CN103992482B - A kind of brush-type copolymer with the triple sensitivity of sugar, temperature and pH and preparation method thereof - Google Patents
A kind of brush-type copolymer with the triple sensitivity of sugar, temperature and pH and preparation method thereof Download PDFInfo
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- CN103992482B CN103992482B CN201410198883.1A CN201410198883A CN103992482B CN 103992482 B CN103992482 B CN 103992482B CN 201410198883 A CN201410198883 A CN 201410198883A CN 103992482 B CN103992482 B CN 103992482B
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Abstract
The invention belongs to macromolecular material and biomedical engineering field, a kind of brush-type copolymer relating to the triple sensitivity of sugar, temperature and pH and preparation method thereof.The method key step is divided into three parts: Part I: RAFT agent causes p-chloromethyl styrene polymerization, Azide causes DMA polymerization as macromole RAFT agent after processing again.The propargyl ester of Part II: α-2 bromo acid is the polymerization of ATRP initiator trigger monomer (2-borate ester-5-ethyl-1,3-dioxane) acrylate (PpBDEMA).Part III: polymer one carries out azide reaction with polymer two and becomes polymer three.After the polymer of present invention offer and sugar response, phenylboric acid comes off and the little molecular complex of sugared formation from polymer, and thus phenylboric acid just can excrete with internal metabolism, has good biocompatibility.The present invention has sugar, temperature, the triple response of pH, more preferable can must be used for drug release, chemical sensor and polymer and the field such as separate.
Description
Technical field
The present invention relates to a kind of brush-type copolymer with the triple sensitivity of sugar, temperature and pH and preparation method thereof.
Background technology
Compared to the more single stimuli responsive system of research, exploitation has dual and multiple stimulation response system to scientific research
And reality application has the meaning of even more important effect.First, the polymeric system with multiple response can be with Study system
Release dynamics, these systems independently can must regulate each respondent behavior for different stimulations, as can be strengthened or subtract simultaneously
Weak drug release.Secondly, organism has the stimuli responsive behavior of complexity, this kind of research to diabetes, grinding of the disease such as cancer
Study carefully of great advantage.The polymer drug conveying material with multiple response can form the micelle of different shape under different stimulated
Or cause the decomposition of micelle, i.e. utilize the self assembly of micelle to realize the controllable release of medicine.
Polymer brush refers to be connected in the one of polymer molecular chain section on various interface or polymer chain to high-density
The special homopolymer of one formed, molecule can occur metamorphosis according to the change of surrounding, as changed temperature, molten
Agent, pH and ionic strength.The macromole of brush-type structure, it is possible to effectively change material surface chemistry and physical property is steady at colloid
Determine the fields such as agent, nanolithographic, microelectronics industry, lubrication and biomaterial to be widely used, the most become high
One of focus in molecular chemistry and physics.
Diabetes are a kind of metabolic diseases being characterized with hyperglycemia.Hyperglycemia then make due to defect of insulin secretion and
Its biological agent is impaired to be caused, and can cause various tissue, particularly eye, kidney, heart, blood vessel, neural chronic lesion, function
Obstacle, reducing blood glucose is the main method treating diabetes at present, and traditional injection and drug administration need doctor and patient tight
Lattice control the consumption of medicine, and long-time use also can make patient produce drug resistance and cause Diabetic liver injury of kidney.So, find
A kind of sugar response medicine carrier is particularly important for the treatment of diabetes.This sugar Response System can realize the controlled of medicine
Release, phenylboric acid and derivant thereof have sugar response.There is two states in phenyl boronic acid derivative, electronegative in aqueous
Tetrahedral structure can form stable borate ester structure with glucose complexation, and it is dissolved in water, and neutral trihedral is tied
The phenylboric acid of structure and glucose form the circulus of instability.By changing pH, and the concentration of glucose in solutions realizes
The purpose of phenylboric acid system sustained-release administration.This method can be convenient and safe intelligently at the site of disease selectivity that blood sugar concentration is high
Release medicine, reaches the purpose efficiently treated.
