CN108003266B - A kind of quadruple stimuli responsive polyaminoacid nanogel and its preparation method and application - Google Patents

A kind of quadruple stimuli responsive polyaminoacid nanogel and its preparation method and application Download PDF

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CN108003266B
CN108003266B CN201711325286.0A CN201711325286A CN108003266B CN 108003266 B CN108003266 B CN 108003266B CN 201711325286 A CN201711325286 A CN 201711325286A CN 108003266 B CN108003266 B CN 108003266B
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雒春辉
位宁
王峰
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Abstract

The invention belongs to intelligent polymer field of material technology, it is related to a kind of quadruple stimuli responsive polyaminoacid nanogel and its preparation method and application.The present invention is merely with vinyl amino acid function monomer, in the presence of Macromolecular chain transfer agent and initiator, prepares nanogel using the method for water phase controllable free-radical polymerisation.This method prepares nanogel using the self-assembling method of polymerisation induced, does not use Small molecular surfactant and organic solvent in nanogel preparation and drug incorporation；Gained nanogel has good biocompatibility and chirality, and is reducing ambient temperature and pH, is being passed through CO2Partial size increases, is dissolved as water-soluble macromolecule after addition reducing agent after gas, therefore can be used for controlling the intelligence release of supporting molecular.

Description

A kind of quadruple stimuli responsive polyaminoacid nanogel and its preparation method and application
Technical field
The invention belongs to intellectual material technical fields, are related to the preparation method and application of polymer nanocomposite gel, specifically relate to And a kind of quadruple stimuli responsive polyaminoacid nanogel and its preparation method and application.
Background technique
Intellectual material refers to being capable of sensing external environment and the material that responds.Intellectual material can according to environment light, The variation of magnetic field, temperature, pH value, reductant-oxidant etc., generates the variation of corresponding physical property or structure, thus is organizing It has a wide range of applications in engineering, drug delivery and sustained release, biosensor and Nano medication.Nanogel typically refers to grain Three-dimensional cross-linked polymer network of the diameter within 200nm, is made of the hydrogel particle entity with nano-scale space.By Portion has gap in the inner, can load a variety of active principles.Relative to other gels, nanogel is small with size, carries medicine High-efficient and fast response time advantage, it is easy to accomplish target administration.Especially stimulating responsive nanogel can be with the external world Environment temperature, pH value of solution, illumination, magnetic field, the variation of specific chemical substance and ionic strength, and occur corresponding expansion or It shrinks, therefore the intelligence release of load component may be implemented.
Currently, the research of substance or double stimuli responsive nanogel is more, such as He L, Li D et al. utilizes Guang ammonia Cystine linkage contained by acid devises a kind of nanogel, which can be swollen under the action of reducing agent and promote medicine Object discharges (He L, Li D, Wang Z, et al. Polymers, 2016,8 (2): 36.).Although the nanogel system Preparation Method is simple, but it only responds reducing agent, thus keeps its application field limited.
Grinding for multiple stimulation response nano gel is carried out to increase targeting characteristic and control measures, existing research personnel Study carefully, multiple stimulation response nano gel is mainly obtained by following two mode at present.A kind of mode is rung using different stimulated It answers the monomer of characteristic to be copolymerized to assign nanogel multiple stimulation response characteristic, it is solidifying to obtain traditional multiple stimulation response nano Glue.For example, Chinese patent CN106883340A discloses a kind of polymer nanocomposite to the response of light, pH and reducing substances (DTT) Photoresponse monomer methacrylic acid