminating in the ammonia that mass concentration is 0.25% by reaction, last lyophilizing, obtains three-arm star-shaped hydrophilic copolymers；Wherein, anhydrous hydrazine is 8:1 with the mol ratio of benzyl protecting group in three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer, dissolves 30g three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer in every 100 milliliters of anhydrous dimethyl formamides.

Embodiment 3:

1) with the step 1 in embodiment 1) identical.

2) synthesis of three arms poly-(Pidolidone-γ-benzyl ester) (tPBLG):

Distillation of reducing pressure under three (2-amino-ethyl) amine hydrogenated calcium backflow 12 hours, nitrogen atmosphere is obtained anhydrous three (2-amino-ethyl) amine, then anhydrous three (2-amino-ethyl) amine is dissolved in anhydrous tetrahydro furan, add BLG-NCA in a nitrogen atmosphere, stirring forms homogeneous solution, reacts 48 hours in 40 DEG C；The reactant liquor cold diethyl ether obtained is precipitated and washing with alcohol after terminating by reaction, obtains white powder tPBLG after vacuum drying；Wherein, the mol ratio of anhydrous three (2-amino-ethyl) amine and BLG-NCA is 1:45, dissolves the BLG-NCA of 5g in every 100 milliliters of anhydrous tetrahydro furans；

By tPBLG under a nitrogen through toluene azeotropic water removing, the tPBLG after obtaining except water, will be dissolved in anhydrous chloroform except the tPBLG after water；S-1-dodecyl-S'-(α is added the most in a nitrogen atmosphere in 0 DEG C, α '-dimethyl-α "-acetic acid) trithiocarbonate (DDACT), DMAP (DMAP) and dicyclohexylcarbodiimide (DCC); precipitate with cold diethyl ether after 48 hours at room temperature reaction the most again; collect precipitation and be also vacuum dried, obtain yellow solid product three arm poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent；Wherein, except the mol ratio of tPBLG, DDACT, DMAP and DCC after water is 1:20:3:60, every 100 milliliters of anhydrous chloroforms dissolve 3g except the tPBLG after water；During azeotropic water removing, reflux temperature was 110 DEG C, except 6 hours water time；

By tPBLG-CTA, N-(3-dimethylamine propyl) Methacrylamide (DMAPMA), N hydroxymethyl acrylamide is dissolved in anhydrous dioxane, azodiisobutyronitrile is added after utilizing nitrogen deoxygenation, react 48 hours in 60 DEG C, after reaction terminates, solvent is removed in decompression, the reaction system being concentrated to give is dissolved to remove solvent with dichloromethane, precipitate in cold diethyl ether after dissolving with dichloromethane again, collect precipitation and be vacuum dried, obtain three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide), i.e. tPBLG-b-PDMAPMA；Wherein, tPBLG-CTA, DMAPMA, N hydroxymethyl acrylamide and 4, the mol ratio of 4'-azo double (cyanopentanoic acid) is 1:144:7.2:0.64, dissolves the tPBLG-CTA of 4g in every 100 milliliters of anhydrous dioxane；

5) 2, the synthesis of the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified: by end methoxy poly (ethylene glycol) that dry molecular weight is 2000Da, dibutyl tin laurate and 2,2'-dithio diethyl isocyanates is dissolved in dry toluene, react 48 hours under 85 DEG C of blanket of nitrogen, in the reaction system obtained, add anhydrous n-hexane make precipitation, obtain 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified；Wherein, holding methoxy poly (ethylene glycol), dibutyl tin laurate and 2, the mol ratio of 2'-dithio diethyl isocyanates is 1:0.04:6, dissolves the end methoxy poly (ethylene glycol) of 5g in every 100 milliliters of dry toluenes；

Toluene azeotropic method is utilized to remove trace water contained by tPBLG-b-PDMAPMA in a nitrogen atmosphere, tPBLG-b-PDMAPMA after obtaining except water, to be dissolved in anhydrous chloroform dissolving except the tPBLG-b-PDMAPMA after water, it is subsequently adding 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified, react 48 hours in 60 DEG C, the reaction system that reaction is concentrated to give after terminating, and with ether sedimentation, then dialyse 48 hours in distilled water, three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is obtained after lyophilizing；Wherein, terminal methyl Polyethylene Glycol that 2,2'-dithio diethyl are isocyanate-modified and except the mol ratio of three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide) after water is 24:1；Every 100 milliliters of anhydrous chloroforms dissolve 5g except the tPBLG-b-PDMAPMA after water；Reflux temperature during azeotropic water removing is 110 DEG C, except the water time is 6 hours；

7) synthesis of three-arm star-shaped hydrophilic copolymers:

Dry three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is dissolved in anhydrous dimethyl formamide, react 24 hours in 40 DEG C after dropping anhydrous hydrazine, the reaction system obtained is dialysed 2 days after terminating in the ammonia that mass concentration is 0.25% by reaction, last lyophilizing, obtains three-arm star-shaped hydrophilic copolymers；Wherein, anhydrous hydrazine is 10:1 with the mol ratio of benzyl protecting group in three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer, dissolves 25g three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer in every 100 milliliters of anhydrous dimethyl formamides.

