CN105646892A - Amphiphilic binary molecular brush polymer and acid-sensitive targeting nanocapsule prepared from same - Google Patents
Amphiphilic binary molecular brush polymer and acid-sensitive targeting nanocapsule prepared from same Download PDFInfo
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Abstract
The invention belongs to the field of functional polymer nanomaterials and particularly discloses an amphiphilic binary molecular brush polymer and an acid-sensitive targeting nanocapsule prepared from the same. The amphiphilic binary molecular brush polymer is mainly prepared by means of atom transfer radical polymerization and click chemical reaction. The nanocapsule is prepared by dissolving the acid-sensitive binary molecular brush polymer into a N,N- dimethylformamide and benzyl benzoate mixed solvent, and dropwise adding the polymer solution into water with pH being 9 under the condition of strong stirring. A folic acid radical group at the tail end of a hydrophilic side chain enables the prepared nanocapsule to have a targeting function. Compared with other acid-sensitive nanocapsules prepared from molecular brush polymers, the acid-sensitive targeting nanocapsule has the advantages that the preparation method is simple; reaction sites can be provided for further functionalization; by introduction of the targeting radical group to the surface of the nanocapsule, targeted release of drugs can be realized so as to effectively weaken toxic and side effects of the drugs on normal tissues and organs; drug loading capacity is high.
Description
Technical field
The invention belongs to functional high-polymer field of nanometer material technology, be specifically related to the acid-sensitive targeted nano capsule of a kind of amphipathic binary molecule brush polymer and preparation thereof.
Background technology
As the main disease of harm human health, cancer has been obtained for the extensive attention of people. The main method that pharmacotherapy is treatment cancer one of is complied with. But many cancer therapy drugs (such as camptothecine, paclitaxel, amycin) all also exists and is insoluble in the shortcoming such as water, poor stability, thus it is difficult to be utilized well by organism. Solve the key that this type of water solubility problems is this kind of pharmaceutical preparation clinical practice. Additionally, most of anti-tumor medicines scarcely have selectivity, medicine is while treatment cancer, and also normal tissue organ often has bigger toxic and side effects big. Therefore, the dissolubility of cancer therapy drug is improved and the selectivity of cancerous cell is extremely urgent.
Polymer nanocapsules is one of modal pharmaceutical carrier, has caused the broad interest of biomedicine field researcher in recent years. The effect of the pharmaceutical carrier developed should be mainly reflected in the following aspects: (1) increases medicine dissolubility in vivo; (2) toxicity to biological tissue in medicine transmittance process in vivo is shielded; (3) medicine residence time in vivo is extended, thus reducing administration number of times and dosage; (4) realize medicine slow releasing, so that the concentration of body fluid Chinese medicine maintains in a Valid concentration for a long time, so both decrease administration number of times, also reduce medicine toxicity in vivo; (5) there is targeting group, reduce the toxic and side effects of medicine normal tissue.
The technology of preparing of Nano capsule mainly has following four: dendrimer prepares method, emulsion/suspension polymerization, matrix polymerization method and self-assembly method.Dendrimer is prepared method and is typically required multistep reaction, and each step is required for taking strict protection/deprotection measure and careful purification, and the difficulty of preparation causes the costliness of price, limits its application as expendable material. Emulsion/suspension polymerization is a kind of traditional polymerization, and technique is simple, but the Nano capsule functionalization prepared is more single, and particle size distribution is wider. Matrix polymerization method, by selecting different size template to be prepared capsule, is accurately controlled size and the distribution of capsule, but usually needs template is carried out post processing, and condition is harsh, and the pattern of capsule is had large effect. Self-assembling method prepares Nano capsule can simply by the structure of regulation and control polymer to control the various functions of capsule, especially emulsion self-assembling method, it is not necessary to adds other auxiliary agents, preparation method environmental friendliness.
