CN102432783B - PH response/hydrophobic group random copolymerization polymer, and preparation method and application thereof - Google Patents

PH response/hydrophobic group random copolymerization polymer, and preparation method and application thereof Download PDF

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CN102432783B
CN102432783B CN 201110269496 CN201110269496A CN102432783B CN 102432783 B CN102432783 B CN 102432783B CN 201110269496 CN201110269496 CN 201110269496 CN 201110269496 A CN201110269496 A CN 201110269496A CN 102432783 B CN102432783 B CN 102432783B
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reaction
hydrophobic group
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CN102432783A (en
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章莉娟
杨友强
林文静
郭新东
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South China University of Technology SCUT
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Abstract

The invention discloses a pH response/ hydrophobic group random copolymerization polymer, and a preparation method and application thereof. A hydrophobic group and pH response group random copolymer is obtained through electron transfer activator regeneration-atom transfer radical polymerization and ring-opening polymerization, and a pH response amphiphilic polymer brush is prepared by triggering the activators regenerated by electron transfer (ARGET) atom transfer radical polymerization (ATRP) of hydrophilic macromolecule monomers by the hydrophobic group and pH response group random copolymer used as macroinitiator, and performing selective hydrolysis reaction. The proportion of functional groups in the polymer molecule is easy to adjust and control; and a synthesis process is simple and the yield is high. Polymer micelle with an inner core formed by hydrophobic groups and a pH response groups, and an outer shell formed by hydrophilic groups can be obtained by a dialysis method; and a water insoluble medicament can be entrapped in the inner core of the micelle, the medicament can be subjected to sustained release in gastric juice, and can be released quickly and controllably under intestinal canal conditions.

Description

A kind of pH response/hydrophobic group random copolymerization polymer and method for making and application
Technical field
The present invention relates to biological medicine and use the macromolecule polymer material field, be specifically related to a kind of pH response/hydrophobic group random copolymerization polymer and method for making and application.
Background technology
As everyone knows, thus oral due to low, the dosage of cost flexibly adjustable, easy to use, can be used for the outpatient and can provide better patient's tolerance effectively to improve result for the treatment of, thereby be easier to be accepted by patient.Yet, hydrophobic or the poorly water-soluble (as camptothecine, taxol, nifedipine etc.) due to the medicine that surpasses half, cause that oral rear optical density is poor, bioavailabilities in stomach and intestine are low, thereby use for the oral administration of this class medicine and still face huge challenge.
The nano core-shell structure micella that is formed by amphipathic multipolymer, has lot of advantages, as it can provide in body, external satisfactory stability, improve the apparent water-soluble of medicine, provide passive and active target ability, can avoid engulfing or being absorbed by tissues such as liver spleens of the interior reticuloendothelial system (RES) of body, change the approach of medicine body-internal-circulation etc., these all be conducive to extend micella in blood cycling time and in the accumulation at tumor tissues position, improve medicine in the activity of privileged site, thereby effectively improve drug effect, reduce side effect.In addition, polymer micelle has lower micelle-forming concentration, larger solubilising space, Stability Analysis of Structures, and the different properties according to the polymer hydrophobic segment can by effect packaging medicines such as chemistry, physics and static, have obvious solubilizing effect to poorly water soluble drugs.With the oral carrier of polymer micelle as poorly water soluble drugs, can control the release of medicine.
The variation that the oral medicine-carried system of a success should be resisted enzyme, can bear again pH.PH responsive polymer micella is owing to keeping dense structure under the low pH environment of gastric juice, reduce the seepage of medicine in gastric juice, and thereby swelling occuring under the intestinal juice environment or dissociates promotes that medicine discharges fast, avoid medicine in the sedimentation of small intestine epithelium tissue, thereby be considered to the desirable oral carrier of insoluble drug.The pH value of human gastric juice is 1.0-2.5, and the pH value in small intestine is 5.1-7.8(Advanced Drug Delivery Reviews, 2007; 59:1121).The p of the carboxylic acids such as polyacrylic acid (PAA), polymethyl acrylic acid (PMAA) K aValue is 5-6, is the maximum pH responsive polymer of report.Along with environment pH changes, this base polymer occurs to change mutually, causes that its micellar structure changes, thereby realizes that medicine-carried system keeps stable under the gastric juice environment, and release efficiency preferably arranged enteron aisle pH environment is next, therefore can be used as the oral way administration and require carrier in the enteron aisle release.Can promote mucous membrane absorption ionizable carboxyl in its structure is distributed in the micella shell after forming micella in, thereby extend carrier micelle, the residence time in enteron aisle, release fully and the absorption of promotion medicine be arranged.
(the Journal of Controlled Release such as Kim, 2008,132:222) synthesized a kind of PEG derivative of wetting ability three blocks, utilize polyacrylic ion/protonation to prepare the nano-micelle that carries taxol, and claim this polymer micelle system to can be used as the oral preparations of taxol.(the International Journal of Pharmaceutics such as Korea S Lee, 2009,375:163) reported petal-shaped micella by the preparation of a kind of polylactic acid-polyglycol-polylysine triblock polymer, utilize Methionin protonated/deprotonation realizes the pH response of Zorubicin is controlled and discharges.(the Journal of Controlled Release such as Canada Sant, 2004,97:301) prepared a kind of nano-micelle that is consisted of by the polyethylene glycol-methacrylic acid derivative, as the oral delivery systme of insoluble drug, utilize the control release that ion/the protonation realization responds environment pH of methacrylic acid.The Sethuraman of Univ Utah USA etc. (Pharmaceutical Research, 2008,25:657) reported a kind of polymer medicament carrying micelle system of coming response environment pH value to change by electrostatic interaction, the target that is used for cancer therapy drug discharges.(the Polymer such as the Huang of Wuhan University, 2009,50:3706) synthesized the poly acrylic acid-poly lactic acid block copolymer, and carry the hydrophobic drug Prednisone acetate with its micella bag, this carrier micelle discharges under strong acidic condition slowly, therefore and release rate is obviously accelerated under neutrality or slightly acidic condition, thinks that this polymer micelle is suitable as the oral package carrier system of insoluble drug.
Patent application WO2008147128-A1, KR2008105005-A, EP2150568-A1 have announced a kind of nanoparticle with pH, temperature dual response function by the monomethoxypolyethylglycol glycol derivative preparation.Patent IN200702360-I3 has announced a kind of pH responsiveness oral tablet with methacrylic acid derivative composition dressing, medicine metoprolol and salt thereof are loaded in kernel by bag, methacrylic derivative with pH responsiveness is coated on the surface, and this tablet can be used as oral control delivery systme.Patent application WO2010018286-A1, ES2333087-A1 have announced the micella that a kind of branch-shape polymer that is connected by polyoxyethylene glycol and linear polyhistidyl form by electrostatic interaction, and with its carrier for medicine and diagnostic reagent.By the pH value that changes environment, the electrically charged character of polyhistidyl is changed, the structure of regulation and control micella realizes that the bag of pH response carries and discharges.Patent application US2005070721-A1, US7229973-B2 have announced a kind of mixed micelle by polylactic acid-polyglycol and the preparation of polyethylene glycol-Histidine, and have shown that this micella has the tumor-targeting function of pH response.KR2009056478-A has announced a kind of degradable polymer that is comprised of urethane derivative main chain and pH responsiveness side chain, and it can be used for the treatment of tumour, inflammation and other diseases by the form of micella or gel as the carrier of the components such as medicine, polypeptide, nucleic acid, protein.
The hydrophilicity of micellar surface is extremely important for keeping its stability, and existing its shell surface hydrophilic group of most of micellar system is more sparse, and this makes the performance steady in a long-term of carrier micelle to be guaranteed.And the polymer molecule brush is the higher graft copolymer of a kind of grafting density, and it can effectively strengthen micella shell density, thereby well solves this difficult problem.Nano-micelle by the self-assembly of hydrophilic polymer brush, micella shell density is high, can strengthen the wetting ability of micellar surface, anti-albumen and thrombocyte adsorptive power, improves the stability of micella, extend the loop cycle of micella, thereby improve the controlled release properties of micelle medicine carrying system.The synthetic method that mostly adopts surface graft modification of present polymer brush.Patent application EP1035218-A, WO200043539-A, EP1144677-A, WO200043539-A1 have announced a kind of method at surface grafting polymerization thing brush, and successfully this polymer brush are used for absorption polypeptide, polysaccharide and nucleic acid.Patent application WO200102452-A, EP1208126-A, WO200102452-A1, AU200057854-A have announced a kind of polymer brush in the stromal surface grafting, and this polymer brush are used for detection and the absorption of the aqueous sample biomolecules such as tissue, blood.
