CN103289099B - A kind of amphipathic acid sensitivity ternary molecular brush polymer constructs acid-sensitive type Nano capsule - Google Patents
A kind of amphipathic acid sensitivity ternary molecular brush polymer constructs acid-sensitive type Nano capsule Download PDFInfo
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Abstract
The invention discloses a kind of amphipathic acid sensitivity ternary molecular brush polymer and acid-sensitive type Nano capsule, this amphipathic acid sensitivity ternary molecular brush polymer has general formula as follows, wherein, A is main polymer chain, B is lipophilicity polymer side chain, C is the polymer side chain of acid sensitivity, and D is hydrophilic high mol side chain, and side chain B, C and D are random to be grafted on main chain A; Acid-sensitive type Nano capsule is scattered in oil and water two-phase system above-mentioned amphipathic acid sensitivity ternary molecular brush polymer, forms stable acid-sensitive type Nano capsule.The invention solves a difficult problem for the speed of the difficult Effective Regulation substance release of traditional intelligence type Nano capsule, adopt emulsion self-assembly method to prepare Nano capsule, simple to operate, easily can mass-producing prepare; The middle blank sensitive acid type Nano capsule covering amount of preparation is large.A-g-(B-r-C-r-D)。
Description
Technical field
The invention belongs to self-assembly polymeric material field, be specifically related to a kind of amphipathic acid sensitivity ternary molecular brush polymer and construct acid-sensitive type Nano capsule.
Background technology
In recent years in decades, in order to improve the performance of drug delivery system, reduce the side effect to human body in useful for drug delivery process, the micella that amphipathic nature polyalcohol independently fills formation has in the solution been used to the carrier of medicine simultaneously.These pharmaceutical carriers can wrap the medicine carrying poorly water-soluble on the one hand, increase the transmittability of medicine; On the other hand, for medicine provides provide protection, on suitable opportunity, carry out slow putting.
Nanometer polymer micelle, at the transmission of medicine, such as cancer therapy drug, has showed great potential using value.But the medicine that usual physical package is carried reaches the violent release of 10 ~ 30% within a few hours, follow by last very long drug diffusion slowly.Can cause medicament storage difficult effectively release in micella like this, medicine and unslow targetedly putting can occur, difficulty is effectively absorbed.Therefore, medicine does not play lethal effect in tumour cell.If medicine difficulty reaches effective cancer cells kill and wound drug level, and the resistance of cancer cells can be caused.Therefore, develop the pharmaceutical carrier with good medicine-releasing performance and have very large necessity.Solution is exactly that construction one has responsive polymer nano-micelle or capsule, and this micella or capsule produce response at specific environmental stimulus, such as light, degraded, reduction, pH change etc.
Nano capsule is hollow structure, is of a size of 1-1000nm, the several order of magnitude less of the size (1-2000 μm) of microcapsule.Nano capsule is relative to nano-micelle, and Nano capsule contains the space of hollow, can load more material, and Nano capsule can be applicable to the high-technology fields such as medicament slow release, catalysis, biotechnology.The size of Nano capsule is less, and it is larger to synthesize more homogeneous Nano capsule difficulty.In recent years, along with novel building-up reactions and the appearance preparing branch art, the method preparing Nano capsule in a large number is also emerged.At present, Nano capsule technology of preparing comprises nanoprecipitation method, emulsion dispersion method, emulsion coagulation method, double emulsion, polymeric coating construction from part, layer assembly method etc.According to the characteristic of polymkeric substance, select different methods to carry out assemble nanometer capsule, the Nano capsule of different structure and performance can be prepared.
Nano capsule is applied to drug release can solve medicine problem poorly soluble in water, provides provide protection simultaneously, discharges under particular circumstances, reach application purpose to medicine.In recent years, researcher develops various intelligent Nano capsule, and as light, degraded, reduction, the intelligent Nano capsule such as pH, intelligent Nano capsule reaches release object by the method for chemistry or physics, thus improves drug absorption rate, reaches result for the treatment of.But the intelligent Nano capsule difficulty of report is by the structure of telomerized polymer and the speed of composition Effective Regulation drug release at present.
Summary of the invention
For overcoming defect and the deficiency of above-mentioned prior art, primary and foremost purpose of the present invention is to provide a kind of amphipathic acid sensitivity ternary molecular brush polymer.