Embodiment 4:

1) with the step 1 in embodiment 1) identical.

2) synthesis of three-arm star-shaped poly-(Pidolidone-γ-benzyl ester) (tPBLG):

Distillation of reducing pressure under three (2-amino-ethyl) amine hydrogenated calcium backflow 12 hours, nitrogen atmosphere is obtained anhydrous three (2-amino-ethyl) amine, then anhydrous three (2-amino-ethyl) amine is dissolved in anhydrous dimethyl formamide, add BLG-NCA in a nitrogen atmosphere, stirring forms homogeneous solution, reacts 60 hours in 30 DEG C；The reactant liquor cold diethyl ether obtained is precipitated and washing with alcohol after terminating by reaction, obtains white powder tPBLG after vacuum drying；Wherein, the mol ratio of three (2-amino-ethyl) amine and BLG-NCA is 1:120, dissolves 5g anhydrous three (2-amino-ethyl) amine in every 100 milliliters of anhydrous dimethyl formamides；

By tPBLG under a nitrogen through toluene azeotropic water removing, tPBLG after obtaining except water, to be dissolved in anhydrous dimethyl formamide except the tPBLG after water, the most in a nitrogen atmosphere in 0 DEG C of S-1-dodecyl-S'-(α, α '-dimethyl-α "-acetic acid) trithiocarbonate (DDACT), DMAP (DMAP) and dicyclohexylcarbodiimide (DCC), precipitate with cold diethyl ether after 48 hours at room temperature reaction again, collect precipitation and be vacuum dried, obtain yellow solid product three arm poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent, i.e. tPBLG-CTA；Wherein, except the mol ratio of tPBLG, DDACT, DMAP and DCC after water is 1:20:3:60, every 100 milliliters of anhydrous dimethyl formamides dissolve 5.5g except the tPBLG after water；During azeotropic water removing, reflux temperature was 110 DEG C, except 6 hours water time；

TPBLG-CTA, N-(3-dimethylamine propyl) Methacrylamide (DMAPMA), N hydroxymethyl acrylamide are dissolved in anhydrous dioxane, then azodiisobutyronitrile is added after utilizing nitrogen deoxygenation, react 48 hours in 60 DEG C, the reaction system that reaction is concentrated under reduced pressure to give after terminating is to remove solvent, precipitate in cold diethyl ether after dissolving with dichloromethane again, collect precipitation and be vacuum dried, obtain three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide), i.e. tPBLG-b-PDMAPMA；Wherein, the mol ratio of tPBLG-CTA, DMAPMA, N hydroxymethyl acrylamide and azodiisobutyronitrile is 1:216:10.8:1.44, dissolves the tPBLG-CTA of 7.5g in every 100 milliliters of anhydrous dioxane；

By end methoxy poly (ethylene glycol) that dry molecular weight is 2000Da, dibutyl tin laurate and 2,2'-dithio diethyl isocyanates is dissolved in dry toluene, react 48 hours under 85 DEG C of blanket of nitrogen, in the reaction system obtained, add anhydrous n-hexane make precipitation, obtain 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified；Wherein, terminal methyl Polyethylene Glycol, dibutyl tin laurate and 2, the mol ratio of 2'-dithio diethyl isocyanates is 1:0.02:8, dissolves the end methoxy poly (ethylene glycol) of 5g in every 100 milliliters of dry toluenes；

Toluene azeotropic method is utilized to remove trace water contained by tPBLG-b-PDMAPMA in a nitrogen atmosphere, tPBLG-b-PDMAPMA after obtaining except water, to be dissolved in anhydrous chloroform except the tPBLG-b-PDMAPMA after water, it is subsequently adding 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified, react 60 hours in 60 DEG C, the reaction system that reaction is concentrated to give after terminating, and with ether sedimentation, then dialyse 48 hours in distilled water, three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is obtained after lyophilizing；Wherein, terminal methyl Polyethylene Glycol that 2,2'-dithio diethyl are isocyanate-modified and except the mol ratio of three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide) after water is 12:1；Every 100 milliliters of anhydrous chloroforms dissolve 5g except the tPBLG-b-PDMAPMA after water；Reflux temperature during azeotropic water removing is 120 DEG C, except the water time is 3 hours；

7) synthesis of three-arm star-shaped three-arm star-shaped hydrophilic copolymers:

Dry three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is dissolved in anhydrous tetrahydro furan, react 24 hours in 40 DEG C after dropping anhydrous hydrazine, the reaction system obtained is dialysed 2 days after terminating in the ammonia that mass concentration is 0.25% by reaction, last lyophilizing, obtains three-arm star-shaped hydrophilic copolymers；Wherein, anhydrous hydrazine is 5:1 with the mol ratio of benzyl protecting group in three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer；Every 100 milliliters of anhydrous tetrahydro furans dissolve 15g three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer.