The research preparing Nano capsule by self-assembly method currently, with respect to block copolymer is more, but the block copolymer difficulty of composite structure complexity is relatively big, limits the diversified capsule of self-assembling method processability. Comparatively speaking, graft copolymer has great advantage in realizing functional diversities. Have some patents and the bibliographical information Nano capsule prepared by graft copolymer at present. Patent CN102911370A reports a kind of Nano capsule constructed by amphipathic ternary molecular brush polymer, solving the difficult difficult problem effectively regulated and control Nano capsule size of tradition segmented copolymer, the photo-crosslinking structure nano capsule size of preparation easily regulates and controlled; Patent CN103059312A reports a kind of amphipathic ternary molecular brush polymer and constructs multichannel Nano capsule, solve the channel-less difficult problem of Conventional nano capsule, the preparation method that patent CN104645908A reports photo-crosslinking type nanometer wax phase change energy storage capsule, solves the problem that prior paraffin capsule difficulty prepares into nanometer particle size. Above patent all have employed photo-crosslinking method to obtain stable Nano capsule. But, part cancer therapy drug such as amycin etc., under ultra-vioket radiation, structure can change; And, after crosslinking latch-up structure, the material being coated on capsule is difficult to discharge; It addition, above capsule surface is absent from active group in order to further targeting modification, the sour environment of tumor locus is not deposited response, thus, above capsule is difficult to be applied to well field of medicine release.
Summary of the invention
For solving the shortcoming and defect part of prior art, the primary and foremost purpose of the present invention is in that to provide a kind of amphipathic binary molecule brush polymer.
Another object of the present invention is to provide the synthetic method of above-mentioned amphipathic binary molecule brush polymer.
It is still another object of the present invention to provide acid-sensitive targeted nano capsule prepared by above-mentioned amphipathic binary molecule brush polymer. This Nano capsule has the advantage that can realize medicine discharges pH sensitivity in cancerous cell targeted delivery and cancerous cell; Drug loading is big; Its target function can effectively reduce medicine normal tissue organ toxic and side effects.
Present invention also offers the purposes of above-mentioned acid-sensitive targeted nano capsule.
The object of the invention is achieved through the following technical solutions:
A kind of amphipathic binary molecule brush polymer has following formula: A-g-(B-r-C);
Wherein, g represents grafting, and r represents random copolymerization, and A is main polymer chain, and B is acid-sensitive polymer side chain, and C is hydrophilic macromolecule side chain, and acid-sensitive polymer side chain B and hydrophilic macromolecule side chain C is randomly grafted on main polymer chain A;
The degree of polymerization of described main polymer chain A is 100��1000; The degree of polymerization of described acid-sensitive polymer side chain B and hydrophilic macromolecule side chain C is 50��400, and percent grafting is 1��100%;
The polymer forming described main polymer chain A can be azido poly hydroxy ethyl acrylate P (HEMA-N3), azido polyhydroxypropyl methaciylate (PHPMA-N3), azido polyhydroxypropyl acrylate (PHPA-N3), Azidoethyl cellulose (EC-N3), alkynyl ethyl cellulose (EC-C �� CH), alkynyl poly hydroxy ethyl acrylate P (HEMA-C �� CH), alkynyl polyhydroxypropyl methaciylate (PHPMA-C �� CH), one in alkynyl polyhydroxypropyl acrylate (PHPA-C �� CH) and alkynyl Poly(Hydroxyethyl Methacrylate) P (HEA-C �� CH);
Forming the polymer of described acid-sensitive polymer side chain B be end is the polymethylacrylic acid diformazan ammonia ethyl ester (PDMAEMA-C �� CH) of alkynyl, polymethylacrylic acid lignocaine ethyl ester (PDEAEMA-C �� CH), polyvinylpyridine (PVPy-C �� CH) and poly-(N, N'-diisopropylamine ethylmethyl acrylate) one in (PDPAEMA-C �� CH), or the polymethylacrylic acid diformazan ammonia ethyl ester (PDMAEMA-N that end is azido3) and polymethylacrylic acid lignocaine ethyl ester (PDEAEMA-N3) in one;
Form the polymer of described hydrophilic macromolecule side chain C to be end be the one in the Polyethylene Glycol (HO-PEG-C �� CH) of alkynyl and polyvinyl alcohol (PVA-C �� CH) or the Polyethylene Glycol (HO-PEG-N that end is azido3);
Above-mentioned amphipathic binary molecule brush polymer can pass through the method synthesis such as living polymerization and some chemistry, and its synthetic method specifically includes following steps:
(1) synthesis main chain, then main chain is carried out functionalization, obtain functionalization trunk polymer;
(2) synthesis side chain, is simultaneously introduced functional group in building-up process or the side chain after synthesis is carried out functionalization, obtaining hydrophilic macromolecule side chain polymer, acid-sensitive polymer side chain polymer;
(3) hydrophilic macromolecule side chain polymer is carried out modified with folic acid, obtain the hydrophilic macromolecule side chain polymer with targeting group;
(4) by functionalization trunk polymer with there is the hydrophilic macromolecule side chain polymer of targeting group, acid-sensitive polymer side chain polymer mixed, carry out the reaction of a step " nitrine-alkynyl " click chemistry in the presence of a catalyst, obtain amphipathic binary molecule brush polymer.