Another object of the present invention is to the synthetic method that above-mentioned amphipathic acid sensitivity ternary molecular brush polymer is provided.
Another object of the present invention is to provide above-mentioned amphipathic acid sensitivity ternary molecular brush polymer to construct the method for acid-sensitive type Nano capsule.
Another object of the present invention is to provide a kind of acid-sensitive type Nano capsule, this acid-sensitive type Nano capsule is prepared by above-mentioned amphipathic acid sensitivity ternary molecular brush polymer, by the structure of Molecular regulator brush, and then Nano capsule is regulated to control the speed of bag year inner material release.
An order more of the present invention is the purposes providing above-mentioned acid-sensitive type Nano capsule.
Object of the present invention is achieved through the following technical solutions: a kind of amphipathic acid sensitivity ternary molecular brush polymer, has general formula as follows:
A-g-(B-r-C-r-D)；
Wherein, g represents grafting, and r represents random distribution, and A is main polymer chain, and B is lipophilicity polymer side chain, and C is the polymer side chain of acid sensitivity, and D is hydrophilic high mol side chain, and side chain B, C and D are randomly grafted on main chain A;
Described amphipathic acid sensitivity ternary molecular brush polymer, the polymerization degree of main chain A is 5 ~ 1000, and the polymerization degree of side chain B, C, D is 5 ~ 1000, and the percentage of grafting of side chain B, C, D is 5 ~ 100%;
Preferably, the polymerization degree of main chain A is 40 ~ 500, and the polymerization degree of side chain B is 20 ~ 300, and percentage of grafting is 5 ~ 40%, and the polymerization degree of side chain C is 50 ~ 120, and percentage of grafting is 5 ~ 40%, and the polymerization degree of side chain D is 30 ~ 114, and percentage of grafting is 5 ~ 40%;
The polymkeric substance of composition main chain A is the one in poly (glycidyl methacrylate) (PGMA) or polyglycidyl acrylate (PGA);
The polymkeric substance of composition lipophilicity polymer side chain B is the one in polystyrene (PS), butyl polyacrylate (PBA), polyacrylonitrile (PAN), the tertiary ester of polyacrylic acid (PtBA), polymethylmethacrylate (PMMA), poly(lactic acid) (PLA), polycaprolactone (PCL) or polyvinyl acetate (PVA) (PVAc);
The polymkeric substance of the polymer side chain C of composition acid sensitivity is the one in polyacrylic acid (PAA), polymethyl acrylic acid (PMA), polymethyl acrylic acid diformazan ammonia ethyl ester (PDMAEMA) or polyacrylic acid dimethylaminoethyl (PDMAEA);
The polymkeric substance of composition hydrophilic high mol side chain D is the one in polyoxyethylene glycol (PEG), polyvinyl alcohol (PVA), polyacrylic acid hydroxyethanoic acid (PHEA), poly hydroxy ethyl acrylate (PHEMA) or polyhydroxypropyl methaciylate (PHPMA);
Above-mentioned amphipathic acid sensitivity ternary molecular brush polymer is by method synthesis such as radical polymerization, controllable free-radical polymerisation or some chemistry, and its synthetic method specifically comprises the following steps:
(1) synthesize main chain, then azide functionalization is carried out to main chain, obtain trunk polymer;
(2) synthesize side chain, in building-up process, introduce alkynyl functional group simultaneously or alkynyl functionalization is carried out to the side chain after synthesis, obtain side chain polymer that is hydrophilic, oleophylic or acid sensitivity;
(3) by a kind of main chain containing azido-to can mix with the side chain alkynyl that is corresponding a kind of hydrophilic, a kind of oleophylic and a kind of acid sensitivity of main chain each Elementary Function group generation chemical reaction, carry out the reaction of a step " nitrine-alkynyl " click chemistry in the presence of a catalyst, obtain amphipathic acid sensitivity ternary molecular brush polymer.