Embodiment 5:

1) with the step 1 in embodiment 1) identical.

2) synthesis of three arms poly-(Pidolidone-γ-benzyl ester) (tPBLG):

Distillation of reducing pressure under three (2-amino-ethyl) amine hydrogenated calcium backflow 12 hours, nitrogen atmosphere is obtained anhydrous three (2-amino-ethyl) amine, then anhydrous three (2-amino-ethyl) amine is dissolved in anhydrous tetrahydro furan, add BLG-NCA in a nitrogen atmosphere, stirring forms homogeneous solution, reacts 60 hours in 40 DEG C；The reactant liquor cold diethyl ether obtained is precipitated and washing with alcohol after terminating by reaction, obtains white powder tPBLG after vacuum drying；Wherein, the mol ratio of anhydrous three (2-amino-ethyl) amine and BLG-NCA is 1:80, dissolves the BLG-NCA of 8g in every 100 milliliters of anhydrous tetrahydro furans；

By tPBLG under a nitrogen through toluene azeotropic water removing, tPBLG after obtaining except water, to be dissolved in anhydrous chloroform except the tPBLG after water, S-1-dodecyl-S'-(α is added the most in a nitrogen atmosphere in 0 DEG C, α '-dimethyl-α "-acetic acid) trithiocarbonate (DDACT), DMAP (DMAP) and dicyclohexylcarbodiimide (DCC), precipitate with cold diethyl ether after 48 hours at room temperature reaction the most again, collect precipitation and be vacuum dried, obtain yellow solid product three arm poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent, i.e. tPBLG-CTA；Wherein, except the mol ratio of tPBLG, DDACT, DMAP and DCC after water is 1:6:3:8, every 100 milliliters of anhydrous chloroforms dissolve 5g except the tPBLG after water；During azeotropic water removing, reflux temperature was 115 DEG C, except 4 hours water time；

TPBLG-CTA, N-(3-dimethylamine propyl) Methacrylamide (DMAPMA), N hydroxymethyl acrylamide are dissolved in anhydrous dioxane, then azodiisobutyronitrile is added after utilizing nitrogen deoxygenation, react 48 hours in 60 DEG C, the reaction system that reaction is concentrated under reduced pressure to give after terminating is to remove solvent, precipitate in cold diethyl ether after dissolving with dichloromethane again, collect precipitation and be vacuum dried, obtain three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide), i.e. obtain tPBLG-b-PDMAPMA；Wherein, the mol ratio of tPBLG-CTA, DMAPMA, N hydroxymethyl acrylamide and azodiisobutyronitrile is 1:72:7.2:0.36, dissolves the tPBLG-CTA of 2g in every 100 milliliters of anhydrous dioxane；

By end methoxy poly (ethylene glycol) that dry molecular weight is 800Da, dibutyl tin laurate and 2,2'-dithio diethyl isocyanates is dissolved in dry toluene, react 48 hours under 85 DEG C of blanket of nitrogen, in the reaction system obtained, add anhydrous n-hexane make precipitation, obtain 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified；Wherein, terminal methyl Polyethylene Glycol, dibutyl tin laurate and 2, the mol ratio of 2'-dithio diethyl isocyanates is 1:0.05:4；Every 100 milliliters of dry toluenes dissolve the end methoxy poly (ethylene glycol) of 12g；

Toluene azeotropic method is utilized to remove trace water contained by tPBLG-b-PDMAPMA in a nitrogen atmosphere, tPBLG-b-PDMAPMA after obtaining except water, to utilize in anhydrous chloroform except the tPBLG-b-PDMAPMA after water is dissolved in, it is subsequently adding 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified, react 52 hours in 60 DEG C, the reaction system that reaction is concentrated to give after terminating, and with ether sedimentation, then dialyse 48 hours in distilled water, three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is obtained after lyophilizing；Wherein, terminal methyl Polyethylene Glycol that 2,2'-dithio diethyl are isocyanate-modified and except the mol ratio of three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide) after water is 25:1；Every 100 milliliters of anhydrous chloroforms dissolve 2g except the tPBLG-b-PDMAPMA after water；Reflux temperature during azeotropic water removing is 115 DEG C, except the water time is 5 hours；

7) synthesis of three-arm star-shaped hydrophilic copolymers:

Dry three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is dissolved in anhydrous chloroform, react 24 hours in 40 DEG C after dropping anhydrous hydrazine, after should terminating, the reaction system obtained is dialysed 2 days in the ammonia that mass concentration is 0.25%, last lyophilizing, obtains three-arm star-shaped hydrophilic copolymers；Wherein, anhydrous hydrazine is 20:1 with the mol ratio of benzyl protecting group in three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer；Every 100 milliliters of anhydrous chloroforms dissolve 8g three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer.

