CN103865069B - There is active target star polymer carrier of physiological environment response function and preparation method thereof - Google Patents
There is active target star polymer carrier of physiological environment response function and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of active target star polymer carrier with physiological environment response function and preparation method thereof, this carrier has has special target function to tumour cell, and can respond intracellular reducing environment and fast degradation. This carrier material is amphiphilic star polymer, and hydrophilic segment material is that end is connected to the initiatively polyethylene glycol of target part; Hydrophobic segment is the star polycaprolactone that degradable absorbs; Between hydrophilic and hydrophobic segment, connect by the disulfide bond chemistry with physiological environment response function, form the star block copolymer of functionalization. Polymer of the present invention can be used as pharmaceutical carrier, forms the nano particle of drug loading in water by self assembly, can be used for the targeted therapy of tumour.
Description
Technical field
The present invention relates to a kind of preparation of the active target star polymer carrier with physiological environment response functionMethod, belongs to medicine controlled releasing technical field.
Background technology
The side effect of cancer therapy drug has seriously hindered its clinical practice. In order to address this problem, research at presentPersons' nano particles that adopt are as pharmaceutical carrier more, such as with nano-micelle bag medicine carrying thing, the master of this applicationWill be according to being, polymer micelle is to carry cancer therapy drug by the endocytosis of cell to enter cell, has got aroundP-glycoprotein, avoids medicine to outflow through exocytosis, thereby makes medicine can be had the swollen of drug resistance of wanting moreOncocyte absorbs in a large number, has improved therapeutic action and has greatly reduced toxic and side effect.
But polymer micelle is also faced with a lot of challenges in the application aspect of cancer therapy drug, is contemplated to be and makes to carryIn the blood circulation of medicine micella before arriving tumour cell, have good stability, can optionally be enriched in againTumor locus, and can discharge fast medicine in tumour cell inside. By cell-targeting and cytoplasmInterior controllable release cancer therapy drug is to reduce oncotherapy to normal cell damage and the pass that overcomes drug resistance problemKey. Therefore, prepare Stability Analysis of Structures, there is targeting and can respond environment in tumour cell and discharge fastThe polymer support of medicine is the focus of current oncotherapy research and technological development.
In the block copolymer structure design that forms micella, amphiphilic star-like polymer is except possessing general amphiphilicOutside the character of property linear block copolymers, because multiple segments are connected in a polyfunctional group core by covalent bondUpper, also have its special character. Star polymer is to pass through chemical bond-linking by least three linear polymer chainsReceive the multi-arm branched polymer forming on same centronucleus, compared with linear polymer, the uniqueness possessingCharacter comprises: molecular surface degree of functionality is high, and molecule chain end is with a large amount of senses for further modificationGroup; Strand not the viscosity of easy entanglement, solution and body be starkly lower than same molecular amount linear polymer,Degree of crystallinity is lower; More easily there is microphase-separated etc. in molecule. Comprehensive these features, with linear amphiphilic block copolymerThing is compared, and star copolymer is easier to form micella in water, also possesses better stability simultaneously.
Compared with human normal cell, most tumors cell surface presents the high expressed of some special receptors,Such as folacin receptor, galactosyl acceptor etc. Therefore, for the specific receptor of tumor cell surface, at medicineOn thing carrier material, connect some corresponding parts by chemical bond, by the special knot of this receptor-ligandClose, just can realize the active target function of pharmaceutical carrier. In addition, in tumour cell inside, glutathione containsAmount, far above the content in extracellular blood, is also greater than the concentration in normal cell. According to this physiologyEnvironmental characteristic, we can connect and have physiological environment response between the hydrophilic and hydrophobic segment of polymerThe disulfide bond of function, just can realize carrier cracking fracture fast under reducing condition in tumour cell, dischargesMedicine causes the quick apoptosis of tumour cell.