spiro-pyrans ester, pH are responded monomeric acrylic, the crosslinking agent N containing cystine linkage by gel, inventor, Bis- (acryloyl) cystamines of N '-, initiator potassium persulfate and emulsifier sodium lauryl sulfate are added to the water reaction and have obtained three Weight responsiveness polyacrylic acid -co- methacrylic acid spiro-pyrans ester nanogel, but the nanogel preparation method is complicated, at This is higher, and residual emulsifiers have adverse effect to human body.Polymer micelle disclosed in Chinese patent CN104072694B is same When have a temperature-responsive, pH response, reduction response and photoresponse, inventor utilize the poly- 2- p-Nitrobenzyl with optical Response Pass through the disulfide bond with reduction responsiveness with the polymethylacrylic acid dimethylaminoethyl with pH and temperature double-response to connect Connect to obtain polymer that self assembly obtains micella in water, preparation step is more, and micella preparation and drug incorporation used it is organic Solvents tetrahydrofurane.Another way is to obtain multiple stimulation response using the monomer homopolymerization with multiple stimulation Response Mechanism Nanogel.Traditional multiple stimulation response nano gel can be overcome using the monomer homopolymerization with multiple stimulation Response Mechanism Defect, however this kind of monomer is very rare, and the multiple response polymer obtained by this kind of monomer, stability or biofacies Capacitive is mostly unsatisfactory.For example, polymethylacrylic acid dimethylaminoethyl (PDMAEMA), which is that one kind is common, to be had pH、CO2And the polymer of the triple responses of temperature, however PDMAEMA easy hydrolysis, stability in alkaline aqueous solution is poor, makes Its application range is restricted；(A New Family of Thermo-, pH-, the and CO2-Responsive such as Wang Homopolymers of Poly [Oligo (ethylene glycol) (N-dialkylamino) methacrylate] s, Macromolecules, 2017,50 (12), 4686-4698) report pH, temperature and CO2Triple response homopolymers Poly [oligo (ethylene glycol) (N-dialkylamino)-methacrylate] s, structure and PDMAEMA class Seemingly, but due to containing ester bond, the stability and biocompatibility of the polymer is not good enough yet.
Biocompatibility refers to a kind of life body tissue performance aitiogenic to non-active material, generally refer to material with Compatibility between host.Chiral molecules has very in the fields such as life science, pharmacy and material science, catalysis, separation Important role.Therefore, it finds and poly- using a kind of monomer material for having both chiral and biocompatibility multiple stimulation response Conjunction obtains stable multiple response nanogel, significant.
In conclusion main problem of the existing technology has: (1) existing substance or double stimuli responsive nanogel, Only to one or two kinds of stimuli responsives, keep its application field limited；(2) traditional multiple stimulation response nano gel generallys use tool There is the monomer of different stimulated response characteristic to be copolymerized to obtain, due to the difference of polymerization activity between monomer and reactivity ratio, causes to polymerize There are deviations for the practical composition and Theoretical Design value of object, and different monomers and the deliquescent difference of homopolymer, cause to prepare work in addition Skill is complicated, and cost is quite high；(3) existing to be polymerize using the multiple response that there is the monomer homopolymerization of multiple stimulation Response Mechanism to obtain Object, stability, biocompatibility be not good enough, its application range is made to be restricted.
Polyaminoacid material has chiral and good biocompatibility, and the nontoxic amino generated in degradation process Acid is easy to be absorbed by organisms and be metabolized, therefore has a wide range of applications in fields such as medicine, organizational projects.It is therefore desirable to study A kind of polyaminoacid nanogel is prepared, to solve problems of the prior art.
Summary of the invention