There is the investigator to begin the polymer molecule brush is applied to the transmission of chemicals.(the AIChE Journal such as Shen of U.S. university of Wyoming, 2008,54:2979) prepare a kind of three layers with polycaprolactone-polymethyl acrylic acid-2-(N, N-dimethylamino) ethyl ester-polyoxyethylene glycol (PCL-PDEAEMA-PEG) copolymer brush and carried the Zorubicin micella.This multilayer drug-loaded micella at pH greater than the 7(healthy tissues) time kept stable, and as pH lower than the 6.5(tumor tissues) time because PDEAEMA is protonated, make the carrier micelle swelling and discharge Zorubicin.This multilayer drug-loaded micella can be avoided the violent release phenomenon, but it is limited by its multilayered structure to the response sensitivity that environment pH changes, thereby can not well regulate and control its release performance.Patent application CN101235121-A has announced a kind of by with mono methoxy polyethylene glycol and vinylformic acid carboxylic acid halides reaction preparation macromonomer, then prepares polymer brush by radical polymerization, and it is prepared into particle as pharmaceutical carrier.The Hu of NUS etc. (Macromolecular Rapid Communications, 2009,30:609) at Fe 3O 4The magnetic kernel surface connects the polylactide of two blocks-polymethyl acrylic acid macrogol ester (PLLA-PPEGMA) polymer brush and has prepared nanoparticle, and the modified with folic acid by the surface is to strengthen its target ability, result shows that this nanoparticle has stronger target penetrativity to tumor tissues, and the bag that can be applicable to cancer therapy drug carries and controlled release.
Report from existing research, the polymer micelle medicine carrying system that is applied at present the oral system of insoluble drug also is far from reaching gratifying performance.How to keep alleviation or the prominent phenomenon of releasing of elimination under the prerequisite of high drug load; How to improve medicine-carried system the response accuracy that environment pH changes is also controlled the efficient that discharges, this is current two topmost difficult problems that face.In conventional medicine-carried system, its drug-loaded layer and pH response layer have certain space length, make the process of pH response-micella swelling-drug release of micella slow, thereby accurate not and sensitive to the response of environment pH variation, if respond group and increase too much pH, its Drug loading capacity is descended, and prominently release phenomenon and also can aggravate.
Summary of the invention
In order to address the above problem, the bag that improves poorly water soluble drugs oral delivery Systems balanth, response sensitivity, medicine carries efficient and controls release performance, the present invention designs the amphipathic nature polyalcohol molecular brush of synthetic a kind of pH response/hydrophobic grouping random copolymerization, and its self-assembled micelle is used for the oral drug-loading system of poorly water soluble drugs.
General plotting of the present invention is as follows: hydrophobic material and pH responsive materials are designed to the random copolymerization form, then form bi-block copolymer molecular brush structure with hydrophilic PEGMA.The amphipathic nature polyalcohol molecular brush structure of this pH response/hydrophobic grouping random copolymerization can increase pH response region in its self-assembled micelle, under the prerequisite of high drug load, effectively alleviation is prominent releases keeping, make pH response-micella swelling-drug release be rendered as a synchronous process, thereby improve pH response sensitivity and the release efficiency of micella, improve the controlled release properties of micelle medicine carrying system, also can effectively solve simultaneously the halfway problem of drug release that exists in material in the past.And this constitutional features of brush shape of hydrophilic block is conducive to improve micella shell density, strengthens wetting ability, anti-albumen and the thrombocyte adsorptive power of micellar surface, improves the stability of micella, thereby extends micella cycling time in vivo.After the carrier micelle oral administration, due to pH response block, as hydrophobic in PMAA in the gastric juice environment; the micella kernel is tight, Stability Analysis of Structures; release amount of medicine is few, thus protection medicine (its reason is that most insoluble drugs are unstable under strong acidic condition, easily decomposes).Enter in enteron aisle, MAA is protonated, and negative electricity on the micellar surface band can be adsorbed on enteron aisle the carrier micelle residence time is obviously extended, and the protonated micella generation swelling that makes of MAA, and drug release rate is accelerated.Can by the content of pH response block in the telomerized polymer brush material, adapt to different release requests.As, for the medicine that can directly absorb in enteron aisle, require carrier micelle to discharge fast medicine in several hours after entering intestinal juice, and then be absorbed.And for the cancer resistance medicine, the nano drug-carrying micella discharges medicine with stable speed in blood circulation in intestinal epithelial cell is ingested blood environment, thereby needs the longer Stable Release time.
The present invention is achieved through the following technical solutions: first synthetic terminal hydroxy group monomer and pH respond the random copolymerization block of monomer, the ring-opening polymerization of recycling pendant hydroxyl group grafting lactone obtains brushing the shape hydrophobic grouping, the polymerization of carrying out subsequently hydrophilic macromonomer obtains the polymer molecule brush, and the tertiary butyl hydrolysis that pH is responded monomer namely obtains pH response amphipathic nature polyalcohol molecular brush material.This polymer molecule brush self-assembly in the aqueous solution is nano-micelle, the effective solubilization poorly water soluble drugs.
Concrete technical scheme is as follows:
A kind of pH response/hydrophobic group random copolymerization polymer, structural formula is
Figure 2011102694969100002DEST_PATH_IMAGE002
Wherein, R 1For
Figure 2011102694969100002DEST_PATH_IMAGE004
, R 2And R 3Be methyl or hydrogen, R 4For
Figure DEST_PATH_IMAGE006
, Or
Figure DEST_PATH_IMAGE010
, T is Br or Cl; X=5 ~ 15, y=35 ~ 140, z=5 ~ 33, m=5,9 or 20, n 1=7 ~ 26, n 2=4 ~ 14, n 3=5 ~ 16.
The number-average molecular weight of described pH response/hydrophobic group random copolymerization polymer is 12000 ~ 30000 g/mol.
Described hydrophobic grouping
Figure DEST_PATH_IMAGE012
With pH response group
Figure DEST_PATH_IMAGE014
Consist of the random copolymerization block.
The preparation method of described a kind of pH response/hydrophobic group random copolymerization polymer comprises the following steps:
(1) preparation macromole evocating agent A: under protection of inert gas and anhydrous condition, with terminal hydroxy group monomer, pH response monomer, catalyst system A, reductive agent, initiator and solvent, react 0.5 ~ 4 h under 60 ~ 90 ℃, after Removal of catalyst, precipitation, filtration, drying obtain macromole evocating agent A;
(2) grafted hydrophobic group: the macromole evocating agent A with hydrophobic monomer, catalyst system B and step (1) under protection of inert gas and solvent exist mixes, react 24 ~ 48 h under 100 ~ 130 ℃, through precipitation, filtration, the dry macromole evocating agent B that gets grafted hydrophobic group;
(3) preparation amphipathic nature polyalcohol molecular brush: the macromole evocating agent B and the solvent that under protection of inert gas, hydrophilic macromonomer, catalyst system A, reductive agent and step (2) are obtained, react 12 ~ 36 h under 30 ~ 90 ℃, after Removal of catalyst, precipitation, filtration, oven dry obtain the amphipathic nature polyalcohol molecular brush;
(4) preparation pH response/hydrophobic group random copolymerization polymer: step (3) product, trifluoroacetic acid are dissolved in reaction 15 min in 0 ℃ of methylene dichloride, then react 12 ~ 36 h under 25 ℃, obtain pH response/hydrophobic group random copolymerization polymer;
In described step (1), the parts by weight of reactant are as follows:
6 ~ 13 parts of terminal hydroxy group monomers
77 ~ 90.2 parts of pH response monomers
1 ~ 5 part of catalyst system A
1 ~ 3 part of initiator
1 ~ 6 part of reductive agent;
In described step (2), the parts by weight of reactant formula is as follows:
54.3 ~ 74.6 parts of macromole evocating agent A
25.3 ~ 45.64 parts of hydrophobic monomers
0.02 ~ 0.4 part of catalyst system B;
In described step (3), the parts by weight of reactant formula is as follows:
22.4 ~ 37.6 parts of hydrophilic macromonomers
0.2 ~ 0.6 part of catalyst system A
0.2 ~ 1.1 part of reductive agent
62 ~ 76 parts of macromole evocating agent B;
In described step (4), the parts by weight of reactant formula is as follows:
5 ~ 9 parts of amphipathic nature polyalcohol molecular brush
8 ~ 34 parts of trifluoroacetic acids
57 ~ 87 parts of methylene dichloride.
Described terminal hydroxy group monomer is hydroxyethyl methylacrylate or Hydroxyethyl acrylate;
Described pH response monomer is Tert-butyl Methacrylate or tert-butyl acrylate;
Described hydrophobic monomer is mixture, rac-lactide or the e-caprolactone of rac-lactide and glycollide;
Described initiator is the 2-isobutyl ethyl bromide;
Described hydrophilic macromonomer is methacrylic acid mono methoxy polyethylene glycol ester, and its structural formula is as follows:
Figure DEST_PATH_IMAGE016
M=5,9 or 20 wherein.