Embodiment 6:

1) with the step 1 in embodiment 1) identical.

Distillation of reducing pressure under three (2-amino-ethyl) amine hydrogenated calcium backflow 12 hours, nitrogen atmosphere is obtained anhydrous three (2-amino-ethyl) amine, then anhydrous three (2-amino-ethyl) amine is dissolved in anhydrous chloroform, add BLG-NCA in a nitrogen atmosphere, stirring forms homogeneous solution, then reacts 70 hours in 25 DEG C；By the reactant liquor cold diethyl ether precipitation obtained and washing with alcohol, after vacuum drying, obtain three arms poly-(Pidolidone-γ-benzyl ester) (tPBLG) of white powder；Wherein, the mol ratio of anhydrous three (2-amino-ethyl) amine and BLG-NCA is 1:90, dissolves 10g anhydrous three (2-amino-ethyl) amine in every 100 milliliters of anhydrous chloroforms；

By tPBLG under a nitrogen through toluene azeotropic water removing, tPBLG after obtaining except water, to be dissolved in anhydrous dimethyl formamide except the tPBLG after water, S-1-dodecyl-S'-(α is added the most in a nitrogen atmosphere in 0 DEG C, α '-dimethyl-α "-acetic acid) trithiocarbonate (DDACT), DMAP (DMAP) and dicyclohexylcarbodiimide (DCC), precipitate with cold diethyl ether after 48 hours at room temperature reaction again, collect precipitation and be vacuum dried, obtain yellow solid product three arm poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent, i.e. tPBLG-CTA；Wherein, except the mol ratio of tPBLG, DDACT, DMAP and DCC after water is 1:18:3:40, every 100 milliliters of anhydrous dimethyl formamides dissolve 6g except the tPBLG after water；During azeotropic water removing, reflux temperature was 110 DEG C, except 6 hours water time；

By tPBLG-CTA, N-(3-dimethylamine propyl) Methacrylamide (DMAPMA), N hydroxymethyl acrylamide is dissolved in anhydrous dioxane, then 4 are added after utilizing nitrogen deoxygenation, 4'-azo is double (cyanopentanoic acid), react 48 hours in 60 DEG C, the reaction system that reaction is concentrated under reduced pressure to give after terminating is to remove solvent, precipitate in cold diethyl ether after dissolving with dichloromethane again, collect precipitation and be vacuum dried, obtain three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide), i.e. obtain tPBLG-b-PDMAPMA；Wherein, tPBLG-CTA, DMAPMA, N hydroxymethyl acrylamide and 4, the mol ratio of 4'-azo double (cyanopentanoic acid) is 1:290:14.4:1.08, dissolves the tPBLG-CTA of 8.5g in every 100 milliliters of anhydrous dioxane.

By end methoxy poly (ethylene glycol) that dry molecular weight is 800Da, dibutyl tin laurate and 2,2'-dithio diethyl isocyanates is dissolved in dry toluene, react 48 hours under 85 DEG C of blanket of nitrogen, in the reaction system obtained, add anhydrous n-hexane make precipitation, obtain 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified；Wherein, terminal methyl Polyethylene Glycol, dibutyl tin laurate and 2, the mol ratio of 2'-dithio diethyl isocyanates is 1:0.07:8, dissolves the end methoxy poly (ethylene glycol) of 16g in every 100 milliliters of dry toluenes；

Toluene azeotropic method is utilized to remove trace water contained by tPBLG-b-PDMAPMA in a nitrogen atmosphere, tPBLG-b-PDMAPMA after obtaining except water, to be dissolved in anhydrous chloroform except the tPBLG-b-PDMAPMA after water, it is subsequently adding 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified, react 45 hours in 60 DEG C, the reaction system that reaction is concentrated to give after terminating, and with ether sedimentation, then dialyse 48 hours in distilled water, three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is obtained after lyophilizing；Wherein, 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified and the tPBLG-b-PDMAPMA except the mol ratio of three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide) after water is 30:1, after dissolving 3.5g removes water in every 100 milliliters of anhydrous chloroforms；Reflux temperature during azeotropic water removing is 120 DEG C, except the water time is 2 hours；

7) synthesis of three-arm star-shaped hydrophilic copolymers:

Dry three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is dissolved in anhydrous dimethyl formamide, react 24 hours in 40 DEG C after dropping anhydrous hydrazine, the reaction system obtained is dialysed 2 days after terminating in the ammonia that mass concentration is 0.25% by reaction, last lyophilizing, obtains three-arm star-shaped hydrophilic copolymers；Wherein, anhydrous hydrazine is 3:1 with the mol ratio of benzyl protecting group in three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer；Every 100 milliliters of anhydrous dimethyl formamides dissolve 12g three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer.