Synthesis main chain described in step (1) is adopt a kind of polymerization process in radical polymerization, controllable free-radical polymerisation or anionoid polymerization;
Azide functionalization described in step (1) introduces azido group on each unit of main chain;
Trunk polymer described in step (1) is P(GMA-N
3) or P(GA-N
3);
Synthesis side chain described in step (2) can adopt a kind of polymerization process in radical polymerization, controllable free-radical polymerisation or anionoid polymerization;
Introducing alkynyl functional group described in step (2) or alkynyl function is carried out to the side chain after synthesis turn to introduce alkynyl group on the end of side chain;
Hydrophilic side chain polymer described in step (2) is the one in PEG-C ≡ CH, PVA-C ≡ CH, PHEA-C ≡ CH, PHEMA-C ≡ CH or PHPMA-C ≡ CH;
The side chain polymer of oleophylic described in step (2) is the one in PS-C ≡ CH, PtBA-C ≡ CH, PBA-C ≡ CH, PAN-C ≡ CH, PMMA-C ≡ CH, PLA-C ≡ CH, PCL-C ≡ CH or PVAc-C ≡ CH;
The side chain polymer of acid sensitivity described in step (2) is the one in PAA-C ≡ CH, PMA-C ≡ CH, PDMAEMA-C ≡ CH or PDMAEA-C ≡ CH;
Catalyzer described in step (3) is the one in following combination: copper sulfate and xitix, cuprous bromide and pentamethyl-diethylenetriamine or cuprous bromide and 2,2'-dipyridyl; Described copper sulfate and the mass ratio of xitix are preferably 1:5;
Above-mentioned amphipathic acid sensitivity ternary molecular brush polymer is scattered in oil and water two-phase system as emulsifying agent by a kind of preparation method of acid-sensitive type Nano capsule, form stable sensitivity Nano capsule, concrete steps are: be dissolved in 1 ~ 50 mass parts tetrahydrofuran (THF) by the above-mentioned amphipathic acid sensitivity ternary molecular brush polymer of 1 ~ 10 mass parts, 50 ~ 200 mass parts oil and water two-phase systems of the adjusted good potential of hydrogen of tetrahydrofuran (THF) instillation of acid sensitivity ternary molecular brush polymer will be dissolved with again, stirring obtains O/w emulsion, thus obtains acid-sensitive type Nano capsule.
Described oil and water two-phase system are the two-phase mixtures system of oil phase and aqueous phase composition; Oil phase wherein should be able to dissolve oleophylic side chain polymer but can not dissolve the side chain polymer of hydrophilic side chain polymkeric substance and acid sensitivity, and the side chain polymer of aqueous phase energy dissolving acid sensitivity and hydrophilic side chain polymkeric substance, oil and water two-phase system can be matched according to amphipathic acid sensitivity ternary molecular brush polymer structure; Described oil phase is preferably in perhydronaphthalene, peruscabin or cyclohexane a kind of; Described aqueous phase is preferably the aqueous solution that pH is 1 ~ 14; In described oil and water two-phase system, the mass ratio of oil phase and aqueous phase is preferably 1:10 ~ 200;
The oleophylic side chain of amphipathic acid sensitivity ternary molecular brush polymer is dissolved in oil phase, and the side chain of its hydrophilic side chain and acid sensitivity is soluble in the aqueous phase, and forms stable " oil-in-water " emulsion, and then forms stable acid-sensitive type Nano capsule.When applying, when acid-sensitive type Nano capsule changes with extraneous pH environment, the conformation of the acid sensitivity side chain be soluble in the aqueous phase will change, and will become hydrophobicity from wetting ability, thus cause capsule generation demulsifying phenomenon, reach release object.The adjustable hydrophilic side-chains of rate of release of acid-sensitive type Nano capsule and the grafting mass ratio of acid sensitivity side chain and control.
A kind of acid-sensitive type Nano capsule, is prepared by above-mentioned preparation method.The particle diameter of described acid-sensitive type Nano capsule is 20 ~ 1000nm, is preferably 50 ~ 230nm.
Above-mentioned acid-sensitive type Nano capsule, with pH environmental change, there is acid-sensitive disintegration in Nano capsule, bag carried the substance release of the inside in external environment, is applied in medicament slow release field, nano-reactor or catalyzer.
The present invention has following advantage and effect relative to prior art:
(1) the present invention adopts amphipathic acid sensitivity ternary molecular brush to construct stable acid-sensitive type Nano capsule.When applying, when pH changes, the conformation of the acid sensitivity side chain be soluble in the aqueous phase will change, hydrophobicity will be become from wetting ability, thus cause capsule generation demulsifying phenomenon, the adjustable hydrophilic side-chains of rate of release of acid-sensitive type Nano capsule and the grafting mass ratio of acid sensitivity side chain and control, solve a difficult problem for traditional intelligence type Nano capsule rate of release difficulty regulation and control.