Catalyst system A described in step (1) and (3) is the complex compound of cupric bromide or cupric chloride and dipyridyl, five methyl diethylentriamine or three (2-pyridylmethyl) amine; Be preferably the complex compound of cupric bromide and five methyl diethylentriamine;
Step (1) and (3) described reductive agent are stannous octoate;
Step (1) and (3) described solvent are toluene or methyl-phenoxide; Be preferably toluene;
The described catalyst system B of step (2) is stannous octoate;
The described solvent of step (2) is toluene.
Step (1) and (3) described Removal of catalyst are after reaction product is dissolved with tetrahydrofuran (THF), to cross the neutral alumina chromatography column and remove catalyzer, adopt tetrahydrofuran (THF) as eluent;
Precipitation described in step (1) and (2) is that the solution after Removal of catalyst is joined in the mixing solutions of 0 ℃ of cold methanol being equivalent to 10 times of its volumes and water, and cold methanol and water volume ratio are 1:1;
Step (3) and (4) described precipitation are that the solution after Removal of catalyst is joined in the 0 ℃ of cold normal hexane that is equivalent to 10 times of its volumes.
The application of described a kind of pH response/hydrophobic group random copolymerization polymer in the micelle medicine carrying system of preparation poorly water soluble drugs.
The micelle medicine carrying system of described poorly water soluble drugs is that pH response/hydrophobic group random copolymerization polymer and poorly water soluble drugs are dissolved in organic solvent, with pH damping fluid dialysis 24 h postlyophilizations, obtains micelle medicine carrying system after stirring 6 h.
Described organic solvent is dimethyl formamide, dimethyl sulfoxide (DMSO) or acetone.
Described pH damping fluid is that the pH value is 2 ~ 4 hydrochloric acid or acetate buffer solution.
Described poorly water soluble drugs is the medicine that solubleness is less than or equal to 1 g in 1 L water.
The mol ratio of the described catalyst system A in step (1) and (3) and initiator or macromole evocating agent B is 0.01 ~ 0.1, is preferably 0.04 ~ 0.06;
The mol ratio 0.1 ~ 1 of step (1) and (3) described reductive agent and initiator or macromole evocating agent B is preferably 0.4 ~ 0.6;
The described catalyst system B of step (2) is stannous octoate, and its consumption is 0.05% ~ 1% of hydrophobic monomer quality, is preferably 0.1% ~ 0.5%;
Temperature of reaction in described step (1) is preferably 70 ~ 80 ℃, and the reaction times is preferably 2 ~ 3 h;
Temperature of reaction in described step (2) is preferably 100 ~ 110 ℃, and the reaction times is preferably 24 ~ 30 h;
Temperature of reaction in described step (3) is preferably 60 ~ 70 ℃, and the reaction times is preferably 18 ~ 24 h;
The mol ratio of described step (4) trifluoroacetic acid and pH response monomer is 1:(5 ~ 10), be preferably 1:(8 ~ 10), the reaction times is preferably 12 ~ 24 h.
Micelle medicine carrying system can be used for Oral administration, slowly discharges in the acidic gastric juice environment by intestines and stomach pH difference regulation and control medicine, discharges fast in nearly neutral intestinal environment.
The invention has the beneficial effects as follows: the present invention designs amphipathic nature polyalcohol molecular brush and the oral drug-loading system of self-assembled micelle thereof of synthetic pH response/hydrophobic grouping random copolymerization, hydrophobic brush shape group and pH response group are designed to the random copolymerization form, both can keep high drug load, can increase again pH responding range in its self-assembled micelle, make the rapidly variation of response environment pH value of micella, release and discharge the phenomenons such as not thorough thereby effectively alleviate to dash forward.The hydrophilic brush shape group of micella shell can improve micella shell density, strengthens wetting ability, anti-albumen and the thrombocyte adsorptive power of micellar surface, extends the cycling time of micella, thereby improves the controlled release properties of micelle medicine carrying system.This micelle medicine carrying system is Stability Analysis of Structures in the gastric juice environment, and the micella kernel is tight, and the cumulative release amount is few, thus the protection medicine.In intestinal environment, the micella swelling, drug release rate is accelerated, and due to micellar surface with negative electricity, can be adsorbed on enteron aisle the carrier micelle residence time obviously extended.Can come the rate of release of regulating medicine by the content of pH response group in telomerized polymer molecular brush material, satisfy the oral release request of different pharmaceutical.The critical aggregate concentration of this polymer molecule brush far below tensio-active agent and conventional polymer micella, be only 1.5 mg/L, thereby its carrier micelle is stable high.Preparation method used is simple to operate, yield is high, product quality is good, can accurately control molecular weight and the polymolecularity of polymer molecule brush.
Description of drawings
Fig. 1 is the building-up reactions formula of macromole evocating agent A.
Fig. 2 is the building-up reactions formula of the macromole evocating agent B of grafted hydrophobic group.
Fig. 3 is the building-up reactions formula of amphipathic nature polyalcohol molecular brush.
Fig. 4 obtains the reaction formula of pH response amphipathic nature polyalcohol molecular brush for hydrolysis.
Fig. 5 is P (HEMA-in embodiment 1 co- tBMA) the gel permeation chromatography figure (GPC) of-Br, moving phase is tetrahydrofuran (THF) (THF).
Fig. 6 is P (HEMA-in embodiment 1 co- tThe proton nmr spectra of BMA)-Br ( 1H NMR), solvent be deuterochloroform ( d-CDCl 3).
Fig. 7 is P (PLAMA-in embodiment 1 co- tBMA) the GPC elution curve of-Br.
Fig. 8 is P (PLAMA-in embodiment 1 co- tBMA)-Br's 1H NMR spectrum, solvent is d-CDCl 3
Fig. 9 is P (PLAMA-in embodiment 1 co- tBMA)- bThe GPC elution curve of-PPEGMA.
Figure 10 is P (PLAMA-in embodiment 1 co- tBMA)- b-PPEGMA's 1H NMR spectrum, solvent is d-CDCl 3
Figure 11 is P (PLAMA-in embodiment 1 co-MAA)- bThe GPC elution curve of-PPEGMA.
Figure 12 is P (PLAMA-in embodiment 1 co-MAA)- b-PPEGMA's 1H NMR spectrum, solvent be deuterium for DMSO ( d 6 -DMSO).
Figure 13 is P (PLAMA-in embodiment 9 co-MAA)- bThe micelle-forming concentration test curve of-PPEGMA.
Figure 14 is P (PLAMA-in embodiment 10 co-MAA)- bThe particle diameter of-PPEGMA micella and size distribution figure.
Figure 15 is P (PLAMA-in embodiment 10 co-MAA)- bThe scanning electron microscope of-PPEGMA micella (SEM) figure.
Figure 16 is P (PLAMA-in embodiment 11 co-MAA)- b-PPEGMA(MAA group molecular weight approximately 5000) carry the release in vitro curve of Ibuprofen BP/EP micella.
Figure 17 is for implementing P (PCLEA-in 12 co-MAA)- b-PPEGMA(MAA group molecular weight approximately 3000) carry the release in vitro curve of Ibuprofen BP/EP micella.
Embodiment
Content for a better understanding of the present invention is described further below in conjunction with concrete embodiment.The abbreviation contrast of the uses such as monomer, catalyzer, initiator is as follows in an embodiment:
Title Abbreviation Title Abbreviation
Hydroxyethyl methylacrylate HEMA Methacrylic acid mono methoxy polyethylene glycol ester PEGMA
Hydroxyethyl acrylate HEA The 2-isobutyl ethyl bromide EBriB
Rac-lactide D, L-LA Stannous octoate Sn(Oct) 2
Glycollide GA Dipyridyl bpy
The e-caprolactone e-CL Five methyl diethylentriamine PMDETA
Tert-butyl Methacrylate tBMA Three (2-pyridylmethyl) amine TPMA
Tert-butyl acrylate tBA Cupric bromide CuBr 2
Methacrylic acid MAA Cupric chloride CuCl 2
Vinylformic acid AA Trifluoroacetic acid TFA
Embodiment 1
(1) synthetic P (HEMA- co- tBMA)-Br(A:B=14:86, A represent terminal hydroxy groups HEMA, and B represents pH response group tBMA, ratio are mass percent, and be lower same).Get 50 mL reaction flasks, with stirrer and CuBr 2(11.2 mg) is placed in reaction flask, vacuumizes after sealing-Tong argon gas three times.Successively with syringe with solvent toluene (20 mL), terminal hydroxy group monomer HEMA(1.2 mL) and pH response monomer tBMA(9.430 mL), part PMDETA(104 mL) add in reaction flask, stir 10 min catalyst complex formed.Again with reductive agent Sn (Oct) 2(202.5 mg) adds in reaction flask, adds initiator EBriB(147 mL after stirring 5 min again), change stirring reaction 2 h in 70 ℃ of oil baths over to.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.The solution that obtains slowly joins precipitation in 0 ℃ of methanol/water of 300 mL (1:1 volume ratio) after rotary evaporation is concentrated, at 45 ℃ of lower vacuum-drying 24 h, obtain white powder after use deionized water wash 2 times.Productive rate is 90%, M n=8335, PDI=1.22.