Synthesis main chain described in step (1) adopts a kind of polymerization in radical polymerization, controllable free-radical polymerisation and anionic polymerisation;
Functionalization described in step (1) is to introduce alkynyl or azido group on each unit of main chain;
Functionalization trunk polymer described in step (1) is azido poly hydroxy ethyl acrylate P (HEMA-N3), azido polyhydroxypropyl methaciylate (PHPMA-N3), azido polyhydroxypropyl acrylate (PHPA-N3), Azidoethyl cellulose (EC-N3), alkynyl ethyl cellulose (EC-C �� CH), alkynyl poly hydroxy ethyl acrylate P (HEMA-C �� CH), alkynyl polyhydroxypropyl methaciylate (PHPMA-C �� CH), one in alkynyl polyhydroxypropyl acrylate (PHPA-C �� CH) and alkynyl Poly(Hydroxyethyl Methacrylate) P (HEA-C �� CH);
Synthesis side chain described in step (2) adopts a kind of polymerization in radical polymerization, controllable free-radical polymerisation and anionic polymerisation;
Introducing functional group described in step (2) and functionalization are to introduce alkynyl or azido group on the end of side chain;
Acid-sensitive polymer side chain polymer described in step (2) is end is the polymethylacrylic acid diformazan ammonia ethyl ester (PDMAEMA-C �� CH) of alkynyl, polymethylacrylic acid lignocaine ethyl ester (PDEAEMA-C �� CH), polyvinylpyridine (PVPy-C �� CH) and poly-(N, N'-diisopropylamine ethylmethyl acrylate) one in (PDPAEMA-C �� CH), or the polymethylacrylic acid diformazan ammonia ethyl ester (PDMAEMA-N that end is azido3) and polymethylacrylic acid lignocaine ethyl ester (PDEAEMA-N3) in one;
Hydrophilic macromolecule side chain polymer described in step (2) is end is the one in the Polyethylene Glycol (HO-PEG-C �� CH) of alkynyl and polyvinyl alcohol (PVA-C �� CH), or the Polyethylene Glycol (HO-PEG-N that end is azido3);
Modified with folic acid that hydrophilic macromolecule side chain polymer is carried out described in step (3) is introducing folic acid group on the hydrophilic side chain polymer carrying out alkynyl;
Catalyst described in step (4) is the one in following combination: copper sulfate and ascorbic acid (amount of substance than for 1:1), cuprous bromide and pentamethyl-diethylenetriamine (amount of substance than for 1:1), cuprous bromide and 2,2'-bipyridyl (amount of substance than for 1:2).
A kind of acid-sensitive targeted nano capsule, particle diameter is 20-1000nm, it is prepared by above-mentioned amphipathic binary molecule brush polymer, specifically comprise the following steps that and above-mentioned amphipathic binary molecule brush polymer is dissolved in N, in dinethylformamide and benzyl benzoate mixed liquor, quickly under stirring, this polymer solution is slowly added dropwise in the water of pH=9, remove DMF through dialysis and obtain acid-sensitive targeted nano capsule. Acid-sensitive hydrophobic side chain is dissolved in oil phase, and the hydrophilic side-chains with targeting group is soluble in the aqueous phase, thus obtaining acid-sensitive hydrophobic side chain at shell, hydrophilic side-chains is in the oil-in-water structure of outer layer. In use, targeting group takes the capsule of bag medicine carrying thing to tumor locus, owing to tumor locus PH is in acidity, the conformation of capsule hydrophobicity acid-sensitive side chain will change, hydrophilic being become from hydrophobicity, thus causing that capsule hydrophobicity inwall dissolves, reaching release purpose.