Summary of the invention
The brush-type copolymer possessing the triple sensitivity of sugar, temperature and pH that the present invention proposes, it is characterised in that described brush-type
The structural formula of copolymer is:
。
The preparation method of the brush-type copolymer possessing the triple sensitivity of sugar, temperature and pH that the present invention proposes, its feature exists
In specifically comprising the following steps that
(1) by poly-(p-azido-methyl styrene), DMA (N, N-DMAA) and AIBN (azo-bis-isobutyl cyanide)
It is dissolved in DMF with mol ratio 1:60-100:0.5, the degassing of three freezing evacuation cycle, under nitrogen atmosphere is protected 68-72 DEG C
Reacting 22-28 hour, reaction dilutes with oxolane after terminating, and diluent precipitates in frost normal hexane, repeats dilution-precipitation
After three times filter, then in vacuum drying oven be dried within 44-52 hour, obtain polymer I;
Polymer I
(2) under nitrogen protection, by α-2 propargyl ester of bromo acid, cuprous bromide, PMDETA and PpBDEMA monomer with
Mol ratio 1:1.2:1.2:60-100 is dissolved in dry methyl phenyl ethers anisole freezing pumping cycle three times, at 85-95 DEG C, stirs 18-60
Hour, concentrate to remove and precipitate in the mixed liquor of normal hexane and ether after mantoquita, obtain polymer II:
Polymer II
(3) polymer I step (1) obtained, the polymer II that step (2) obtains are dissolved in DMF, fast after fully dissolving
Speed adds in the catalyst system and catalyzing of CuBr and PMDETA composition, after three freezings-evacuation cycle degassing, protects at nitrogen atmosphere
Protecting lower 48-52 DEG C to react 10-14 hour, reaction adds THF after terminating and is diluted, and crosses neutral alumina column subsequently and removes copper
Salt, precipitates three times in the ether that filtrate refreezes after concentrating, and obtains solid product, then is dried 44-50 hour in vacuum drying oven
Obtain polymer III;
Polymer III.
The method have the advantages that
1) sugar response polymer drug delivering material provided by the present invention has sugared response functional group, its special dredging
Water segmented structure is provided that self assembly power in aqueous phase, forms nano-particle.
2) the little molecule benzene boron after sugar response polymer drug delivering material itself provided by the present invention and sugar respond
Acid sugar ester and become the polymer of double-hydrophilic and be respectively provided with good biocompatibility.The polymer that the present invention provides rings with sugar
Should come off from polymer and the sugar little molecular complex of formation by phenylboric acid afterwards, thus phenylboric acid just can be with internal metabolism
Excrete, there is good biocompatibility.
3) present invention has sugar, temperature, the triple response of pH, more preferable can must be used for drug release, chemical sensor and gather
The fields such as compound separation.
Detailed description of the invention
Elaborate below by embodiment: the present embodiment is implemented under premised on technical solution of the present invention,
Give detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to the embodiment of subordinate.
Embodiment 1:
1) by poly-for 0.189g (0.1mmol) (p-azido-methyl styrene), 0.9913 (10mmol) DMA (N, N-dimethyl
Acrylamide), 3mg (0.02mol) AIBN (azo-bis-isobutyl cyanide) is dissolved in 4mlDMF, three freezing evacuation cycle degassings,
Under nitrogen atmosphere is protected, 70 DEG C are reacted 24 hours.Reaction dilutes with oxolane after terminating, and diluent is in frost normal hexane
Precipitation, repeat dissolve-precipitation three times after filter, then in vacuum drying oven be dried within 48 hours, obtain polymer I;
2) under nitrogen protection, by 0.0193g (0.1mmol) α-2 propargyl ester of bromo acid, 0.0173g 0.0208g
(0.12mmol) cuprous bromide, (0.12mmol) PMDETA and 2.738 (10mmol) PpBDEMA monomer are dissolved in dry methyl phenyl ethers anisole
Middle freezing pumping cycle three times, at 90 DEG C, stirs 18-60 hour, at normal hexane and the mixed liquor of ether after concentration removing mantoquita
Middle precipitation, obtains polymer II:
3) by 0.7930g (0.1mmol) polymer I, 4.3808g (0.2mmol) polymer II is dissolved in DMF, the most molten
Following catalyst system and catalyzing it is rapidly added: CuBr, PMDETA, after three freezings-evacuation cycle degassing, at nitrogen atmosphere after solution
Protecting lower 50 DEG C to react 12 hours, reaction adds THF after terminating and is diluted, and crosses neutral alumina column subsequently and removes mantoquita, filter
The ether that liquid refreezes after concentrating precipitates three times, obtains solid product dialysis and remove raw material, then in vacuum drying oven, be dried 48
Hour obtain being polymerized III.