At present, Chinese patent application 200910273157.0 and 201110004873.6 has been announced and has been contained two sulphurThe preparation method of the copolymer of key, but do not relate to the target of carrier, and carrier polymer is not that star is poly-Compound. According to analysis above, these polymeric materials can not be realized the stability of carrier in blood circulation,Can not realize the targeted therapeutic to oncotherapy. But, in this individual system relating at us, IAccording to the physiological environment feature of tumour, designed one and can in blood circulation, keep stable, again can be rightQuick cracking broken height strand discharges anti-tumour cell target fast with responding reducing condition in cellThe star polymer carrier of tumour medicine. This carrier in vivo can also complete biodegradable.
Summary of the invention
The object of the invention is to provide a kind of active target star polymer with physiological environment response function and carriesThe preparation method of body. Make the star polymer of its acquisition ensure that carrier keeps stability in blood circulation.
A preparation method with the active target star polymer carrier of physiological environment response function, comprisesFollowing step:
(1) preparation of star polycaprolactone: taking stannous chloride as catalyst, add polyalcohol and caprolactone,Vacuumizing after 3 hours, spend ring-opening polymerisation in temperature 150, react 6 hours blending theory molecular weight 8000Star polycaprolactone, after product is cooling, dissolve with carrene, precipitating in a large amount of ice ethanol, suction filtration,Product vacuum drying, obtains the preparation of star polycaprolactone;
(2), star polycaprolactone end is introduced disulfide bond: ring-type dithio dipropyl acid anhydrides and (1) gainedThe reaction of star polycaprolactone terminal hydroxyl, with dimethyl formamide, DMF makees solvent, adds 4-dimethylaminoPyridine DMAP and triethylamine catalytic reaction are carried out, under 35 degree water bath condition, and stirring reaction 24h; InsteadAfter should finishing, carry out acidification reaction liquid with 0.1M watery hydrochloric acid, reactant liquor poured in the long-pending distilled water of hexaploid,With the long-pending dichloromethane extraction of dliploid three times, collect dichloromethane layer, add anhydrous sodium sulfate to dewater, mistakeAfter filter, clear filtrate is revolved to steaming, ice ether precipitating, suction filtration, be able to molecular formula PER-(PCL-SS-COOH) 4For the amphiphilic block copolymer of main body;
(3), the formation of amphiphilic star-like block copolymer: the hydrophobic segment product that takes 1 equivalent(PER-(PCL-SS-COOH) 4) is dissolved in a certain amount of DMF, by this solution with constant pressure funnel slowlySplash in the DMF solution of 8～10 equivalent amination PEG, under catalyst n HS and DCC existence,Connect into amphipathic block copolymer by amido link, reacting liquid filtering, rotary evaporation, ice ethanol precipitating,Obtain amphiphilic star-like block copolymer;
(4), there is the preparation of the active target star polymer carrier of physiological environment response function: after activationThe amphiphilic block copolymer prepared with previous step of target material react with equivalent proportion 4:1, stirring at room temperature 24H, solvent is methyl-sulfoxide DMSO; After reaction finishes, with the dialysis of 1000 grams/mol of molecular cut offsBag dialysis 3 days, after dialysis finishes, freeze drying obtains final goal product.
Cheap being easy to get of raw material of the inventive method, method is ripe simple, and application prospect is wide. Each step relating toRapid and method, those skilled in the art all can realize.
The present invention also aims to the object obtaining with above-mentioned means.
An active target star polymer carrier with physiological environment response function, this carrier material is toolHave the amphiphilic star polymer of four arms or six arm star structures, hydrophilic segment material is that end is connected to initiatively targetTo the polyethylene glycol of part; Hydrophobic segment is the star polycaprolactone that degradable absorbs; Hydrophilic and hydrophobic segmentBetween connect by the disulfide bond with physiological environment response function, form the star block copolymerization of functionalizationThing, this polymer can be used as pharmaceutical carrier, forms the nanometer of drug loading in water by self assemblyGrain, for the targeted therapy of tumour.
Like this, the introducing of targeted molecular is enriched in around tumour cell carrier micelle selectively, and logicalCross receptor mediated endocytosis and enter tumour cell; Polymer hydrophilic and hydrophobic segment between connectThere is the disulfide bond of physiological environment response function, can make carrier under reducing condition, split fast in tumour cellSeparate fracture, discharge medicine and cause the quick apoptosis of tumour cell. Hydrophobic segment key component is polycaprolactone composition,Complete biodegradable in vivo. Therefore, this carrier can improve the result for the treatment of of tumour, simultaneously canReduce the toxic and side effect of medicine.