Above-mentioned acid-sensitive targeted nano capsule can be applicable in drug targeting release, nano-reactor or catalyst.
Compared with prior art, the present invention has the following advantages and beneficial effect:
(1) present invention adopts emulsion self-assembly method to prepare Nano capsule, simple to operate, easily can scale prepare. The Nano capsule covering amount of preparation is big.
(2) surface that the present invention prepares has targeting group Nano capsule, solves the problem that conventional capsules cannot realize Targeting delivery, it is possible to realize the targeted delivery of medicine.
(3) capsule prepared by the present invention has acid-sensitive, solves conventional capsules and cancer site is absent from the problem of response, and capsule disintegrates at tumor locus and discharges medicine, can effectively reduce medicine normal tissue organ toxic and side effects.
Accompanying drawing explanation
Fig. 1 is the drug release situation after targeting and non-targeted capsule bag load amycin (DOX) under hepatoma carcinoma cell sour environment.
Detailed description of the invention
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited to this.
Embodiment 1
A kind of amphipathic binary molecule brush polymer, is prepared by following steps:
(1)P(HEMA-N3) synthesis of main chain
By amount of substance ratio; take 1 part of 2-isobutyl bromide mono methoxy ethyl ester initiator, 100 parts of hydroxyethyl methylacrylates (HEMA), 100 parts of methanol, 1 part of CuCl and 1 part 2; 2'-bipyridyl; 50 DEG C carry out ATRP reaction under nitrogen protection, and obtaining the degree of polymerization (DP) is the PHEMA of 101.
By amount of substance ratio, taking 1 part of PHEMA, 150 parts of dibromo-isobutyl acylbromides, 1000 parts of anhydrous pyridines reactions overnight, after being concentrated by product, Direct precipitation is in water, obtains P (HEMA-Br).
By amount of substance ratio, take a P (HEMA-Br), three parts of NaN3With 100 parts of DMF, reaction 48h at 50 DEG C, concentrating and precipitating obtains trunk polymer P (HEMA-N in water3)��
The synthesis of (2) two kinds of side chains
The synthesis of hydrophilic macromolecule side chain: by amount of substance ratio, take 1 part of Polyethylene Glycol (Mn=5000), 1 part of 2-propynyl acetic acid, 4 parts of DMAPs (DMAP), 6 parts of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCl) and 500 parts of dichloromethane, 30 DEG C are reacted 24 hours, obtain HO-PEG-C �� CH after crossing column purification.
The synthesis of acid-sensitive polymer side chain: by amount of substance ratio; take 1 part of trimethyl silicane propargyl-2-bromine isobutyl ester initiator, 80 parts of diethylaminoethyl methacrylates (DEAEMA), 460 parts of methanol, 1 part of CuBr and 1 part of N; N; N'; N'; "-pentamethyl-diethylenetriamine (PMDETA), 50 DEG C carry out ATRP reaction 6 hours to N under nitrogen protection, obtain the PDEAEMA-C �� CH that trimethyl silicane alkynyl is end. By amount of substance ratio, take the PDEAEMA polymer that 1 part of trimethyl silicane alkynyl is end, be dissolved in 5000 oxolanes, add 2 parts of tetrabutyl ammonium fluorides, be hydrolyzed 24h under room temperature, after sloughing trimethyl silicane group, obtain the PDEAEMA-C �� CH that DP is 75.
(3) hydrophilic macromolecule side chain is carried out modified with folic acid: by amount of substance ratio, taking a HO-PEG-C �� CH, 2 parts of folic acid, 4 parts of DMAPs (DMAP), 6 parts of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCl) and 500 parts of dichloromethane, 30 DEG C of reactions obtain HC �� C-PEG-folic acid for 24 hours.
(4) synthesis of amphipathic binary molecule brush polymer P HEMA-g-(PDEAEMA-r-PEG-folic acid)
By amount of substance ratio, take 1 part of P (HEMA-N3), 30 parts of HC �� C-PEG-folic acid, 9 parts of PDEAEMA-C �� CH be dissolved in 1000 parts of dimethylformamides (DMF), add 1 part of CuSO4And 2 parts of sodium ascorbates, react 24 hours at 30 DEG C, obtain amphipathic binary molecule brush polymer P HEMA-g-(PDEAEMA-r-PEG-folic acid), the percent grafting of MPEG, PDEAEMA side chain respectively 13%, 2%.