In described step (1), the parts by weight of reactant are as follows:
13 parts of terminal hydroxy group monomers
82 parts of pH response monomers
1 part of catalyst system A
2 parts of initiators
2 parts of reductive agents;
(2) synthetic P (PLAMA- co- tBMA)-Br(AB:C=63:37, AB represent step (1) product, and C represents hydrophobic grouping PLA, and be lower same).Get 50 dry mL reaction flasks of baking, with stirrer, monomer D, L-LA(4 g), P (HEMA- co- tBMA)-Br(6.67 g) add in reaction flask, vacuumize after sealing-Tong argon gas 3 times, add successively solvent toluene (20 mL) and Sn (Oct) under argon shield 2(4 mg), with liquid nitrogen carry out three times freezing-bleed-ramp cycle after, change in 100 ℃ of oil baths reaction 24 h over to.After reaction is completed, first pressure reducing and steaming toluene, then use 40 mL tetrahydrofuran (THF)s with polymer dissolution, and with 0 ℃ of methanol/water of 300mL (1:1 volume ratio) precipitation, filter, then at 45 ℃ of lower vacuum-drying 24 h, obtain white powder.Productive rate is 84%, M n=13502, PDI=1.31.
In described step (2), the parts by weight of reactant formula is as follows:
62.49 parts of macromole evocating agent A
37.47 parts of hydrophobic monomers
0.04 part of catalyst system B;
(3) synthetic P (PLAMA- co- tBMA)- b-PPEGMA(ABC:D=73:27, ABC represent step (2) product, and D represents hydrophilic radical PEGMA, and be lower same).Get 50 mL reaction flasks, with stirrer, CuBr 2(6.7 mg) and P (PLAMA- co- tBMA)-Br(8.1 g) be placed in reaction flask, vacuumize after sealing-Tong argon gas three times.Successively with syringe with solvent toluene (20 mL), hydrophilic macromonomer PEGMA 300(3 g.300 its molecular weight of expression, lower with), part PMDETA(63 mL) add in reaction flask, stir 10 min catalyst complex formed.Again with reductive agent Sn (Oct) 2(121.5 mg) adds in reaction flask, changes stirring reaction 30 h in 60 ℃ of oil baths over to after stirring 5 min.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.The solution that obtains slowly joins in 0 ℃ of normal hexane of 300 mL after rotary evaporation is concentrated and precipitates, and at 35 ℃ of lower vacuum-drying 24 h, obtains white powder after filtering.Productive rate is 80%, M n=17335, PDI=1.30.
In described step (3), the parts by weight of reactant formula is as follows:
26.6 parts of hydrophilic macromonomers
0.5 part of catalyst system A
1.1 parts of reductive agents
71.8 parts of macromole evocating agent B;
(4) hydrolysis obtains P (PLAMA- co-MAA)- b-PPEGMA.Take P (PLAMA- co- tBMA)- b-PPEGMA(1.73 g) to 50 mL round-bottomed flasks, add anhydrous methylene chloride (20 mL) dissolve polymer, dropwise slowly add trifluoroacetic acid (3.7 mL) after being cooled to 0 ℃ with ice-water bath, reaction 15 min under 0 ℃, more at room temperature react 18 h.Rotary evaporation is removed after solvent with tetrahydrofuran (THF) (10 mL) dissolving, more slowly joins in 0 ℃ of normal hexane of 50 mL and precipitate.Filtration is placed on 40 ℃ of lower vacuum-drying 24 h.Productive rate 85%, M n=14025, PDI=1.25.
In described step (4), the parts by weight of reactant formula is as follows:
5 parts of amphipathic nature polyalcohol molecular brush
16 parts of trifluoroacetic acids
79 parts of methylene dichloride
The reaction formula of pH response amphipathic nature polyalcohol molecular brush of the present invention is as shown in Fig. 1,2,3 and 4.
Embodiment 2
(1) synthetic P (HEMA- co- tBA)-Br(A:B=11:89).Get 50 mL reaction flasks, with stirrer and CuBr 2(22.3 mg) is placed in reaction flask, vacuumizes after sealing-Tong argon gas three times.Successively with syringe with solvent benzol methyl ether (20 mL), monomer HEMA(0.6 mL) and tBA(6.035 mL), part bpy(312.4 mg) add in reaction flask, stir 10 min catalyst complex formed.Again with reductive agent Sn (Oct) 2(405.1 mg) adds in reaction flask, adds initiator EBriB(147 mL after stirring 5 min), change stirring reaction 4 h in 60 ℃ of oil baths over to.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.The solution that obtains slowly joins precipitation in 0 ℃ of methanol/water of 300 mL (1:1 volume ratio) after rotary evaporation is concentrated, at 45 ℃ of lower vacuum-drying 24 h, obtain white powder after use deionized water wash 2 times.Productive rate is 86%, M n=5798, PDI=1.27.
In described step (1), the parts by weight of reactant are as follows:
9 parts of terminal hydroxy group monomers
77 parts of pH response monomers
5 parts of catalyst system A
3 parts of initiators
6 parts of reductive agents;
(2) synthetic P (PCLMA- co- tBA)-Br(AB:C=59:41).Get 50 dry mL reaction flasks, with stirrer, monomer e-CL(3.2 g), P (HEMA- co- tBA)-Br(4.64 g) add in reaction flask, vacuumize after sealing-Tong argon gas 3 times, add successively solvent toluene (20 mL) and Sn (Oct) under argon shield 2(32 mg), with liquid nitrogen carry out three times freezing-bleed-ramp cycle after, change in 110 ℃ of oil baths reaction 24 h over to.After reaction is completed, first pressure reducing and steaming toluene, then use 40 mL tetrahydrofuran (THF)s with polymer dissolution, with 0 ℃ of methanol/water of 300mL (1:1 volume ratio) precipitation, at 45 ℃ of lower vacuum-drying 24 h, obtain white powder after filtering.Productive rate is 80%, M n=10198, PDI=1.35.
In described step (2), the parts by weight of reactant formula is as follows:
58.9 parts of macromole evocating agent A
40.7 parts of hydrophobic monomers
0.4 part of catalyst system B;
(3) synthetic P (PCLMA- co- tBA)- b-PPEGMA(ABC:D=63:37).Get 50 mL reaction flasks, with stirrer, CuCl 2(1 mg) and P (PCLMA- co- tBA)-Br(6.12 g) be placed in reaction flask, vacuumize after sealing-Tong argon gas three times.Successively with syringe with solvent benzol methyl ether (20 mL), hydrophilic monomer PEGMA 475(3.6 g), part bpy(18.7 mg) add in reaction flask, stir 10 min catalyst complex is formed.Again with reductive agent Sn (Oct) 2(24.3 mg) adds in reaction flask, changes stirring reaction 12 h in 90 ℃ of oil baths over to after stirring 5 min.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.The solution that obtains slowly joins in 0 ℃ of normal hexane of 300 mL after rotary evaporation is concentrated and precipitates, and at 35 ℃ of lower vacuum-drying 24 h, obtains white powder after filtering.Productive rate is 75%, M n=14571, PDI=1.33.
In described step (3), the parts by weight of reactant formula is as follows:
37.6 parts of hydrophilic macromonomers
0.2 part of catalyst system A
0.2 part of reductive agent
62 parts of macromole evocating agent B;
(4) hydrolysis obtains P (PCLMA- co-AA)- b-PPEGMA.Take P (PCLMA- co- tBA)- b-PPEGMA(1.46 g) to 50 mL round-bottomed flasks, add anhydrous methylene chloride (20 mL) dissolve polymer, dropwise slowly add trifluoroacetic acid (1.6 mL) after being cooled to 0 ℃ with ice-water bath, reaction 15 min under 0 ℃, more at room temperature react 12 h.Rotary evaporation is removed after solvent with tetrahydrofuran (THF) (10 mL) dissolving, more slowly joins in 0 ℃ of normal hexane of 50 mL and precipitate.Filtration is placed on 40 ℃ of lower vacuum-drying 24 h.Productive rate 82%, M n=12108, PDI=1.26.
In described step (4), the parts by weight of reactant formula is as follows:
5 parts of amphipathic nature polyalcohol molecular brush
8 parts of trifluoroacetic acids
87 parts of methylene dichloride
Embodiment 3
(1) synthetic P (HEMA- co- tBMA)-Br(A:B=9:91).Get 50 mL reaction flasks, with stirrer and CuBr 2(8.9 mg) is placed in reaction flask, vacuumizes after sealing-Tong argon gas three times.Successively with syringe with solvent toluene (20 mL), monomer HEMA(1.2 mL) and tBMA(15.1 mL), part PMDETA(83.5 mL) add in reaction flask, stir 10 min catalyst complex formed.Again with reductive agent Sn (Oct) 2(162 mg) adds in reaction flask, adds initiator EBriB(147 mL after stirring 5 min), change stirring reaction 1 h in 80 ℃ of oil baths over to.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.The solution that obtains slowly joins precipitation in 0 ℃ of methanol/water of 300 mL (1:1 volume ratio) after rotary evaporation is concentrated, at 45 ℃ of lower vacuum-drying 24 h, obtain white powder after use deionized water wash 2 times.Productive rate is 87%, M n=14710, PDI=1.18.