Brief description of the drawings
The synthetic route of Fig. 1 star polycaprolactone.
The synthetic route of Fig. 2 amphiphilic star-like block copolymer.
The synthetic route of Fig. 3 target material.
Detailed description of the invention
(1) preparation of star polycaprolactone (synthetic route is as shown in Figure 1): taking stannous chloride as catalyst,Polyalcohol is the core of star structure. Conventionally,, for the pentaerythrite of 1 equivalent, drop in oneself of 70 equivalentsEster, the stannous chloride of gross mass 1%, makes the star polycaprolactone of blending theory molecular weight 8000. Taking out veryAfter empty 3 hours, spend ring-opening polymerisation in temperature 150, react 6 hours. After product is cooling, with carreneDissolve, precipitating in a large amount of ice ethanol, suction filtration, product vacuum drying, obtains four arm polycaprolactones.
In above preparation process, the molecule of the core as hub-and-spoke configuration using, can be glycerine, seasonThe one of this class polyalcohol of penta tetrol and bipentaerythrite, what form respectively is the star of three arms, four arms and six armsShape structure. Designed this section star polymer theoretical molecular can be 500 to 10000.
(2) preparation of dithiodipropionic acid cyclic acid anhydride: a certain amount of dithiodipropionic acid temperature in chloroacetic chloride65 spend back flow reaction, can obtain the ring-type inner-acid anhydride of dithiodipropionic acid.
(3) star polycaprolactone end is introduced disulfide bond: above-mentioned synthetic ring-type dithio dipropyl acid anhydrides and starShape polycaprolactone terminal hydroxyl can react, and makees solvent with dimethyl formamide (DMF), adds 4-diformazan ammoniaYl pyridines (DMAP) and triethylamine catalytic reaction are carried out, under 35 degree water bath condition, and stirring reaction 24h.After reaction finishes, carry out acidification reaction liquid with 0.1M watery hydrochloric acid. Pour reactant liquor into hexaploid long-pending distilled waterIn, with the long-pending dichloromethane extraction of dliploid three times. Collect dichloromethane layer, add anhydrous sodium sulfate to dewater.Filter, clear filtrate is revolved to steaming, ice ether precipitating, suction filtration, obtain product. Product molecular formulaPER-(PCL-SS-COOH)4。
(4) preparation of bisamination polyethylene glycol: adopt Gabriel method to carry out the amination of polyethylene glycol.For the method for PEG double-end amino, also can use other ripe amination methods, for example, use PEGAfter the PEG of synthetic sulfonylation, in high temperature and high pressure kettle, react with ammoniacal liquor.
(5) formation of amphiphilic star-like block copolymer (as shown in synthetic route Fig. 2): according to such scheme,The hydrophobic segment product (PER-(PCL-SS-COOH) 4) that takes 1 equivalent is dissolved in a certain amount of DMF, and this is moltenLiquid slowly splashes in the DMF solution of 8～10 equivalent amination PEG, at catalyst with constant pressure funnelNHS and DCC connect into amphipathic block copolymer by amido link under existing. Reacting liquid filtering, revolveTurn evaporation, ice ethanol precipitating, obtain product.
(6) preparation of target material: the source of targeted molecular can be the one in folic acid and galactose molecule,Its acceptor all has the situation at human body tumour cell surface overexpression.
(a) preparation of folate-targeted material (as shown in synthetic route Fig. 3): folic acid is through the NHS of equivalentActivate under ice-water bath condition with DCC. Amphiphilic block copolymer prepared by the folic acid after activation and previous step withEquivalent proportion 4:1 reaction, stirring at room temperature 24h, solvent is methyl-sulfoxide (DMSO). After reaction finishes,With the bag filter dialysis of 1000 grams/mol of molecular cut offs 3 days. After dialysis finishes, freeze drying obtains finallyProduct, has folate-targeted group and has the star polymer of disulfide bond.