A kind of Nano capsule, adopts emulsion self-assembly method to prepare, and its preparation method comprises the following steps:
Take 1 part of two parent's property binary molecule brush polymer P HEMA-g-(PDEAEMA-r-PEG-folic acid) and be dissolved in 10 parts of N, in dinethylformamide and 1 portion of benzyl benzoate mixed liquor, under room temperature mechanical agitation 1000rpm, this polymer solution is added drop-wise in the water of 100 parts of pH=9, after stirring 30 minutes, transfer to dialysis in bag filter and remove DMF, obtaining and stablize acid-sensitive hydrophobic side chain in inside, hydrophilic side-chains is in the oil-in-water structure of outer layer. PH response value is 6.5.
Embodiment 2
Raw material and preparation method are with embodiment 1, and the consumption of para Toluic Acid's benzyl ester is adjusted, and probes into the consumption impact on capsule stability of benzyl benzoate, and result is as shown in table 1.
The impact on capsule stability of the consumption of table 1 benzyl benzoate
As shown in Table 1, when benzyl benzoate is more than a certain value, it is impossible to obtain stable emulsion.
Embodiment 3
The degree of polymerization of PDEAEMA, with embodiment 1, is adjusted by raw material and preparation method, probes into the degree of polymerization impact on capsule size of PDEAEMA, and result is as shown in table 2.
The impact on capsule size of the degree of polymerization of table 2PDEAEMA
As can be seen from Table 2, by regulating the degree of polymerization of merit PDEAEMA, the Nano capsule of various sizes of response can be prepared.
Embodiment 4
Acid-sensitive polymer side chain and hydrophilic macromolecule side chain mass ratio, with embodiment 1, are adjusted by raw material and preparation method, probe into acid-sensitive polymer side chain and the impact on capsule size of the hydrophilic macromolecule side chain mass ratio, and result is as shown in table 3.
Table 3 acid-sensitive polymer side chain and the impact on capsule size of the hydrophilic macromolecule side chain mass ratio
As can be seen from Table 3, polymer brush dredges/hydrophilic side chain mass ratio difference, and the Nano capsule size obtained is also different.
Embodiment 5
Acid-sensitive polymer side chain length, with embodiment 1, is adjusted by raw material and preparation method, probes into the impact on capsule PH response value of the acid-sensitive polymer side chain degree of polymerization, and result is as shown in table 4.
The impact on capsule PH response value of the table 4 acid-sensitive polymer side chain degree of polymerization
As can be seen from Table 4, the PDEAEMA degree of polymerization is more big, and capsule PH response value is more little.
Embodiment 6
Raw material and preparation method are with embodiment 1, it is respectively adopted modified with folic acid and the hydrophilic side-chains of non-folate modification, prepare targeting and non-targeted capsule, after contrasting targeting and non-targeted capsule bag load amycin (DOX), the drug release situation under hepatoma carcinoma cell sour environment. As it is shown in figure 1, after DOX, 4h by targeting capsule bag load, enter nucleus in a large number, and the DOX of non-targeted capsule bag load, then only enter nucleus on a small quantity. This shows, the acid-sensitive targeting capsule that this patent prepares has under hepatoma carcinoma cell sour environment and well pinpoints releasing effect.
Embodiment 7
(1)P(HEMA-N3) synthesis of main chain
By amount of substance ratio; take 1 part of 2-isobutyl bromide mono methoxy ethyl ester initiator, 100 parts of hydroxyethyl methylacrylates (HEMA), 100 parts of methanol, 1 part of CuCl and 1 part 2; 2'-bipyridyl; 50 DEG C carry out ATRP reaction under nitrogen protection, and obtaining the degree of polymerization (DP) is the PHEMA of 101.
By amount of substance ratio, taking 1 part of PHEMA, 150 parts of dibromo-isobutyl acylbromides, 1000 parts of anhydrous pyridines reactions overnight, after being concentrated by product, Direct precipitation is in water, obtains P (HEMA-Br).