Embodiment 7:

1) γ-benzyl ester-Pidolidone-N-carboxyanhydrides (BLG-NCA) synthesis:

Pidolidone-γ-benzyl ester is added in anhydrous tetrahydro furan, add triphosgene the most under nitrogen atmosphere, concentrating under reduced pressure is reacted to formation settled solution to remove major part solvent subsequently in 50 DEG C, the reaction system obtained after the most backward concentration adds anhydrous n-hexane and makes precipitation, the precipitation anhydrous n-hexane recrystallization that will obtain, obtains γ-benzyl ester-Pidolidone-N-carboxyanhydrides (BLG-NCA)；Wherein, Pidolidone-γ-benzyl ester is 1:0.38 with the mol ratio of triphosgene, dissolves the Pidolidone-γ-benzyl ester of 15g in every 100 milliliters of anhydrous tetrahydro furans；

2) with embodiment 6 step 2) identical；

By tPBLG under a nitrogen through toluene azeotropic water removing, tPBLG after obtaining except water, to be dissolved in anhydrous dimethyl formamide except the tPBLG after water, 4-cyano group-4-[(dodecyl sulfanyl thiocarbonyl group) sulfanyl] valeric acid is added the most in a nitrogen atmosphere in 0 DEG C, DMAP (DMAP) and dicyclohexylcarbodiimide (DCC), precipitate with cold diethyl ether after 24 hours at room temperature reaction again, collect precipitation and be vacuum dried, obtain yellow solid product three arm poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent, i.e. tPBLG-CTA；Wherein, except tPBLG, 4-cyano group-4-[(the dodecyl sulfanyl thiocarbonyl group) sulfanyl] valeric acid after water, the mol ratio of DMAP and DCC are 1:6:3:6, every 100 milliliters of anhydrous dimethyl formamides dissolve 4g except the tPBLG after water；During azeotropic water removing, reflux temperature was 110 DEG C, except 6 hours water time；

By tPBLG-CTA, N-(3-dimethylamine propyl) Methacrylamide (DMAPMA), N hydroxymethyl acrylamide is dissolved in anhydrous dioxane, then 4 are added after utilizing nitrogen deoxygenation, 4'-azo is double (cyanopentanoic acid), react 36 hours in 65 DEG C, the reaction system that reaction is concentrated under reduced pressure to give after terminating is to remove solvent, precipitate in cold diethyl ether after dissolving with dichloromethane again, collect precipitation and be vacuum dried, obtain three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide), i.e. obtain tPBLG-b-PDMAPMA；Wherein, tPBLG-CTA, DMAPMA, N hydroxymethyl acrylamide and 4, the mol ratio of 4'-azo double (cyanopentanoic acid) is 1:290:14.4:1.08, dissolves the tPBLG-CTA of 7g in every 100 milliliters of anhydrous dioxane.

By end methoxy poly (ethylene glycol) that dry molecular weight is 3000Da, dibutyl tin laurate and 2,2'-dithio diethyl isocyanates is dissolved in dry toluene, react 48 hours under 85 DEG C of blanket of nitrogen, in the reaction system obtained, add anhydrous n-hexane make precipitation, obtain 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified；Wherein, terminal methyl Polyethylene Glycol, dibutyl tin laurate and 2, the mol ratio of 2'-dithio diethyl isocyanates is 1:0.08:3, dissolves the end methoxy poly (ethylene glycol) of 24g in every 100 milliliters of dry toluenes；

Toluene azeotropic method is utilized to remove trace water contained by tPBLG-b-PDMAPMA in a nitrogen atmosphere, tPBLG-b-PDMAPMA after obtaining except water, to be dissolved in anhydrous chloroform except the tPBLG-b-PDMAPMA after water, it is subsequently adding 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified, react 45 hours in 64 DEG C, the reaction system that reaction is concentrated to give after terminating, and with ether sedimentation, then dialyse 57 hours in distilled water, three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is obtained after lyophilizing；Wherein, 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified and the tPBLG-b-PDMAPMA except the mol ratio of three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide) after water is 36:1, after dissolving 4g removes water in every 100 milliliters of anhydrous chloroforms；Reflux temperature during azeotropic water removing is 120 DEG C, except the water time is 2 hours；

7) synthesis of three-arm star-shaped hydrophilic copolymers:

Dry three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is dissolved in anhydrous dimethyl formamide, react 24 hours in 40 DEG C after dropping anhydrous hydrazine, the reaction system obtained is dialysed 2 days after terminating in the ammonia that mass concentration is 0.25% by reaction, last lyophilizing, obtains three-arm star-shaped hydrophilic copolymers；Wherein, anhydrous hydrazine is 3:1 with the mol ratio of benzyl protecting group in three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer；Every 100 milliliters of anhydrous dimethyl formamides dissolve 16g three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer.