(b) preparation of galactolipin target material: preparation method and upper same, change folic acid into lactobionic acid, just canObtain galactolipin target group and have the star polymer of disulfide bond.
Embodiment 1
Take 0.17 gram of pentaerythrite, 10 restrain oneself lactone and 0.1 gram of stannous chloride, are placed in single port bottle,Vacuumize after 3h, ring-opening polymerisation under temperature 150 degree conditions, took out after 6 hours, treated that product is from meltingBe cooled to solid state, add 5mL carrene to make to dissolve, splash into precipitating in 250mL ice ethanol,Suction filtration, vacuum drying, obtains four arm polycaprolactones.
Take 2 grams of dithiodipropionic acids, add 20 grams of chloroacetic chlorides, spend back flow reaction in temperature 65, magnetic forceStir after 4h, rotary evaporation is removed majority of organic solvent, with ice ether precipitating, suction filtration, vacuum drying,Obtain.
Take 1 part of dithio dipropyl acid anhydrides and 5.2 grams of above-mentioned star polycaprolactones, join 70mLIn DMF, catalyst DMAP0.3176 gram, triethylamine 0.4mL, spends under water bath condition in temperature 35,Stirring reaction 24h. After reaction finishes, using the 0.1M salt acid for adjusting pH value configuring is 5, then willThis reactant liquor is poured in the long-pending distilled water of hexaploid, with the long-pending dichloromethane extraction of dliploid, and coextraction three times.Collect bottom dichloromethane layer, add anhydrous sodium sulfate to dewater. Treat liquid level clarification, filter out sodium sulphate,Filtrate is revolved to steaming, and a large amount of ice ether precipitatings, suction filtration, obtain product. Product molecular formulaPER-(PCL-SS-COOH)4。
Claim the polyethylene glycol (PEG) of 3 grams of bisaminations to be dissolved in 50mLDMF, be placed in there-necked flask,Claim in addition 1.2 grams of hydrophobic segment product P ER-(PCL-SS-COOH) 4 to be dissolved in 30mLDMF, by thisSolution slowly splashes in the DMF solution of amination polyethylene glycol, adds NHS and the DCC of catalytic amount,Room temperature reaction 24h. Reacting liquid filtering, revolve steaming, a large amount of ice ethanol precipitating, suction filtration, in triplicate, vacuumThe dry star amphipathic nature block polymer product that obtains.
Claim 0.022 gram of folic acid, 0.0103 gram of DCC, 0.0058 gram of NHS, adds 20mL diformazan AsiaMagnetic agitation 12h in sulfone (DMSO), front 2h carries out under ice-water bath condition. Deserve to be called step synthetic3 grams of star amphipathic nature block polymer products, be dissolved in 50mLDMSO the folic acid solution having activatedSplash in this polymer solution reaction 24h. After reaction finishes, with 1000 grams/mol of molecular cut offsBag filter dialysis 3 days, freeze drying obtains end product: the active target four with physiological environment response functionArm star polymer carrier.
Embodiment 2
This example is that the pentaerythrite in embodiment 1 is changed and does bipentaerythrite, the bipentaerythrite of input and oneselfThe ratio of lactone is 1:105, and other implementation methods embodiment 1 obtains the radial copolymer of six arms with this.
Embodiment 3
This example is that the folate molecule in embodiment 1 is changed and does lactobionic acid additive method with embodiment 1, Ke YiheBecome to obtain galactolipin target group and have the star four arm polymer of disulfide bond.
Embodiment 4
This example is that the folate molecule in embodiment 1 is changed and does lactobionic acid, and pentaerythrite changes and does bipentaerythrite, otherMethod, with embodiment 1, can be synthesized star six arms that obtain galactolipin target group and have disulfide bond poly-Compound.