By amount of substance ratio, take a P (HEMA-Br), three parts of NaN3With 100 parts of DMF, reaction 48h at 50 DEG C, concentrating and precipitating obtains trunk polymer P (HEMA-N in water3)
The synthesis of (2) two kinds of side chains
The synthesis of hydrophilic macromolecule side chain: by amount of substance ratio, take 1 part of Polyethylene Glycol (Mn=5000), 1 part of 2-propynyl acetic acid, 4 parts of DMAPs (DMAP), 6 parts of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCl) and 500 parts of dichloromethane, 30 DEG C are reacted 24 hours, obtain HO-PEG-C �� CH after crossing column purification.
The synthesis of acid-sensitive polymer side chain: by amount of substance ratio; take 1 part of trimethyl silicane propargyl-2-bromine isobutyl ester initiator, 80 parts of diethylaminoethyl methacrylates (DMAEMA), 500 parts of methanol, 1 part of CuBr and 1 part of N; N; N'; N'; "-pentamethyl-diethylenetriamine (PMDETA), 50 DEG C carry out ATRP reaction 6 hours to N under nitrogen protection, obtain the PDMAEMA-C �� CH that trimethyl silicane alkynyl is end. By amount of substance ratio, take the PDMAEMA polymer that 1 part of trimethyl silicane alkynyl is end, be dissolved in 5000 oxolanes, add 2 parts of tetrabutyl ammonium fluorides, be hydrolyzed 24h under room temperature, after sloughing trimethyl silicane group, obtain the PDMAEMA-C �� CH that DP is 75.
(3) hydrophilic macromolecule side chain is carried out modified with folic acid: by amount of substance ratio, take a HO-PEG-C �� CH, 2 parts of folic acid, 4 parts of DMAPs (DMAP), 6 parts of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCl) and 500 parts of dichloromethane, 30 DEG C of reactions obtain HC �� C-PEG-folic acid for 24 hours.
(4) synthesis of amphipathic binary molecule brush polymer P HEMA-g-(PDMEAMA-r-PEG-folic acid)
By amount of substance ratio, take 1 part of P (HEMA-N3), 30 parts of HC �� C-PEG-folic acid, 9 parts of PDMAEMA-C �� CH be dissolved in 1000 parts of dimethylformamides (DMF), add 1 part of CuSO4And 2 parts of sodium ascorbates, react 24 hours at 30 DEG C, obtain amphipathic binary molecule brush polymer P HEMA-g-(PDMAEMA-r-PEG-folic acid), the percent grafting of MPEG, PDMAEMA side chain respectively 13%, 2%.
A kind of Nano capsule, adopts emulsion self-assembly method to prepare, and its preparation method comprises the following steps:
Take 1 part of two parent's property binary molecule brush polymer P HEMA-g-(PDMAEMA-r-PEG-folic acid) and be dissolved in 10 parts of N, in dinethylformamide and 1 portion of benzyl benzoate mixed liquor, under room temperature mechanical agitation 1000rpm, this polymer solution is added drop-wise in the water of 100 parts of PH=9, after stirring 30 minutes, transfer to dialysis in bag filter and remove DMF, obtaining and stablize acid-sensitive hydrophobic side chain in inside, hydrophilic side-chains is in the oil-in-water structure of outer layer. PH response value is 8.5.
Embodiment 8
Acid-sensitive polymer side chain length, with embodiment 7, is adjusted by raw material and preparation method, probes into the impact on capsule PH response value of the acid-sensitive polymer side chain degree of polymerization, and result is as shown in table 5.
The impact on capsule PH response value of the table 5 acid-sensitive polymer side chain degree of polymerization
As can be seen from Table 5, by regulating the degree of polymerization of PDMAEMA, the acid-sensitive Nano capsule of different PH response value can be prepared.
Embodiment 9
Backbone polymerization degree, with embodiment 7, is adjusted by raw material and preparation method, probes into the impact on capsule size of the backbone polymerization degree, and result is as shown in table 6.
The impact on capsule size of the table 6 backbone polymerization degree
As can be seen from Table 6, by regulating the degree of polymerization of main chain, various sizes of acid-sensitive Nano capsule can be prepared.