Embodiment 8:

1) γ-benzyl ester-Pidolidone-N-carboxyanhydrides (BLG-NCA) synthesis:

Pidolidone-γ-benzyl ester is added in anhydrous tetrahydro furan, add triphosgene the most under nitrogen atmosphere, concentrating under reduced pressure is reacted to formation settled solution to remove major part solvent subsequently in 50 DEG C, the reaction system obtained after the most backward concentration adds anhydrous n-hexane and makes precipitation, the precipitation anhydrous n-hexane recrystallization that will obtain, obtains γ-benzyl ester-Pidolidone-N-carboxyanhydrides (BLG-NCA)；Wherein, Pidolidone-γ-benzyl ester is 1:0.4 with the mol ratio of triphosgene, dissolves the Pidolidone-γ-benzyl ester of 5g in every 100 milliliters of anhydrous tetrahydro furans；

2) with the step 2 of embodiment 6) identical；

By tPBLG under a nitrogen through toluene azeotropic water removing, tPBLG after obtaining except water, to be dissolved in anhydrous chloroform except the tPBLG after water, 4-cyanopentanoic acid dithiobenzoic acid, DMAP (DMAP) and dicyclohexylcarbodiimide (DCC) is added the most in a nitrogen atmosphere in 0 DEG C, precipitate with cold diethyl ether after 72 hours at room temperature reaction the most again, collect precipitation and be vacuum dried, obtain yellow solid product three arm poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent, i.e. tPBLG-CTA；Wherein, except tPBLG, 4-cyanopentanoic acid dithiobenzoic acid after water, the mol ratio of DMAP and DCC are 1:6:3:8, every 100 milliliters of anhydrous chloroforms dissolve 5g except the tPBLG after water；During azeotropic water removing, reflux temperature was 115 DEG C, except 4 hours water time；

TPBLG-CTA, N-(3-dimethylamine propyl) Methacrylamide (DMAPMA), N hydroxymethyl acrylamide are dissolved in anhydrous dioxane, then azodiisobutyronitrile is added after utilizing nitrogen deoxygenation, react 72 hours in 61 DEG C, the reaction system that reaction is concentrated under reduced pressure to give after terminating is to remove solvent, precipitate in cold diethyl ether after dissolving with dichloromethane again, collect precipitation and be vacuum dried, obtain three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide), i.e. obtain tPBLG-b-PDMAPMA；Wherein, the mol ratio of tPBLG-CTA, DMAPMA, N hydroxymethyl acrylamide and azodiisobutyronitrile is 1:72:7.2:0.36, dissolves the tPBLG-CTA of 2g in every 100 milliliters of anhydrous dioxane；

By end methoxy poly (ethylene glycol) that dry molecular weight is 800Da, dibutyl tin laurate and 2,2'-dithio diethyl isocyanates is dissolved in dry toluene, react 48 hours under 85 DEG C of blanket of nitrogen, in the reaction system obtained, add anhydrous n-hexane make precipitation, obtain 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified；Wherein, terminal methyl Polyethylene Glycol, dibutyl tin laurate and 2, the mol ratio of 2'-dithio diethyl isocyanates is 1:0.05:4；Every 100 milliliters of dry toluenes dissolve the end methoxy poly (ethylene glycol) of 30g；

Toluene azeotropic method is utilized to remove trace water contained by tPBLG-b-PDMAPMA in a nitrogen atmosphere, tPBLG-b-PDMAPMA after obtaining except water, to utilize in anhydrous chloroform except the tPBLG-b-PDMAPMA after water is dissolved in, it is subsequently adding 2, the terminal methyl Polyethylene Glycol that 2'-dithio diethyl is isocyanate-modified, react 52 hours in 65 DEG C, the reaction system that reaction is concentrated to give after terminating, and with ether sedimentation, then dialyse 48 hours in distilled water, three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is obtained after lyophilizing；Wherein, terminal methyl Polyethylene Glycol that 2,2'-dithio diethyl are isocyanate-modified and except the mol ratio of three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide) after water is 25:1；Every 100 milliliters of anhydrous chloroforms dissolve 2g except the tPBLG-b-PDMAPMA after water；Reflux temperature during azeotropic water removing is 115 DEG C, except the water time is 5 hours；

7) synthesis of three-arm star-shaped hydrophilic copolymers:

Dry three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is dissolved in anhydrous chloroform, react 24 hours in 40 DEG C after dropping anhydrous hydrazine, after should terminating, the reaction system obtained is dialysed 2 days in the ammonia that mass concentration is 0.25%, last lyophilizing, obtains three-arm star-shaped hydrophilic copolymers；Wherein, anhydrous hydrazine is 20:1 with the mol ratio of benzyl protecting group in three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer；Every 100 milliliters of anhydrous chloroforms dissolve 22g three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer.