In described step (1), the parts by weight of reactant are as follows:
9 parts of terminal hydroxy group monomers
88 parts of pH response monomers
1 part of catalyst system A
1 part of initiator
1 part of reductive agent;
(2) synthetic P (PLGAMA- co- tBMA)-Br(AB:C=75:25).Get 50 dry mL reaction flasks, with stirrer, monomer D, L-LA(2 g) and GA(2 g), P (HEMA- co- tBMA)-Br(11.77 g) add in reaction flask, vacuumize after sealing-Tong argon gas 3 times, add successively solvent toluene (20 mL) and Sn (Oct) under argon shield 2(4 mg), with liquid nitrogen carry out three times freezing-bleed-ramp cycle after, change in 100 ℃ of oil baths reaction 30 h over to.After reaction is completed, first pressure reducing and steaming toluene, then use 40 mL tetrahydrofuran (THF)s with polymer dissolution, with 0 ℃ of methanol/water of 300mL (1:1 volume ratio) precipitation, at 45 ℃ of lower vacuum-drying 24 h, obtain white powder after filtering.Productive rate is 82%, M n=19543, PDI=1.20.
In described step (2), the parts by weight of reactant formula is as follows:
74.62 parts of macromole evocating agent A
25.35 parts of hydrophobic monomers
0.03 part of catalyst system B;
(3) synthetic P (PLGAMA- co- tBMA)- b-PPEGMA(ABC:D=74:26).Get 50 mL reaction flasks, with stirrer, CuBr 2(6.7 mg) and P (PLGAMA- co- tBMA)-Br(11.7 g) be placed in reaction flask, vacuumize after sealing-Tong argon gas three times.Successively with syringe with solvent toluene (20 mL), hydrophilic monomer PEGMA 300(4.2 g), part PMDETA(63 mL) add in reaction flask, stir 10 min catalyst complex is formed.Again with reductive agent Sn (Oct) 2(121.5 mg) adds in reaction flask, changes stirring reaction 18 h in 70 ℃ of oil baths over to after stirring 5 min.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.The solution that obtains slowly joins in 0 ℃ of normal hexane of 300 mL after rotary evaporation is concentrated and precipitates, and at 35 ℃ of lower vacuum-drying 24 h, obtains white powder after filtering.Productive rate is 78%, M n=24739, PDI=1.21.
In described step (3), the parts by weight of reactant formula is as follows:
26 parts of hydrophilic macromonomers
0.4 part of catalyst system A
0.8 part of reductive agent
72.8 parts of macromole evocating agent B;
(4) hydrolysis obtains P (PLGAMA- co-MAA)- b-PPEGMA.Take P (PLGAMA- co- tBMA)- b-PPEGMA(2.47 g) to 50 mL round-bottomed flasks, add anhydrous methylene chloride (20 mL) dissolve polymer, dropwise slowly add trifluoroacetic acid (6.2 mL) after being cooled to 0 ℃ with ice-water bath, reaction is 15 minutes under 0 ℃, more at room temperature reacts 24 h.Rotary evaporation is removed after solvent with tetrahydrofuran (THF) (10 mL) dissolving, more slowly joins in 0 ℃ of cold normal hexane of 50 mL and precipitate.Filtration is placed on 40 ℃ of lower vacuum-drying 24 h.Productive rate 87%, M n=19600, PDI=1.20.
In described step (4), the parts by weight of reactant formula is as follows:
6 parts of amphipathic nature polyalcohol molecular brush
24 parts of trifluoroacetic acids
70 parts of methylene dichloride
Embodiment 4
(1) synthetic P (HEMA- co- tBA)-Br(A:B=10:90).Get 50 mL reaction flasks, with stirrer and CuBr 2(13.4 mg) is placed in reaction flask, vacuumizes after sealing-Tong argon gas three times.Successively with syringe with solvent toluene (10 mL) and methyl-phenoxide (10 mL), monomer HEMA(1.8 mL) and tBA(20.1 mL), part TPMA(174.2 mg) add in reaction flask, stir 10 min catalyst complex formed.Again with reductive agent Sn (Oct) 2(243 mg) adds in reaction flask, adds initiator EBriB(147 mL after stirring 5 min), change stirring reaction 0.5 h in 90 ℃ of oil baths over to.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.The solution that obtains slowly joins precipitation in 0 ℃ of methanol/water of 300 mL (1:1 volume ratio) after rotary evaporation is concentrated, at 45 ℃ of lower vacuum-drying 24 h, obtain white powder after use deionized water wash 2 times.Productive rate is 84%, M n=20172, PDI=1.25.
In described step (1), the parts by weight of reactant are as follows:
9 parts of terminal hydroxy group monomers
88 parts of pH response monomers
1 part of catalyst system A
1 part of initiator
1 part of reductive agent;
(2) synthetic P (PLAMA- co- tBA)-Br(AB:C=67:33).Get 50 dry mL reaction flasks, with stirrer, monomer D, L-LA(8 g), P (HEMA- co- tBA)-Br(16.14 g) add in reaction flask, vacuumize after sealing-Tong argon gas 3 times, add successively solvent toluene (30 mL) and Sn (Oct) under argon shield 2(4 mg), with liquid nitrogen carry out three times freezing-bleed-ramp cycle after, change in 130 ℃ of oil baths reaction 48 h over to.After reaction is completed, first pressure reducing and steaming toluene, then use 40 mL tetrahydrofuran (THF)s with polymer dissolution, with 0 ℃ of methanol/water of 300mL (1:1 volume ratio) precipitation, 45 ℃ of lower vacuum-dryings 24 hours, obtain white powder after filtering.Productive rate is 76%, M n=32514, PDI=1.29.
In described step (2), the parts by weight of reactant formula is as follows:
66.85 parts of macromole evocating agent A
33.13 parts of hydrophobic monomers
0.02 part of catalyst system B;
(3) synthetic P (PLAMA- co- tBA)- b-PPEGMA(ABC:D=76:24).Get 50 mL reaction flasks, with stirrer, CuCl 2(6.1 mg) and P (PLAMA- co- tBA)-Br(19.5 g) be placed in reaction flask, vacuumize after sealing-Tong argon gas three times.Successively with syringe with solvent benzol methyl ether (20 mL), hydrophilic monomer PEGMA 1000(6 g), part TPMA(104.5 mg) add in reaction flask, stir 10 min catalyst complex is formed.Again with reductive agent Sn (Oct) 2(145.8 mg) adds in reaction flask, changes stirring reaction 24 h in 70 ℃ of oil baths over to after stirring 5 min.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.Slowly join after the solution rotating evaporation concentration that obtains in 0 ℃ of normal hexane of 300 mL and precipitate, at 35 ℃ of lower vacuum-drying 24 h, obtain white powder after filtering.Productive rate is 74%, M n=39814, PDI=1.30.
In described step (3), the parts by weight of reactant formula is as follows:
23 parts of hydrophilic macromonomers
0.4 part of catalyst system A
0.6 part of reductive agent
76 parts of macromole evocating agent B;
(4) hydrolysis obtains P (PLAMA- co-AA)- b-PPEGMA.Take P (PLAMA- co- tBA)- b-PPEGMA(3.98 g) to 50 mL round-bottomed flasks, add anhydrous methylene chloride (20 mL) dissolve polymer, dropwise slowly add trifluoroacetic acid (10.6 mL) after being cooled to 0 ℃ with ice-water bath, reaction 15 min under 0 ℃, more at room temperature react 30 h.Rotary evaporation is removed after solvent with tetrahydrofuran (THF) (10 mL) dissolving, more slowly joins in 0 ℃ of normal hexane of 50 mL and precipitate.Filtration is placed on 40 ℃ of lower vacuum-drying 24 h.Productive rate 81%, M n=31535, PDI=1.25.
In described step (4), the parts by weight of reactant formula is as follows:
9 parts of amphipathic nature polyalcohol molecular brush
34 parts of trifluoroacetic acids
57 parts of methylene dichloride
Embodiment 5
(1) synthetic P (HEA- co- tBA)-Br(A:B=12:88).Get 50 mL reaction flasks, with stirrer and CuBr 2(8.9 mg) is placed in reaction flask, vacuumizes after sealing-Tong argon gas three times.Successively with syringe with solvent toluene (20 mL), monomer HEA(1.1 mL) and tBA(10.1 mL), part PMDETA(83.5 mL) add in reaction flask, stir 10 min catalyst complex formed.Again with reductive agent Sn (Oct) 2(162 mg) adds in reaction flask, adds initiator EBriB(147 mL after stirring 5 min), change stirring reaction 2 h in 80 ℃ of oil baths over to.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.The solution that obtains slowly joins precipitation in 0 ℃ of methanol/water of 300 mL (1:1 volume ratio) after rotary evaporation is concentrated, at 45 ℃ of lower vacuum-drying 24 h, obtain white powder after use deionized water wash 2 times.Productive rate is 86%, M n=11079, PDI=1.20.