(2) the present invention adopts emulsion self-assembly method to prepare Nano capsule, simple to operate, easily can mass-producing preparation.The acid-sensitive type Nano capsule of preparation has great covering amount to hydrophobic material, and the size of covering amount depends on the solubleness of coating at oil phase, and little with the morphological relationship of capsule.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
Number involved in following examples is all mass fractions.
Embodiment 1
A kind of amphipathic acid sensitivity ternary molecular brush polymer, is prepared by following steps:
(1) P (GMA-N
3) synthesis of main chain
Get 2 parts of 2-isobutyl ethyl bromide initiators, 200 parts of glycidyl methacrylate (GMA), 100 parts of phenyl ether, 2 parts of CuBr and 2 part N; N; N'; N'; N "-pentamethyl-diethylenetriamine (PMDETA); 30 DEG C are carried out ATRP and react 1.5 hours under nitrogen protection, obtain the poly (glycidyl methacrylate) (PGMA) that the polymerization degree (DP) is 60.
Get 100 parts of PGMA(DP=60), 100 parts of NaN
3, 500 parts of dimethyl formamide (DMF) and 1 part of AlCl
3, 50 DEG C of reactions 24 hours, obtain P (GMA-N
3), as main chain.
The synthesis of (2) three kinds of side chains
The synthesis of hydrophilic side chain: get 100 parts of mono methoxy polyethylene glycols (Mn=5000), 20 parts of 2-propynyl acetic acid, 20 parts of DMAPs (DMAP), 20 parts of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochlorides (EDC.HCl) and 200 parts of methylene dichloride, 30 DEG C are reacted 24 hours, obtain PEG-C ≡ CH(DP=114).
The synthesis of oleophylic side chain: get 2 parts of bromo acid propynyl ester initiators, 100 parts of polystyrene (PS), 100 parts of toluene, 2 parts of CuBr and 2 part N; N; N'; N'; N "-pentamethyl-diethylenetriamine (PMDETA); 90 DEG C are carried out ATRP and react 5 hours under nitrogen protection, obtain the PS-C ≡ CH that the polymerization degree (DP) is 50.
The synthesis of acid sensitivity side chain: get 1 part of bromo acid propynyl ester initiator, 150 parts of polymethyl acrylic acid diformazan ammonia ethyl ester (PDMAEMA), 100 parts of methyl alcohol, 1 part of CuBr and 1 part N; N; N'; N'; N "-pentamethyl-diethylenetriamine (PMDETA); 50 DEG C are carried out ATRP and react 12 hours under nitrogen protection, obtain the PDMAEMA-C ≡ CH that the polymerization degree (DP) is 80.
(3) synthesis of amphipathic acid sensitivity ternary molecular brush PGMA-g-(PS-r-PDMAEMA-r-PEG)
Get 10 parts of P (GMA-N
3), 20 parts of PEG-C ≡ CH, 40 parts of PS-C ≡ CH, 20 parts of PDMAEMA-C ≡ CH are dissolved in 500 parts of dimethyl formamides (DMF), then add 1 part of CuSO
4and 5 parts of sodium ascorbates, react 24 hours at 30 DEG C, obtain amphipathic acid sensitivity ternary molecular brush polymer PGMA-g-(PEG-r-PDMAEMA-r-PS), the percentage of grafting of PEG, PDMAEMA, PS side chain is respectively 10%, 10%, 20%.
A kind of acid-sensitive type Nano capsule, adopt emulsion self-assembly method to obtain, its preparation method comprises the following steps:
Getting 3 parts of amphipathic acid sensitivity ternary molecular brush polymer PGMA-g-(PS-r-PDMAEMA-r-PEG) is dissolved in 8 parts of tetrahydrofuran (THF)s, under 30 DEG C of mechanical stirring 1000rpm, the tetrahydrofuran (THF) being dissolved with PGMA-g-(PS-r-PDMAEMA-r-PEG) is instilled 1 part of perhydronaphthalene and 100 parts of pH are in the mixing solutions of the water of 4, stir after 30 minutes, obtain O/w emulsion, namely obtain Nano capsule.
When this acid-sensitive type Nano capsule is raised to more than 6.5 from 4 with pH, the conformation of PDMAEMA side chain occurs to become raw, becomes hydrophobicity, cause acid-sensitive type Nano capsule to disintegrate from hydrophilic.