Embodiment 9:

1) with the step 1 of embodiment 6) identical；

2) with the step 2 of embodiment 6) identical；

By tPBLG under a nitrogen through toluene azeotropic water removing, tPBLG after obtaining except water, to be dissolved in anhydrous chloroform except the tPBLG after water, 4-cyano group-4-(thiobenzoyl) valeric acid, DMAP (DMAP) and dicyclohexylcarbodiimide (DCC) is added the most in a nitrogen atmosphere in 0 DEG C, precipitate with cold diethyl ether after 72 hours at room temperature reaction the most again, collect precipitation and be vacuum dried, obtain yellow solid product three arm poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent, i.e. tPBLG-CTA；Wherein, except tPBLG, 4-cyano group-4-(thiobenzoyl) valeric acid after water, the mol ratio of DMAP and DCC are 1:6:3:8, every 100 milliliters of anhydrous chloroforms dissolve 2.5g except the tPBLG after water；During azeotropic water removing, reflux temperature was 115 DEG C, except 4 hours water time；

4) with the step 4 of embodiment 6) identical；

5) with the step 5 of embodiment 6) identical；

6) with the step 6 of embodiment 6) identical；

7) dry three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is dissolved in anhydrous chloroform, react 24 hours in 40 DEG C after dropping anhydrous hydrazine, after should terminating, the reaction system obtained is dialysed 2 days in the ammonia that mass concentration is 0.25%, last lyophilizing, obtains three-arm star-shaped hydrophilic copolymers；Wherein, anhydrous hydrazine is 20:1 with the mol ratio of benzyl protecting group in three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer；Every 100 milliliters of anhydrous chloroforms dissolve 5g three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer.

Cold diethyl ether temperature in above-described embodiment 1-9 is subzero-20 DEG C, and vacuum drying temperature is at 30 DEG C, and freeze temperature is-40 DEG C, when reaction system concentrates, is concentrated to 1st/1 to two/3rds of original volume.

In the present invention 2,2'-dithio diethyl isocyanate-modified end the i.e. Application No. 201310229284.7 of methoxy poly (ethylene glycol) Chinese patent embodiment 4 step 3) the product 2,2'-isocyanate-modified Polyethylene Glycol of dithio diethyl.

Claims

1. the synthetic method of a three-arm star-shaped hydrophilic copolymers, it is characterised in that comprise the steps:

To be dissolved in anhydrous organic solvent, then at nitrogen gas except three arms after water poly-(Pidolidone-γ-benzyl ester) In 0 DEG C～4 DEG C RAFT agent, DMAP and two hexamethylenes added with a carboxyl under atmosphere Base carbodiimide, then precipitate with cold diethyl ether after room temperature reaction 24 hours～72 hours, collects precipitation true Empty dry, obtain three arms poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent；Wherein, after except water Three arms poly-(Pidolidone-γ-benzyl ester), the RAFT agent with a carboxyl, DMAP And the mol ratio of dicyclohexylcarbodiimide is 1:(6～20): 3:(6～60)；

2) conjunction of three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide) Become:

By poly-for three arms (Pidolidone-γ-benzyl ester) macromole RAFT agent, N-(3-dimethylamine propyl) first Base acrylamide, N hydroxymethyl acrylamide are dissolved in anhydrous dioxane, then add under oxygen-free environment Enter initiator, react 36 hours～72 hours in 60 DEG C～65 DEG C, the reaction that reaction is concentrated to give after terminating System, then precipitate in cold diethyl ether after dichloromethane dissolving, collect precipitation and be also vacuum dried, obtain three Arm star poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)；Wherein, three arm Poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent, N-(3-dimethylamine propyl) Methacrylamide And the mol ratio of N hydroxymethyl acrylamide is 1:(72～290): (3.6～14.4)；

3) three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-poly- Glycol copolymer synthesizes:

By except the three-arm star-shaped after water poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) metering system Amide) it is dissolved in anhydrous chloroform, it is subsequently adding 2, the end methoxy that 2'-dithio diethyl is isocyanate-modified Base Polyethylene Glycol, reacts 36 hours～72 hours in 60 DEG C～65 DEG C, and it is anti-that reaction is concentrated to give after terminating Answer system, and with ether sedimentation, then dialyse in distilled water, last lyophilizing, obtain the poly-(L-of three-arm star-shaped Glutamic acid-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer；Wherein, The end methoxy poly (ethylene glycol) of isocyanation esterification and except the three-arm star-shaped poly-(Pidolidone-γ-benzyl ester) after water-poly- The mol ratio of (N-(3-dimethylamine propyl) Methacrylamide) is (9～36): 1；

4) synthesis of three-arm star-shaped hydrophilic copolymers: by poly-for three-arm star-shaped (Pidolidone-γ-benzyl ester)-poly- (N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer carries out hydrazinolysis removing benzyl, obtains three Arm star hydrophilic copolymers.