In described step (1), the parts by weight of reactant are as follows:
11 parts of terminal hydroxy group monomers
85 parts of pH response monomers
1 part of catalyst system A
2 parts of initiators
1 part of reductive agent;
(2) synthetic P (PLAEA- co- tBA)-Br(AB:C=61:39).Get 50 dry mL reaction flasks, with stirrer, monomer D, L-LA(5.6 g), P (HEA- co- tBA)-Br(8.86 g) add in reaction flask, vacuumize after sealing-Tong argon gas 3 times, add successively solvent toluene (30 mL) and Sn (Oct) under argon shield 2(11.2 mg), with liquid nitrogen carry out three times freezing-bleed-ramp cycle after, change in 100 ℃ of oil baths reaction 24 h over to.After reaction is completed, first pressure reducing and steaming toluene, then use 40 mL tetrahydrofuran (THF)s with polymer dissolution, with 0 ℃ of methanol/water of 300mL (1:1 volume ratio) precipitation, at 45 ℃ of lower vacuum-drying 24 h, obtain white powder after filtering.Productive rate is 81%, M n=18863, PDI=1.25.
In described step (2), the parts by weight of reactant formula is as follows:
61.22 parts of macromole evocating agent A
38.7 parts of hydrophobic monomers
0.08 part of catalyst system B;
(3) synthetic P (PLAEA- co- tBA)- b-PPEGMA(ABC:D=76:24).Get 50 mL reaction flasks, with stirrer, CuBr 2(5.4 mg) and P (PLAEA- co- tBA)-Br(11.32 g) be placed in reaction flask, vacuumize after sealing-Tong argon gas three times.Successively with syringe with solvent toluene (20 mL), hydrophilic monomer PEGMA 475(3.6 g), part bpy(80 mg) add in reaction flask, stir 10 min catalyst complex is formed.Again with reductive agent Sn (Oct) 2(97.2 mg) adds in reaction flask, changes stirring reaction 24 h in 70 ℃ of oil baths over to after stirring 5 min.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.The solution that obtains slowly joins in 0 ℃ of normal hexane of 300 mL after rotary evaporation is concentrated and precipitates, and at 35 ℃ of lower vacuum-drying 24 h, obtains white powder after filtering.Productive rate is 79%, M n=25193, PDI=1.24.
In described step (3), the parts by weight of reactant formula is as follows:
23.8 parts of hydrophilic macromonomers
0.6 part of catalyst system A
0.6 part of reductive agent
75 parts of macromole evocating agent B;
(4) hydrolysis obtains P (PLAEA- co-AA)- b-PPEGMA.Take P (PLAEA- co- tBA)- b-PPEGMA(2.52 g) to 50 mL round-bottomed flasks, add anhydrous methylene chloride (20 mL) dissolve polymer, dropwise slowly add trifluoroacetic acid (4.3 mL) after being cooled to 0 ℃ with ice-water bath, reaction 15 min under 0 ℃, more at room temperature react 18 h.Rotary evaporation is removed after solvent with tetrahydrofuran (THF) (10 mL) dissolving, more slowly joins in 0 ℃ of normal hexane of 50 mL and precipitate.Filtration is placed on 40 ℃ of lower vacuum-drying 24 h.Productive rate 86%, M n=21347, PDI=1.22.
In described step (4), the parts by weight of reactant formula is as follows:
7 parts of amphipathic nature polyalcohol molecular brush
18 parts of trifluoroacetic acids
75 parts of methylene dichloride
Embodiment 6
(1) synthetic P (HEA- co- tBMA)-Br(A:B=10:90).Get 50 mL reaction flasks, with stirrer and CuBr 2(11.2 mg) is placed in reaction flask, vacuumizes after sealing-Tong argon gas three times.Successively with syringe with solvent benzol methyl ether (20 mL), monomer HEA(0.5 mL) and tBMA(5.657 mL), part PMDETA(104.4 mL) add in reaction flask, stir 10 min catalyst complex formed.Again with reductive agent Sn (Oct) 2(202.5 mg) adds in reaction flask, adds initiator EBriB(147 mL after stirring 5 min), change stirring reaction 3 h in 70 ℃ of oil baths over to.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.The solution that obtains slowly joins precipitation in 0 ℃ of methanol/water of 300 mL (1:1 volume ratio) after rotary evaporation is concentrated, at 45 ℃ of lower vacuum-drying 24 h, obtain white powder after use deionized water wash 2 times.Productive rate is 84%, M n=5953, PDI=1.25.
In described step (1), the parts by weight of reactant are as follows:
9 parts of terminal hydroxy group monomers
83 parts of pH response monomers
2 parts of catalyst system A
3 parts of initiators
3 parts of reductive agents;
(2) synthetic P (PCLEA- co- tBMA)-Br(AB:C=54:46).Get 50 dry mL reaction flasks, with stirrer, monomer e-CL(4 g), P (HEA- co- tBMA)-Br(4.76 g) add in reaction flask, vacuumize after sealing-Tong argon gas 3 times, add successively solvent toluene (20 mL) and Sn (Oct) under argon shield 2(4 mg), with liquid nitrogen carry out three times freezing-bleed-ramp cycle after, change in 110 ℃ of oil baths reaction 30 h over to.After reaction is completed, first pressure reducing and steaming toluene, then use 40 mL tetrahydrofuran (THF)s with polymer dissolution, with 0 ℃ of methanol/water of 300mL (1:1 volume ratio) precipitation, at 45 ℃ of lower vacuum-drying 24 h, obtain white powder after filtering.Productive rate is 77%, M n=11397, PDI=1.32.
In described step (2), the parts by weight of reactant formula is as follows:
54.31 parts of macromole evocating agent A
45.64 parts of hydrophobic monomers
0.05 part of catalyst system B;
(3) synthetic P (PCLEA- co- tBMA)- b-PPEGMA(ABC:D=69:31).Get 50 mL reaction flasks, with stirrer, CuBr 2(5.4 mg) and P (PCLEA- co- tBMA)-Br(6.84 g) be placed in reaction flask, vacuumize after sealing-Tong argon gas three times.Successively with syringe with solvent toluene (20 mL), hydrophilic monomer PEGMA 300(3 g), part PMDETA(50 mL) add in reaction flask, stir 10 min catalyst complex is formed.Again with reductive agent Sn (Oct) 2(97.2 mg) adds in reaction flask, changes stirring reaction 24 h in 60 ℃ of oil baths over to after stirring 5 min.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.The solution that obtains slowly joins in 0 ℃ of normal hexane of 300 mL after rotary evaporation is concentrated and precipitates, and at 35 ℃ of lower vacuum-drying 24 h, obtains white powder after filtering.Productive rate is 75%, M n=15926, PDI=1.34.
In described step (3), the parts by weight of reactant formula is as follows:
30 parts of hydrophilic macromonomers
0.5 part of catalyst system A
1 part of reductive agent
68.5 parts of macromole evocating agent B;
(4) hydrolysis obtains P (PCLEA- co-MAA)- b-PPEGMA.Take P (PCLEA- co- tBMA)- b-PPEGMA(1.59 g) to 50 mL round-bottomed flasks, add anhydrous methylene chloride (20 mL) dissolve polymer, dropwise slowly add trifluoroacetic acid (1.6 mL) after being cooled to 0 ℃ with ice-water bath, reaction 15 min under 0 ℃, more at room temperature react 12 h.Rotary evaporation is removed after solvent with tetrahydrofuran (THF) (10 mL) dissolving, more slowly joins in 0 ℃ of normal hexane of 50 mL and precipitate.Filtration is placed on 40 ℃ of lower vacuum-dryings 24 hours.Productive rate 84%, M n=13863, PDI=1.27.
In described step (4), the parts by weight of reactant formula is as follows:
5 parts of amphipathic nature polyalcohol molecular brush
8 parts of trifluoroacetic acids
87 parts of methylene dichloride
Embodiment 7
(1) synthetic P (HEA- co- tBA)-Br(A:B=28:72).Get 50 mL reaction flasks, with stirrer and CuBr 2(2.2 mg) is placed in reaction flask, vacuumizes after sealing-Tong argon gas three times.Successively with syringe with solvent benzol methyl ether (20 mL), monomer HEA(1.6 mL) and tBA(16.1 mL), part TPMA(29 mg) add in reaction flask, stir 10 min catalyst complex formed.Again with reductive agent Sn (Oct) 2(40.5 mg) adds in reaction flask, adds initiator EBriB(147 mL after stirring 5 min again), change stirring reaction 1 h in 90 ℃ of oil baths over to.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.The solution that obtains slowly joins precipitation in 0 ℃ of methanol/water of 300 mL (1:1 volume ratio) after rotary evaporation is concentrated, at 45 ℃ of lower vacuum-drying 24 h, obtain white powder after use deionized water wash 2 times.Productive rate is 81%, M n=17459, PDI=1.31.