Embodiment 2
Preparation method and raw material composition are all with embodiment 1, only the hydrophilic side chain of amphipathic acid sensitivity ternary molecular brush polymer of embodiment 1 and the percentage of grafting of acid sensitivity side chain are regulated, the acid-sensitive type Nano capsule of different structure can be obtained, thus be not the acid-sensitive type Nano capsule driving response performance.The grafting ratio of three kinds of side chains is in table 1.
Table 1: the synthesis of the amphipathic acid sensitivity ternary molecular brush polymer of different structure
The amphipathic acid sensitivity ternary molecular brush polymer of being synthesized by table 1 constructs acid-sensitive type Nano capsule, and the acid-sensitive characteristic of the acid-sensitive type Nano capsule constructed is grow with the increase of PDMAEMA grafting amount.
Embodiment 3
Preparation method and raw material composition, all with embodiment 1, only change the composition of the oleophylic side chain of the amphipathic acid sensitivity ternary molecular brush polymer of embodiment 1, can obtain the acid-sensitive type Nano capsule of different-grain diameter size.The composition of oleophylic side chain and Nano capsule size are in table 2.
Oil-wet side chain polymerization degree is that the preparation method of PtBA, PMMA, PCL, PLA, PMA, PVAc, PAN of 50 prepares similar to PS, is to be prepared by conventional ARTP.
The percentage of grafting of often kind of amphipathic nature polyalcohol molecular brush PEG, PDMAEMA, oleophylic side chain is respectively 15%, 25%, 20%.
Table 2: the impact of molecular brush oleophylic side chain composition on acid-sensitive type Nano capsule particle diameter
As can be seen from Table 2, by changing the composition of oleophylic side chain, the acid-sensitive type Nano capsule of different-grain diameter size can be prepared.
Embodiment 4
Preparation method and raw material composition, all with embodiment 1, only change the composition of the hydrophilic side chain of the amphipathic acid sensitivity ternary molecular brush polymer of embodiment 1, can obtain the acid-sensitive type Nano capsule of different-grain diameter size.The composition of hydrophilic side chain and Nano capsule size are in table 3.
The hydrophilic side chain polymerization degree is that the preparation method of PHEMA, PHEA, PVA, PHPMA of 30 is prepared by atom transfer radical polymerization method (ARTP).
Often kind of amphipathic nature polyalcohol molecular brush percentage of grafting that is hydrophilic, PDMAEMA, PS side chain is respectively 15%, 25%, 20%.
Table 3: the impact of molecular brush hydrophilic side chain composition on acid-sensitive type Nano capsule particle diameter
As can be seen from Table 3, by changing the composition of hydrophilic side chain, the acid-sensitive type Nano capsule of different-grain diameter size can be prepared.
Embodiment 5
A kind of amphipathic acid sensitivity ternary molecular brush polymer, is prepared by following steps:
(1) P (GA-N
3) synthesis of main chain
Get 1 part of 2-isobutyl ethyl bromide initiator, 300 parts of GA, 100 parts of phenyl ether, 1 part of CuBr and 1 part PMDETA, 30 DEG C are carried out ATRP and react 3 hours under nitrogen protection, and the preparation polymerization degree (DP) is the PGMA of 150.
Get 100 parts of PGA(DP=150), 100 parts of NaN
3, 500 parts of DMF and 1 part AlCl
3, 50 DEG C of reactions 24 hours, obtained P (GA-N
3), as main chain.
The synthesis of (2) three kinds of side chains
The synthesis of hydrophilic side chain: get 100 parts of mono methoxy polyethylene glycols (Mn=2000), 20 parts of 2-propynyl acetic acid, 20 parts of DMAP, 20 parts of EDC.HCl and 200 part methylene dichloride, 30 DEG C are reacted 24 hours, and the obtained polymerization degree is the PEG-C ≡ CH of 47.
The synthesis of oleophylic side chain: get 1 part of bromo acid propynyl ester initiator, 300 parts of PS, 100 parts of toluene, 1 part of CuBr and 1 part PMDETA, 90 DEG C are carried out ATRP and react 9 hours under nitrogen protection, obtain the PS-C ≡ CH that the polymerization degree (DP) is 120.