The synthetic method of three-arm star-shaped hydrophilic copolymers the most according to claim 1, its feature exists In, described step 1) in poly-(Pidolidone-γ-benzyl ester) be to use following methods to prepare: by anhydrous Three (2-amino-ethyl) amine be dissolved in anhydrous organic solvent, add γ-benzyl ester-Pidolidone in a nitrogen atmosphere -N-carboxyanhydrides, stirring forms homogeneous solution, then in 25 DEG C～40 DEG C reactions 48 hours～72 little Time, the reactant liquor cold diethyl ether obtained is precipitated and washing with alcohol after terminating, obtains after vacuum drying by reaction Poly-(Pidolidone-γ-benzyl ester)；Wherein, anhydrous three (2-amino-ethyl) amine and γ-benzyl ester-Pidolidone-N- The mol ratio of carboxyanhydrides is (1:30)～(1:120), and step 1) in anhydrous organic solvent be Anhydrous dimethyl formamide, anhydrous chloroform or anhydrous tetrahydro furan.

The synthetic method of three-arm star-shaped hydrophilic copolymers the most according to claim 2, its feature exists In: described anhydrous three (2-amino-ethyl) amine is the backflow of hydrogenated calcium, and under nitrogen atmosphere, decompression is distilled Arrive.

The synthetic method of three-arm star-shaped hydrophilic copolymers the most according to claim 2, its feature exists In, described γ-benzyl ester-Pidolidone-N-carboxyanhydrides is synthesized by following steps: by Pidolidone-γ- Benzyl ester adds in anhydrous tetrahydro furan, adds triphosgene the most under nitrogen atmosphere, subsequently in 50 DEG C of reactions extremely Concentrate after forming settled solution, the reaction system obtained adds anhydrous n-hexane carry out after the most backward concentration Precipitation, the precipitation anhydrous n-hexane recrystallization that will obtain, obtain in γ-benzyl ester-Pidolidone-N-carboxyl ring Anhydride；Wherein, Pidolidone-γ-benzyl ester is 1:(0.35～0.4 with the mol ratio of triphosgene).

The synthetic method of three-arm star-shaped hydrophilic copolymers the most according to claim 1, its feature exists In, described step 4) method of hydrazinolysis removing benzyl is: by poly-for three-arm star-shaped (Pidolidone-γ-benzyl ester)- Poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer is dissolved in anhydrous organic solvent, drips React 18 hours～48 hours in 30 DEG C～40 DEG C after adding anhydrous hydrazine, the reactant that reaction will obtain after terminating Tie up to the ammonia that mass concentration is 0.25% is dialysed, last lyophilizing, obtain three-arm star-shaped hydrophilic copolymers； Wherein, anhydrous hydrazine and three-arm star-shaped poly-(Pidolidone-γ-benzyl ester)-poly-(N-(3-dimethylamine propyl) metering system Amide) mol ratio of benzyl protecting group is (3～20) in-ethylene glycol copolymer: 1.

The synthetic method of three-arm star-shaped hydrophilic copolymers the most according to claim 1, its feature exists In described step 1) in RAFT agent with a carboxyl be S-1-dodecyl-S'-(α, α '- Dimethyl-α "-acetic acid) trithiocarbonate, 4-cyano group-4-[(dodecyl sulfanyl thiocarbonyl group) sulfanyl] penta Acid, 4-cyano group-4-(thiobenzoyl) valeric acid or 4-cyanopentanoic acid dithiobenzoic acid.

The synthetic method of three-arm star-shaped hydrophilic copolymers the most according to claim 1, its feature exists In described step 2) in initiator be azodiisobutyronitrile or 4,4'-azo is double (cyanopentanoic acid), and Three arms poly-(Pidolidone-γ-benzyl ester) macromole RAFT agent is 1 with the mol ratio of initiator: (0.36～1.44).

The synthetic method of three-arm star-shaped hydrophilic copolymers the most according to claim 1, its feature exists In, described step 3) in 2, the isocyanate-modified end methoxy poly (ethylene glycol) of 2'-dithio diethyl is Adopt and synthesize with the following method: by end methoxy poly (ethylene glycol) that molecular weight is 800～4000Da, two Laurels Acid dibutyl tin and 2,2'-dithio diethyl isocyanates is dissolved in dry toluene, under 85 DEG C of blanket of nitrogen React 48 hours, in the reaction system obtained, add anhydrous n-hexane precipitate, collect precipitation the trueest Empty dry, i.e. obtain 2, the end methoxy poly (ethylene glycol) that 2'-dithio diethyl is isocyanate-modified；Wherein, End methoxy poly (ethylene glycol), dibutyl tin laurate and 2,2'-dithio diethyl isocyanates mole Ratio is 1:(0.02～0.08): (3～8).

9. three arm stars of the method synthesis that a kind uses in claim 1～8 described in any one claim Shape hydrophilic copolymers, it is characterised in that its chemical name be three-arm star-shaped poly-(Pidolidone-γ-hydrazides)- Poly-(N-(3-dimethylamine propyl) Methacrylamide)-ethylene glycol copolymer, chemical constitution is:

10. three-arm star-shaped hydrophilic copolymers as claimed in claim 9 is as loading amycin and gene The application of the carrier of medicine.