Claims (5)
1. one kind has the preparation side of the active target star polymer carrier of physiological environment response functionMethod, comprises following step:
(1) preparation of star polycaprolactone: taking stannous chloride as catalyst, add in polyalcohol and oneselfEster, vacuumized after 3 hours, in 150 DEG C of ring-opening polymerisations of temperature, reacted and synthesized for 6 hoursThe star polycaprolactone of theoretical molecular 8000, after product is cooling, dissolves with carrene,Precipitating in a large amount of ice ethanol, suction filtration, product vacuum drying, obtains the system of star polycaprolactoneStandby;
(2), star polycaprolactone end is introduced disulfide bond: ring-type dithio dipropyl acid anhydrides and (1)The reaction of gained star polycaprolactone terminal hydroxyl, with dimethyl formamide, DMF makees solvent, addsEnter DMAP DMAP and triethylamine catalytic reaction is carried out, at 35 DEG C of water-bath barsUnder part, stirring reaction 24h; After reaction finishes, carry out acidification reaction liquid with 0.1M watery hydrochloric acid,Reactant liquor is poured in the long-pending distilled water of hexaploid, with the long-pending dichloromethane extraction of dliploid three times,Collect dichloromethane layer, add anhydrous sodium sulfate to dewater, after filtration, clear filtrate is revolved to steaming, iceEther precipitating, suction filtration, be able to the amphiphilic that molecular formula PER-(PCL-SS-COOH) 4 is main bodyBlock copolymer;
(3), the formation of amphiphilic star-like block copolymer: the hydrophobic segment product that takes 1 equivalent(PER-(PCL-SS-COOH) 4) is dissolved in a certain amount of DMF, by this solution constant voltage dropping liquidFunnel slowly splashes in the DMF solution of 8～10 equivalent amination PEG, at catalystNHS and DCC connect into amphipathic block copolymer by amido link under existing, reactionLiquid filtration, rotary evaporation, ice ethanol precipitating, obtain amphiphilic star-like block copolymer;
(4), there is the preparation of the active target star polymer carrier of physiological environment response function: liveThe amphiphilic block copolymer that target material after change is prepared with previous step reacts with equivalent proportion 4:1,Stirring at room temperature 24h, solvent is methyl-sulfoxide DMSO; After reaction finishes, use molecular cut offThe bag filter dialysis of 1000 grams/mol 3 days, after dialysis finishes, freeze drying obtains final goalProduct.
2. method according to claim 1, is characterized in that, described polyalcohol is Ji WusiAlcohol, in step (1), the weight ratio that feeds intake of pentaerythrite and caprolactone is 1.7:100.
3. method according to claim 1, is characterized in that, described polyalcohol is two seasons pentaTetrol, in step (1), the weight ratio that feeds intake of bipentaerythrite and caprolactone is 1:105.
4. method according to claim 1, is characterized in that, described target material is folic acidWith one of galactolipin.
5. there is an active target star polymer carrier for physiological environment response function, this carrierMaterial is the amphiphilic star polymer with four arms or six arm star structures, hydrophilic segment materialFor end is connected to the initiatively polyethylene glycol of target part; Hydrophobic segment is the star that degradable absorbsPolycaprolactone; Between hydrophilic and hydrophobic segment by thering is the disulfide bond of physiological environment response functionConnect, form the star block copolymer of functionalization, this polymer can be used as pharmaceutical carrier,In water, form the nano particle of drug loading by self assembly, for the targeted therapy of tumour,It is characterized in that, adopt the method for claim 1 or 2 or 3 or 4 to make.
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| CN105968370B (en) * | 2016-06-22 | 2019-05-24 | 国家纳米科学中心 | The polyethylene glycol polycaprolactone triblock polymer and its preparation method and application of triple disulfide bond connections |
| CN108299649B (en) * | 2017-01-13 | 2021-06-15 | 上海干云生物科技有限公司 | Multi-arm star-shaped block polymer and preparation method and application thereof |
| CN107744503B (en) * | 2017-08-14 | 2020-04-07 | 浙江工业大学 | Preparation method of enzyme-sensitive amphiphilic polyester MePEG-Peptide-PER-CL administration nanoparticle |
| CN115191428B (en) * | 2022-07-25 | 2023-08-22 | 西安交通大学 | Amphiphilic star-type polymer-loaded pesticide preparation and preparation method thereof |
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