The synthesis of acid sensitivity side chain: get 2 parts of bromo acid propynyl ester initiators, 200 parts of vinylformic acid (AA), 200 parts of DMF, 1 part of CuBr and 1 part PMDETA; 50 DEG C are carried out ATRP and react 6 hours under nitrogen protection, and the obtained polymerization degree (DP) is the PAA-C ≡ CH of 100.
(3) synthesis of amphipathic acid sensitivity ternary molecular brush polymer PGA-g-(PS-r-PAA-r-PEG)
By 10 parts of P (GA-N
3), 20 parts of PEG-C ≡ CH, 40 parts of PS-C ≡ CH, 30 parts of PAA-C ≡ CH are dissolved in 500 parts of DMF, then add 1 part of CuSO
4and 5 parts of sodium ascorbates, react 24 hours at 30 DEG C, the percentage of grafting of obtained amphipathic ternary molecular brush polymer PGA-g-(PEG-r-PAA-r-PS), amphipathic nature polyalcohol molecular brush PEG, PAA, PS side chain is respectively 15%, 25%, 20%.
A kind of acid-sensitive type Nano capsule, adopt emulsion self-assembly method to obtain, its preparation method comprises the following steps:
The PGA-g-(PS-r-PAA-r-PEG) that 8 parts are synthesized is dissolved in 20 parts of tetrahydrofuran (THF)s, under 30 DEG C of mechanical stirring 1000rpm, tetrahydrofuran (THF) to be instilled in the water of 1 part of perhydronaphthalene and 200 parts of pH10 in mixing solutions, stir after 30 minutes, be prepared into O/w emulsion, namely obtain acid-sensitive type Nano capsule.
When this acid-sensitive type Nano capsule drops to below 5 from 10 with pH, the conformation of PAA side chain occurs to become raw, becomes hydrophobicity, cause acid-sensitive type Nano capsule to disintegrate from hydrophilic.
Embodiment 6
Preparation method and raw material composition are all with embodiment 5, only the hydrophilic side chain of amphipathic acid sensitivity ternary molecular brush polymer of embodiment 5 and the percentage of grafting of acid sensitivity side chain are regulated, the acid-sensitive type Nano capsule of different structure can be obtained, thus be not the acid-sensitive type Nano capsule driving response performance.The grafting ratio of three kinds of side chains is in table 5.
The amphipathic acid sensitivity ternary molecular brush polymer of being synthesized by table 4 constructs acid-sensitive type Nano capsule, and the acid-sensitive characteristic of the acid-sensitive type Nano capsule constructed is grow with the increase of PAA grafting amount.
Table 4: the synthesis of the amphipathic acid sensitivity ternary molecular brush polymer of different structure
Embodiment 7
Preparation method and raw material composition, all with embodiment 1, only change the composition of the oleophylic side chain of the amphipathic acid sensitivity ternary molecular brush polymer of embodiment 1, can obtain the acid-sensitive type Nano capsule of different-grain diameter size.The composition of oleophylic side chain and Nano capsule size are in table 5.
Oil-wet side chain polymerization degree is that the preparation method of PtBA, PMMA, PCL, PLA, PMA, PVAc, PAN of 120 prepares similar to PS, is be prepared by atom transfer radical polymerization method (ARTP).
The percentage of grafting of often kind of amphipathic nature polyalcohol molecular brush PEG, PAA, oleophylic side chain is respectively 15%, 25%, 20%.
Table 5: the impact of molecular brush oleophylic side chain composition on acid-sensitive type Nano capsule particle diameter
As can be seen from Table 5, by changing the composition of oleophylic side chain, the acid-sensitive type Nano capsule of different-grain diameter size can be prepared.
Embodiment 8
Preparation method and raw material composition, all with embodiment 5, only change the composition of the hydrophilic side chain of the amphipathic acid sensitivity ternary molecular brush polymer of embodiment 5, can obtain the acid-sensitive type Nano capsule of different-grain diameter size.The composition of hydrophilic side chain and Nano capsule size are in table 6.
The hydrophilic side chain polymerization degree is that the preparation method of PHEMA, PHEA, PVA, PHPMA of 30 is prepared by atom transfer radical polymerization method (ARTP).
Often kind of amphipathic nature polyalcohol molecular brush percentage of grafting that is hydrophilic, PDMAEMA, PS side chain is respectively 15%, 25%, 20%.