Embodiment 2:
1) with embodiment 1 step 1);
2) under nitrogen protection, by 0.0193g (0.1mmol) α-2 propargyl ester of bromo acid, 0.0173g 0.0208g
(0.12mmol) cuprous bromide, (0.12mmol) PMDETA and 2.1904g (8mmol) PpBDEMA monomer are dissolved in dry benzene first
In ether, freezing pumping cycle three times, at 90 DEG C, stir 18-60 hour, in normal hexane and the mixing of ether after concentration removing mantoquita
Liquid precipitates, obtains polymer II:
3) with embodiment 1 step 3).
Embodiment 3:
1) with embodiment 1 step 1);
2) under nitrogen protection, by 0.0193g (0.1mmol) α-2 propargyl ester of bromo acid, 0.0173g0.0208g
(0.12mmol) cuprous bromide, (0.12mmol) PMDETA and 1.6428g (6mmol) PpBDEMA monomer are dissolved in dry benzene first
In ether, freezing pumping cycle three times, at 90 DEG C, stir 18-60 hour, in normal hexane and the mixing of ether after concentration removing mantoquita
Liquid precipitates, obtains polymer II:
3) with embodiment 1 step 3).
Claims (2)
1. the brush-type copolymer possessing the triple sensitivity of sugar, temperature and pH, it is characterised in that the knot of described brush-type copolymer
Structure formula is:
。
2. possess a preparation method for the brush-type copolymer of the triple sensitivity of sugar, temperature and pH as claimed in claim 1, its
It is characterised by specifically comprising the following steps that
(1) by poly-(p-azido-methyl styrene), DMA (N, N-DMAA) and AIBN (azo-bis-isobutyl cyanide) to rub
You are dissolved in DMF than 1:60-100:0.5, three freezing evacuation cycle degassings, 68-72 DEG C of reaction under nitrogen atmosphere is protected
22-28 hour, reaction diluted with oxolane after terminating, and diluent precipitates in frost normal hexane, repeated dilution-precipitation three times
Rear filtration, then in vacuum drying oven be dried within 44-52 hour, obtain polymer I;
Polymer I
(2) under nitrogen protection, by propargyl for alpha-brominated isopropylformic acid. ester, cuprous bromide, PMDETA and PpBDEMA monomer with mole
It is dissolved in dry methyl phenyl ethers anisole freezing pumping cycle three times than 1:1.2:1.2:60-100, at 85-95 DEG C, stirs 18-60 hour,
Concentrate to remove and precipitate in the mixed liquor of normal hexane and ether after mantoquita, obtain polymer II:
Polymer II
(3) polymer I step (1) obtained, the polymer II that step (2) obtains are dissolved in DMF, add rapidly after fully dissolving
Enter in the catalyst system and catalyzing of CuBr and PMDETA composition, after three freezings-evacuation cycle degassing, under nitrogen atmosphere is protected
48-52 DEG C is reacted 10-14 hour, and reaction adds THF after terminating and is diluted, and crosses neutral alumina column subsequently and removes mantoquita, filter
Liquid precipitates three times after concentrating in the ether of frost, obtains solid product, then is dried in vacuum drying oven and is gathered for 44-50 hour
Compound III;
Polymer III.
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