In described step (1), the parts by weight of reactant are as follows:
10 parts of terminal hydroxy group monomers
87 parts of pH response monomers
1 part of catalyst system A
1 part of initiator
1 part of reductive agent;
(2) synthetic P (PCLEA- co- tBA)-Br(AB:C=68:32).Get 50 dry mL reaction flasks, with stirrer, monomer e-CL(6.4 g), P (HEA- co- tBA)-Br(13.9 g) add in reaction flask, vacuumize after sealing-Tong argon gas 3 times, add successively solvent toluene (30 mL) and Sn (Oct) under argon shield 2(32 mg), with liquid nitrogen carry out three times freezing-bleed-ramp cycle after, change in 120 ℃ of oil baths reaction 36 h over to.After reaction is completed, first pressure reducing and steaming toluene, then use 40 mL tetrahydrofuran (THF)s with polymer dissolution, with 0 ℃ of methanol/water of 300mL (1:1 volume ratio) precipitation, at 45 ℃ of lower vacuum-drying 24 h, obtain white powder after filtering.Productive rate is 76%, M n=26149, PDI=1.36.
In described step (2), the parts by weight of reactant formula is as follows:
68.3 parts of macromole evocating agent A
31.5 parts of hydrophobic monomers
0.2 part of catalyst system B;
(3) synthetic P (PCLEA- co- tBA)- b-PPEGMA(ABC:D=76:24).Get 50 mL reaction flasks, with stirrer, CuBr 2(8 mg) and P (PCLEA- co- tBA)-Br(15.69 g) be placed in reaction flask, vacuumize after sealing-Tong argon gas three times.Successively with syringe with solvent toluene (20 mL), hydrophilic monomer PEGMA 1000(4.8 g), part TPMA(104.5 mg) add in reaction flask, stir 10 min catalyst complex is formed.Again with reductive agent Sn (Oct) 2(145.8 mg) adds in reaction flask, changes stirring reaction 18 h in 80 ℃ of oil baths over to after stirring 5 min.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.The solution that obtains slowly joins in 0 ℃ of normal hexane of 300 mL after rotary evaporation is concentrated and precipitates, and at 35 ℃ of lower vacuum-drying 24 h, obtains white powder after filtering.Productive rate is 71%, M n=35276, PDI=1.35.
In described step (3), the parts by weight of reactant formula is as follows:
23.1 parts of hydrophilic macromonomers
0.6 part of catalyst system A
0.7 part of reductive agent
75.6 parts of macromole evocating agent B;
(4) hydrolysis obtains P (PCLEA- co-AA)- b-PPEGMA.Take P (PCLEA- co- tBA)- b-PPEGMA(3.53 g) to 50 mL round-bottomed flasks, add anhydrous methylene chloride (20 mL) dissolve polymer, dropwise slowly add trifluoroacetic acid (6.9 mL) after being cooled to 0 ℃ with ice-water bath, reaction 15 min under 0 ℃, more at room temperature react 24 h.Rotary evaporation is removed after solvent with tetrahydrofuran (THF) (10 mL) dissolving, more slowly joins in 0 ℃ of normal hexane of 50 mL and precipitate.Filtration is placed on 40 ℃ of lower vacuum-drying 24 h.Productive rate 81%, M n=28916, PDI=1.28.
In described step (4), the parts by weight of reactant formula is as follows:
9 parts of amphipathic nature polyalcohol molecular brush
25 parts of trifluoroacetic acids
66 parts of methylene dichloride
Embodiment 8
(1) synthetic P (HEA- co- tBMA)-Br(A:B=7:93).Get 50 mL reaction flasks, with stirrer and CuBr 2(13.4 mg) is placed in reaction flask, vacuumizes after sealing-Tong argon gas three times.Successively with syringe with solvent toluene (10 mL) methyl-phenoxide (10 mL), monomer HEA(1.1 mL) and tBMA(18.86 mL), part bpy(187.4 mg) add in reaction flask, stir 10 min catalyst complex formed.Again with reductive agent Sn (Oct) 2(243 mg) adds in reaction flask, adds initiator EBriB(147 mL after stirring 5 min), change stirring reaction 4 h in 60 ℃ of oil baths over to.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.The solution that obtains slowly joins precipitation in 0 ℃ of methanol/water of 300 mL (1:1 volume ratio) after rotary evaporation is concentrated, at 45 ℃ of lower vacuum-drying 24 h, obtain white powder after use deionized water wash 2 times.Productive rate is 80%, M n=18677, PDI=1.34.
In described step (1), the parts by weight of reactant are as follows:
6.3 parts of terminal hydroxy group monomers
90.2 parts of pH response monomers
1.1 parts of catalyst system A
1.1 parts of initiators
1.3 parts of reductive agents;
(2) synthetic P (PLGAEA- co- tBMA)-Br(AB:C=84:16).Get 50 dry mL reaction flasks, with stirrer, monomer D, L-LA(2.8 g) and GA(2.8 g), P (HEA- co- tBMA)-Br(14.9 g) add in reaction flask, vacuumize after sealing-Tong argon gas 3 times, add successively solvent toluene (30 mL) and Sn (Oct) under argon shield 2(11.2 mg), with liquid nitrogen carry out three times freezing-bleed-ramp cycle after, change in 110 ℃ of oil baths reaction 30 h over to.After reaction is completed, first pressure reducing and steaming toluene, then use 40 mL tetrahydrofuran (THF)s with polymer dissolution, with 0 ℃ of methanol/water of 300mL (1:1 volume ratio) precipitation, at 45 ℃ of lower vacuum-drying 24 h, obtain white powder after filtering.Productive rate is 75%, M n=27085, PDI=1.37.
In described step (2), the parts by weight of reactant formula is as follows:
72.65 parts of macromole evocating agent A
27.3 parts of hydrophobic monomers
0.05 part of catalyst system B;
(3) synthetic P (PLGAEA- co- tBMA)- b-PPEGMA(ABC:D=77:23).Get 50 mL reaction flasks, with stirrer, CuCl 2(10.2 mg) and P (PLGAEA- co- tBMA)-Br(16.3 g) be placed in reaction flask, vacuumize after sealing-Tong argon gas three times.Successively with syringe with solvent toluene (10 mL) and methyl-phenoxide (10 mL), hydrophilic monomer PEGMA 475(4.8 g), part PMDETA(125 mL) add in reaction flask, stir 10 min catalyst complex is formed.Again with reductive agent Sn (Oct) 2(243 mg) adds in reaction flask, changes stirring reaction 36 h in 30 ℃ of oil baths over to after stirring 5 min.After reaction is completed, be cooled to room temperature, add 50 mL tetrahydrofuran (THF) dilutions, then remove by filter catalyzer with the neutral alumina pillar, tetrahydrofuran (THF) is made eluent.The solution that obtains slowly joins in 0 ℃ of normal hexane of 300 mL after rotary evaporation is concentrated and precipitates, and at 35 ℃ of lower vacuum-drying 24 h, obtains white powder after filtering.Productive rate is 70%, M n=35854, PDI=1.35.
In described step (3), the parts by weight of reactant formula is as follows:
22.4 parts of hydrophilic macromonomers
0.5 part of catalyst system A
1.1 parts of reductive agents
76 parts of macromole evocating agent B;
(4) hydrolysis obtains P (PLGAEA- co-MAA)- b-PPEGMA.Take P (PLGAEA- co- tBMA)- b-PPEGMA(3.58 g) to 50 mL round-bottomed flasks, add anhydrous methylene chloride (20 mL) dissolve polymer, dropwise slowly add trifluoroacetic acid (8.9 mL) after being cooled to 0 ℃ with ice-water bath, reaction 15 min under 0 ℃, more at room temperature react 36 h.Rotary evaporation is removed after solvent with tetrahydrofuran (THF) (10 mL) dissolving, more slowly joins in 0 ℃ of normal hexane of 50 mL and precipitate.Filtration is placed on 40 ℃ of lower vacuum-drying 24 h.Productive rate 80%, M n=29183, PDI=1.30.
In described step (4), the parts by weight of reactant formula is as follows:
8 parts of amphipathic nature polyalcohol molecular brush
31 parts of trifluoroacetic acids
61 parts of methylene dichloride;
Embodiment 9
The fluorescent probe method is measured embodiment 1 product P (PLAMA- co-MAA)- bThe micelle-forming concentration of-PPEGMA.
(1) preparation pyrene solution: pyrene is mixed with 6 ' 10 with acetone -5The solution of M.