Embodiment 10
Acid-sensitive polymer side chain and hydrophilic macromolecule side chain mass ratio, with embodiment 7, are adjusted by raw material and preparation method, probe into acid-sensitive polymer side chain and the impact on capsule size of the hydrophilic macromolecule side chain mass ratio, and result is as shown in table 7.
Table 7 acid-sensitive polymer side chain and the impact on capsule size of the hydrophilic macromolecule side chain mass ratio
As can be seen from Table 7, by regulating acid-sensitive polymer side chain and hydrophilic macromolecule side chain mass ratio, various sizes of acid-sensitive Nano capsule can be prepared.
Embodiment 11
Acid-sensitive polymer side chain and hydrophilic macromolecule side chain mass ratio, with embodiment 7, are adjusted, probe into the impact on capsule size of total percent grafting by raw material and preparation method, and result is as shown in table 8.
The total percent grafting impact on capsule size of table 8
As can be seen from Table 8, by regulating acid-sensitive polymer side chain and hydrophilic macromolecule side chain mass ratio, various sizes of acid-sensitive Nano capsule can be prepared.
Above-described embodiment is the present invention preferably embodiment; but embodiments of the present invention are also not restricted to the described embodiments; the change made under other any spirit without departing from the present invention and principle, modification, replacement, combination, simplification; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (8)
1. an amphipathic binary molecule brush polymer, it is characterised in that described amphipathic binary molecule brush polymer has following formula: A-g-(B-r-C);
Wherein, g represents grafting, and r represents random copolymerization, and A is main polymer chain, and B is acid-sensitive polymer side chain, and C is hydrophilic macromolecule side chain, and acid-sensitive polymer side chain B and hydrophilic macromolecule side chain C is randomly grafted on main polymer chain A;
The polymer forming described main polymer chain A is the one in azido poly hydroxy ethyl acrylate, azido polyhydroxypropyl methaciylate, azido polyhydroxypropyl acrylate, Azidoethyl cellulose, alkynyl ethyl cellulose, alkynyl poly hydroxy ethyl acrylate, alkynyl polyhydroxypropyl methaciylate, alkynyl polyhydroxypropyl acrylate and alkynyl Poly(Hydroxyethyl Methacrylate);
Forming the polymer of described acid-sensitive polymer side chain B be end is the polymethylacrylic acid diformazan ammonia ethyl ester of alkynyl, polymethylacrylic acid lignocaine ethyl ester, polyvinylpyridine and poly-(N, N'-diisopropylamine ethylmethyl acrylate) in one, or the one in the polymethylacrylic acid diformazan ammonia ethyl ester that end is azido and polymethylacrylic acid lignocaine ethyl ester;
Form the polymer of described hydrophilic macromolecule side chain C to be end be the one in the Polyethylene Glycol of alkynyl and polyvinyl alcohol, or end is the Polyethylene Glycol of azido.
2. amphipathic binary molecule brush polymer according to claim 1, it is characterised in that the degree of polymerization of described main polymer chain A is 100��1000; The degree of polymerization of described acid-sensitive polymer side chain B and hydrophilic macromolecule side chain C is 50��400, and percent grafting is 1��100%.
3. the synthetic method of the amphipathic binary molecule brush polymer described in claim 1 or 2, it is characterised in that comprise the following steps:
(1) synthesis main chain, then main chain is carried out functionalization, obtain functionalization trunk polymer;
(2) synthesis side chain, is simultaneously introduced functional group in building-up process or the side chain after synthesis is carried out functionalization, obtaining hydrophilic macromolecule side chain polymer, acid-sensitive polymer side chain polymer;
(3) hydrophilic macromolecule side chain polymer is carried out modified with folic acid, obtain the hydrophilic macromolecule side chain polymer with targeting group;
(4) by functionalization trunk polymer with there is the hydrophilic macromolecule side chain polymer of targeting group, acid-sensitive polymer side chain polymer mixed, carry out the reaction of a step " nitrine-alkynyl " click chemistry in the presence of a catalyst, obtain amphipathic binary molecule brush polymer.