Table 6: the impact of molecular brush hydrophilic side chain composition on Nano capsule particle diameter
As can be seen from Table 6, by changing the composition of hydrophilic side chain, the acid-sensitive type Nano capsule of different-grain diameter size can be prepared.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (10)
1. an amphipathic acid sensitivity ternary molecular brush polymer, is characterized in that having general formula as follows:
A-g-(B-r-C-r-D)
Wherein, g represents grafting, and r represents random distribution, and A is main polymer chain, and B is lipophilicity polymer side chain, and C is the polymer side chain of acid sensitivity, and D is hydrophilic high mol side chain, and side chain B, C and D are randomly grafted on main chain A;
The polymkeric substance of composition main chain A is the one in poly (glycidyl methacrylate) or polyglycidyl acrylate;
The polymkeric substance of composition lipophilicity polymer side chain B is the one in polystyrene, butyl polyacrylate, polyacrylonitrile, the polyacrylic acid tert-butyl ester, polymethyl acrylate, polymethylmethacrylate, poly(lactic acid), polycaprolactone or polyvinyl acetate (PVA);
The polymkeric substance of polymer side chain C of composition acid sensitivity is the one in polymethyl acrylic acid diformazan ammonia ethyl ester or polyacrylic acid dimethylaminoethyl;
The polymkeric substance of composition hydrophilic high mol side chain D is the one in polyoxyethylene glycol, polyvinyl alcohol, polyacrylic acid hydroxyethanoic acid, poly hydroxy ethyl acrylate or polyhydroxypropyl methaciylate.
2. amphipathic acid sensitivity ternary molecular brush polymer according to claim 1, it is characterized in that: described amphipathic acid sensitivity ternary molecular brush polymer, the polymerization degree of main chain A is 5 ~ 1000, the polymerization degree of side chain B, C, D is 5 ~ 1000, and the percentage of grafting of side chain B, C, D is 5 ~ 100%.
3. amphipathic acid sensitivity ternary molecular brush polymer according to claim 2, it is characterized in that: described amphipathic acid sensitivity ternary molecular brush polymer, the polymerization degree of main chain A is 40 ~ 500, the polymerization degree of side chain B is 20 ~ 300, percentage of grafting is 5 ~ 40%, and the polymerization degree of side chain C is 50 ~ 120, and percentage of grafting is 5 ~ 40%, the polymerization degree of side chain D is 30 ~ 114, percentage of grafting 5 ~ 40%.
4. the synthetic method of the amphipathic acid sensitivity ternary molecular brush polymer described in any one of claims 1 to 3, is characterized in that comprising the following steps:
(1) synthesize main chain, then azide functionalization is carried out to main chain, obtain trunk polymer;
(2) synthesize side chain, in building-up process, introduce alkynyl functional group simultaneously or alkynyl functionalization is carried out to the side chain after synthesis, obtain side chain polymer that is hydrophilic, oleophylic or acid sensitivity;
(3) by a kind of main chain containing nitrine to can mix with the side chain alkynyl that is corresponding a kind of hydrophilic, a kind of oleophylic and a kind of acid sensitivity structure of main chain each Elementary Function group generation chemical reaction, carry out the reaction of a step " nitrine-alkynyl " click chemistry in the presence of a catalyst, obtain amphipathic acid sensitivity ternary molecular brush polymer.
5. the synthetic method of amphipathic acid sensitivity ternary molecular brush polymer according to claim 4, is characterized in that:
Synthesis main chain described in step (1) is adopt a kind of polymerization process in radical polymerization, controllable free-radical polymerisation or anionoid polymerization;
Azide functionalization described in step (1) introduces azido group on each unit of main chain;
Trunk polymer described in step (1) is P (GMA-N
3) or P (GA-N
3);
Synthesis side chain described in step (2) is adopt a kind of polymerization process in radical polymerization, controllable free-radical polymerisation or anionoid polymerization;
Introducing alkynyl functional group described in step (2) or alkynyl function is carried out to the side chain after synthesis turn to introduce alkynyl group on the end of side chain;
Hydrophilic side chain polymer described in step (2) is the one in PEG-C ≡ CH, PVA-C ≡ CH, PHEA-C ≡ CH, PHEMA-C ≡ CH or PHPMA-C ≡ CH;
The side chain polymer of oleophylic described in step (2) is the one in PS-C ≡ CH, PtBA-C ≡ CH, PBA-C ≡ CH, PAN-C ≡ CH, PMMA-C ≡ CH, PLA-C ≡ CH, PCL-C ≡ CH or PVAc-C ≡ CH;
Acid sensitivity side chain polymer described in step (2) is the one in PDMAEMA-C ≡ CH or PDMAEA-C ≡ CH.