(2) sample product solution: take 10 mg P (PLAMA- co-MAA)- b-PPEGMA is dissolved in 5 mL acetone, dropwise joins in 100 mL deionized waters, obtains 0.1 mg/mL solution after volatilization acetone, is diluted to subsequently a series of concentration (0.0001 ~ 0.1 mg/ml).Get 20 10 mL volumetric flasks, every adds 0.1 mL pyrene solution, then adds respectively the polymers soln of above-mentioned different concns to be made into sample liquid.In sample liquid, the concentration of pyrene is 6 ' 10 -7M。
(3) fluorescence spectrum test: as emission wavelength, specimen liquid is got at the excitation spectrum of 300-350nm with 373 nm I 338/ I 335Ratio is to concentration logarithm log CFigure 13 is seen in mapping, and curve break is the micelle-forming concentration value.Record P (PLAMA- co-MAA)- bThe micelle-forming concentration of-PPEGMA is 1.5 mg/L.
Embodiment 10
Preparation P (PLAMA- co-MAA)- bThe carrier micelle of-PPEGMA, and characterize its size distribution and pattern.
Adopt dialysis method to prepare carrier micelle.Accurately take 8 mg Ibuprofen BP/EPs, 40 mg P (PLAMA- co-MAA)- b-PPEGMA is dissolved in 50 mL dimethyl formamides, after stirring 4 h under room temperature, changes dialysis tubing (MWCO3000) over to, and with 1L deionized water dialysis 24 h, every 4 h change the medium of once dialysing.The filtering head that is 0.45 μ m with the micellar solution via hole diameter filters postlyophilization.Adopt dynamic light scattering method to survey its particle diameter and size distribution.Laser light scattering method gets P (PLAMA- co-MAA)- bThe median size of-PPEGMA carrier micelle is 80 nm, and size distribution is 0.015, sees Figure 14.It is spherical adopting SEM to observe its pattern, sees Figure 15.
Embodiment 11
Extracorporeal releasing experiment: accurately take 10 mg carrier micelle powder, be placed in dialysis tubing (MWCO3000), then add respectively 5 mL pH 1.2 hydrochloride buffers (simulated gastric fluid) or pH 7.4 phosphate buffered saline buffers (simulated intestinal fluid), seal dialysis tubing, change medicament dissolution instrument over to, add 35 mL pH damping fluids.Design temperature is at 37 ℃, and stirring velocity is 120 rpm.2 mL that take a sample at regular intervals, and add 2 mL fresh buffer.Discharge ibuprofen concentration in liquid with the determined by ultraviolet spectrophotometry different time, draw its release in vitro curve.
Figure 16 is P (PLAMA- co-MAA)- b-PPEGMA(MAA group molecular weight 5000, embodiment 1 product) release in vitro curve, Figure 17 is P (PCLEA- co-MAA)- b-PPEGMA(MAA group molecular weight 3000, embodiment 6 products) release in vitro curve.In the gastric juice environment (pH 1.2), drug release speed is all very slow: 8 h discharge 18%, 24 h and only discharge 23%, effectively protect medicine to avoid the erosion of gastric juice environment.In intestinal environment (pH 7.4), P (PLAMA- co-MAA)- b-PPEGMA carrier micelle just discharges 50%, 10 h at 2 h and has discharged 90%, 14 h release fully; P (PCLEA- co-MAA)- bDischarged 35-45% in-PPEGMA carrier micelle 8 h, 24 h discharge 60%, 56 h and discharge fully.

Claims (10)

1. a pH response/hydrophobic group random copolymerization polymer, is characterized in that, structural formula is
Figure FDA0000251295561
Wherein, R 1For
Figure FDA0000251295562
R 2And R 3Be methyl or hydrogen, R 4For
Figure FDA0000251295563
T is Br or Cl; X=5 ~ 15, y=35 ~ 140, z=5 ~ 33, m=5,9 or 20, n 1=7 ~ 26, n 2=4 ~ 14, n 3=5 ~ 16.
2. a kind of pH response/hydrophobic group random copolymerization polymer according to claim 1, is characterized in that, the number-average molecular weight of described pH response/hydrophobic group random copolymerization polymer is 12000 ~ 30000 g/mol.
3. the preparation method of a kind of pH response/hydrophobic group random copolymerization polymer claimed in claim 1, is characterized in that, comprises the following steps:
(1) preparation macromole evocating agent A: under protection of inert gas and anhydrous condition, with terminal hydroxy group monomer, pH response monomer, catalyst system A, reductive agent, initiator and solvent, react 0.5 ~ 4 h under 60 ~ 90 ℃, after Removal of catalyst, precipitation, filtration, drying obtain macromole evocating agent A; Described initiator is the 2-isobutyl ethyl bromide;
(2) grafted hydrophobic group: the macromole evocating agent A with hydrophobic monomer, catalyst system B and step (1) under protection of inert gas and solvent exist mixes, react 24 ~ 48 h under 100 ~ 130 ℃, through precipitation, filtration, the dry macromole evocating agent B that gets grafted hydrophobic group;
(3) preparation amphipathic nature polyalcohol molecular brush: the macromole evocating agent B and the solvent that under protection of inert gas, hydrophilic macromonomer, catalyst system A, reductive agent and step (2) are obtained, react 12 ~ 36 h under 30 ~ 90 ℃, after Removal of catalyst, precipitation, filtration, oven dry obtain the amphipathic nature polyalcohol molecular brush;
(4) preparation pH response/hydrophobic group random copolymerization polymer: step (3) product, trifluoroacetic acid are dissolved in reaction 15 min in 0 ℃ of methylene dichloride, then react 12 ~ 36 h under 25 ℃, obtain pH response/hydrophobic group random copolymerization polymer;
In described step (1), the parts by weight of reactant are as follows:
Figure FDA0000251295564
In described step (2), the parts by weight of reactant formula is as follows:
54.3 ~ 74.6 parts of macromole evocating agent A
25.3 ~ 45.64 parts of hydrophobic monomers
0.02 ~ 0.4 part of catalyst system B;
In described step (3), the parts by weight of reactant formula is as follows:
22.4 ~ 37.6 parts of hydrophilic macromonomers
0.2 ~ 0.6 part of catalyst system A
0.2 ~ 1.1 part of reductive agent
62 ~ 76 parts of macromole evocating agent B;
In described step (4), the parts by weight of reactant formula is as follows:
5 ~ 9 parts of amphipathic nature polyalcohol molecular brush
8 ~ 34 parts of trifluoroacetic acids
57 ~ 87 parts of methylene dichloride.
4. preparation method according to claim 3, is characterized in that, described terminal hydroxy group monomer is hydroxyethyl methylacrylate or Hydroxyethyl acrylate;
Described pH response monomer is Tert-butyl Methacrylate or tert-butyl acrylate;
Described hydrophobic monomer is mixture, rac-lactide or the 6-caprolactone of rac-lactide and glycollide;
Described hydrophilic macromonomer is methacrylic acid mono methoxy polyethylene glycol ester, and its structural formula is as follows:
Figure FDA0000251295565
M=5,9 or 20 wherein.
5. according to claim 3 or 4 described preparation methods, is characterized in that, catalyst system A described in step (1) and (3) is the complex compound of cupric bromide or cupric chloride and dipyridyl, five methyl diethylentriamine or three (2-pyridylmethyl) amine;
Step (1) and (3) described reductive agent are stannous octoate;
Step (1) and (3) described solvent are toluene or methyl-phenoxide;
The described catalyst system B of step (2) is stannous octoate;
The described solvent of step (2) is toluene.
6. preparation method according to claim 5, is characterized in that, step (1) and (3) described Removal of catalyst are after reaction product is dissolved with tetrahydrofuran (THF), to cross the neutral alumina chromatography column and remove catalyzer, adopt tetrahydrofuran (THF) as eluent;
Precipitation described in step (1) and (2) is that the solution after Removal of catalyst is joined in the mixing solutions of 0 ℃ of cold methanol being equivalent to 10 times of its volumes and water, and cold methanol and water volume ratio are 1:1;
Step (3) and (4) described precipitation are that the solution after Removal of catalyst is joined in the 0 ℃ of cold normal hexane that is equivalent to 10 times of its volumes.
7. the application of a kind of pH response/hydrophobic group random copolymerization polymer claimed in claim 1 in the micelle medicine carrying system of preparation poorly water soluble drugs.
8. application according to claim 7, it is characterized in that, the micelle medicine carrying system of described poorly water soluble drugs is that pH response/hydrophobic group random copolymerization polymer and poorly water soluble drugs are dissolved in organic solvent, use pH damping fluid dialysis 24 h postlyophilizations after stirring 6 h, obtain micelle medicine carrying system.
9. application according to claim 8, is characterized in that, described organic solvent is dimethyl formamide, dimethyl sulfoxide (DMSO) or acetone.
10. application according to claim 8, is characterized in that, described pH damping fluid is that the pH value is 2 ~ 4 hydrochloric acid or acetate buffer solution.
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