4. the synthetic method of amphipathic binary molecule brush polymer according to claim 3, it is characterised in that
Functionalization trunk polymer described in step (1) is the one in azido poly hydroxy ethyl acrylate, azido polyhydroxypropyl methaciylate, azido polyhydroxypropyl acrylate, Azidoethyl cellulose, alkynyl ethyl cellulose, alkynyl poly hydroxy ethyl acrylate, alkynyl polyhydroxypropyl methaciylate, alkynyl polyhydroxypropyl acrylate and alkynyl Poly(Hydroxyethyl Methacrylate);
Acid-sensitive polymer side chain polymer described in step (2) is end is the polymethylacrylic acid diformazan ammonia ethyl ester of alkynyl, polymethylacrylic acid lignocaine ethyl ester, polyvinylpyridine and poly-(N, N'-diisopropylamine ethylmethyl acrylate) in one, or the one in the polymethylacrylic acid diformazan ammonia ethyl ester that end is azido and polymethylacrylic acid lignocaine ethyl ester;
Hydrophilic macromolecule side chain polymer described in step (2) is end is the one in the Polyethylene Glycol of alkynyl and polyvinyl alcohol, or end is the Polyethylene Glycol of azido.
5. the synthetic method of amphipathic binary molecule brush polymer according to claim 3, it is characterized in that, catalyst described in step (4) is the one in following combination: copper sulfate and ascorbic acid, cuprous bromide and pentamethyl-diethylenetriamine, cuprous bromide and 2,2'-bipyridyls.
6. an acid-sensitive targeted nano capsule, it is characterised in that described acid-sensitive targeted nano capsule grain diameter is 20��1000nm, the amphipathic binary molecule brush polymer that described acid-sensitive targeted nano capsule is described in claim 1 or 2 prepares.
7. acid-sensitive targeted nano capsule according to claim 6, it is characterized in that, described acid-sensitive targeted nano capsule is prepared by following steps: amphipathic binary molecule brush polymer is dissolved in N, in dinethylformamide and benzyl benzoate mixed liquor, under stirring, this polymer solution is added drop-wise in the water of pH=9, removes DMF through dialysis and obtain acid-sensitive targeted nano capsule.
8. the application in drug targeting release, nano-reactor or catalyst field of the acid-sensitive targeted nano capsule described in claim 6.
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| CN108187068A (en) * | 2018-01-15 | 2018-06-22 | 江南大学 | A kind of preparation and its application of novel photosensitive agent composite Nano multifunctional material |
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| CN103289099A (en) * | 2013-06-07 | 2013-09-11 | 中科院广州化学有限公司 | Amphiphilic acid-sensitive ternary molecular brush polymer constructed acid-sensitive nanocapsule |
| CN104306982A (en) * | 2014-09-10 | 2015-01-28 | 济南大学 | Preparation of star-shaped folic acid-polyethylene glycol-polycaprolactone copolymer |
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| CN103059312A (en) * | 2012-12-12 | 2013-04-24 | 中科院广州化学有限公司 | Amphipathic ternary molecular brush polymer constructed multichannel nanocapsule |
| CN103289099A (en) * | 2013-06-07 | 2013-09-11 | 中科院广州化学有限公司 | Amphiphilic acid-sensitive ternary molecular brush polymer constructed acid-sensitive nanocapsule |
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| CN108066285A (en) * | 2017-11-30 | 2018-05-25 | 江南大学 | A kind of Liver targeting conveys the integration nanosystems and preparation method of gene/drug altogether |
| CN108187068A (en) * | 2018-01-15 | 2018-06-22 | 江南大学 | A kind of preparation and its application of novel photosensitive agent composite Nano multifunctional material |
| WO2019136866A1 (en) * | 2018-01-15 | 2019-07-18 | 江南大学 | Preparation of novel photosensitizer composite nano multifunctional material and use thereof |
| JP2021510708A (en) * | 2018-01-15 | 2021-04-30 | 江南大学Ｊｉａｎｇｎａｎ Ｕｎｉｖｅｒｓｉｔｙ | Preparation of new photosensitizer composite nano-multifunctional material and its use |
| JP7055881B2 (en) | 2018-01-15 | 2022-04-18 | 江南大学 | Preparation and use of new photosensitizer composite nano-multifunctional materials |
| US11359044B2 (en) * | 2018-01-15 | 2022-06-14 | Jiangnan University | Preparation and application of novel multifunctional nanocomposite material with new photosensitizer |
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