6. the synthetic method of amphipathic acid sensitivity ternary molecular brush polymer according to claim 4, is characterized in that:
Catalyzer described in step (3) is the one in following combination: copper sulfate and xitix, cuprous bromide and pentamethyl-diethylenetriamine or cuprous bromide and 2,2'-dipyridyl; Described copper sulfate and the mass ratio of xitix are 1:5.
7. a preparation method for acid-sensitive type Nano capsule, is characterized in that comprising the steps:
Amphipathic acid sensitivity ternary molecular brush polymer described in 1 ~ 10 any one of mass parts claims 1 to 3 is dissolved in 1 ~ 50 mass parts tetrahydrofuran (THF), 50 ~ 200 mass parts oil and water two-phase systems of the adjusted good potential of hydrogen of tetrahydrofuran (THF) instillation of acid sensitivity ternary molecular brush polymer will be dissolved with again, stirring obtains O/w emulsion, thus obtains acid-sensitive type Nano capsule.
8. the preparation method of acid-sensitive type Nano capsule according to claim 7, is characterized in that:
Described oil and water two-phase system are the two-phase mixtures system of oil phase and aqueous phase composition; Described oil phase is a kind of in perhydronaphthalene, peruscabin or cyclohexane; Described aqueous phase to be pH be 1 ~ 14 the aqueous solution; In described oil and water two-phase system, the mass ratio of oil phase and aqueous phase is 1:10 ~ 200.
9. an acid-sensitive type Nano capsule, it is characterized in that being prepared by the preparation method described in any one of claim 7 ~ 8, the particle diameter of described acid-sensitive type Nano capsule is 20 ~ 1000nm.
10. acid-sensitive type Nano capsule according to claim 9, with pH environmental change, there is acid-sensitive disintegration in Nano capsule, bag carried the substance release of the inside in external environment, applies in medicament slow release field, nano-reactor or catalyzer.
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| CN103755968B (en) * | 2013-12-31 | 2016-08-17 | 中科院广州化学有限公司 | A kind of pH and the ternary molecular brush polymer of temperature dual response and the Nano capsule of preparation thereof |
| US20180325785A1 (en) * | 2015-11-25 | 2018-11-15 | Asanuma Corporation | Method for manufacturing capsule |
| CN105778112B (en) * | 2016-03-09 | 2018-07-06 | 中科院广州化学有限公司南雄材料生产基地 | A kind of amphipathic pH value response ternary brush polymer and nanoporous capsule |
| CN105646890B (en) * | 2016-03-09 | 2018-07-06 | 中科院广州化学有限公司南雄材料生产基地 | A kind of chemical crosslinking pH value response multiarm polymers and nanoporous capsule |
| CN105646891B (en) * | 2016-03-14 | 2019-02-01 | 中科院广州化学有限公司南雄材料生产基地 | A kind of amphipathic ternary molecular brush polymer and its vermiform unimolecular micelle constructed |
| CN105801873B (en) * | 2016-03-14 | 2019-03-22 | 中科院广州化学有限公司南雄材料生产基地 | Amphipathic binary molecule brush polymer and its pH responsiveness unimolecule nano-micelle constructed |
| CN105646892A (en) * | 2016-03-14 | 2016-06-08 | 中科院广州化学有限公司南雄材料生产基地 | Amphiphilic binary molecular brush polymer and acid-sensitive targeting nanocapsule prepared from same |
| CN108047453B (en) * | 2017-12-21 | 2021-03-02 | 西北大学 | Degradable aliphatic polyester and preparation method and application thereof |
| CN108187068B (en) | 2018-01-15 | 2019-04-23 | 江南大学 | A kind of preparation and its application of photosensitizer composite Nano multifunctional material |
| CN108395507A (en) * | 2018-03-08 | 2018-08-14 | 广州锐澄医疗技术有限公司 | A kind of preparation method of the lacrimal bolt with drug slow release function |
| CN108948363A (en) * | 2018-06-05 | 2018-12-07 | 常州大学 | A method of preparing the multiple response hydrogel of ordered structure |
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