In order to overcome the deficiencies of the prior art, existing multiple response nanogel and technology of preparing there are aiming at the problem that, this The first purpose of invention is to provide a kind of quadruple stimuli responsive polyaminoacid nanogel, and nanogel provided by the invention has Good biocompatibility and chirality, and reducing ambient temperature and pH, be passed through CO2Partial size increases, reduction is added after gas It is dissolved as water-soluble macromolecule after agent, therefore can be used for controlling the intelligence release of supporting molecular.Another object of the present invention is A kind of preparation method of quadruple stimuli responsive polyaminoacid nanogel is provided, merely with vinyl amino acid function monomer, In In the presence of chain-transferring agent and initiator, nanogel is prepared using the method for water phase controllable free-radical polymerisation；It is lured using polymerization The self-assembling method led prepares nanogel, and nanogel preparation and drug incorporation are living without using organic solvent and small molecule surface Property agent, preparation method are more environmentally protective.Third object of the present invention is to provide a kind of quadruple stimuli responsive polyaminoacid to receive The purposes of rice gel, nanogel of the invention can be used for controlling the intelligence release of supporting molecular.
To achieve the above object, the present invention provides a kind of quadruple stimuli responsive polyaminoacid nanogel, feature exists In: the polyaminoacid nanogel is by Macromolecular chain transfer agent, N, bis- (acryloyl) cystamines of N '-, water soluble starter, ammonia Base acid monomers are polymerized in water；Wherein, the Macromolecular chain transfer agent is the water that thiocarbonic acid ester structure is contained in end Soluble macromolecular；The amino acid monomer is vinyl amino acid.
Further, the vinyl amino acid is one of following amino acid monomers, monomer A-1:N- acryloyl-sweet Propylhomoserin-L-Leu-N, N- dimethylamino acetamide, monomer A-2:N- methacryl-glycine-L-Leu-N, N- bis- Methylamino acetamide, monomer A-3:N- acryloyl-glycine-L-Leu-N, N- dimethylaminopropylamide, monomer B-1: methyl Acryloyl-L- the third ammonia-N, N diethyl acetamide, monomer B-2: methacryl-L- the third ammonia-N, N dimethyl propionamide, monomer B-3: methacryl-L- the third ammonia-N, N diethyl propionamide, molecular structural formula are respectively as follows:
。
Further, in step S1, the nanogel is reducing ambient temperature, is reducing pH, is passed through CO2Grain after gas Diameter increases, and is dissolved as water-soluble macromolecule after reducing agent is added, the reducing agent is preferably DL- dithiothreitol (DTT) (DTT).
The present invention also provides a kind of preparation method of quadruple stimuli responsive polyaminoacid nanogel, step includes:
S1, by Macromolecular chain transfer agent, N, bis- (acryloyl) cystamines of N '-, water soluble starter, amino acid monomer according to Molar ratio be 1 ︰, 1~6 ︰, 0.1~0.6 ︰ 20~500 ratio be added reactor in, then plus deionized water make solid content 8~30 wt%；
S2, it is passed through inert gas deoxygenation, the deoxygenation time is 10~30min, then poly- under the conditions of temperature is 50~80 DEG C It closes, polymerization time is 1~7 h；
S3, dialysis remove the impurity in solution, and freeze-drying obtains quadruple stimuli responsive polyaminoacid nanogel；
Wherein, in step S1: the Macromolecular chain transfer agent is the high water solubility that thiocarbonic acid ester structure is contained in end Molecule；The amino acid monomer is vinyl amino acid, the water soluble starter be water-soluble azo class initiator or Persulfate.
Further, in step S1: by the Macromolecular chain transfer agent, N, bis- (acryloyl) cystamines of N '-, water-soluble initiation Agent, amino acid monomer are added in reactor according to the ratio that molar ratio is 1 ︰, 2~5 ︰, 0.2~0.5 ︰ 30~400；Described consolidating contains Amount is 10~25 wt%.
Further, in step S2, the deoxygenation time is 15~20min, and the temperature is 55~75 DEG C, described Polymerization time is 1~6 h.
Further, in step S3, the dialysis is to dialyse in distilled water, and dialysis time is 12 ~ 36 h；Described is cold It is 36 ~ 72 h that the dry time, which is lyophilized,.
Further, the vinyl amino acid is preferably one of following monomers, monomer A-1:N- acryloyl-sweet ammonia Acid-L-Leu-N, N- dimethylamino acetamide, monomer A-2:N- methacryl-glycine-L-Leu-N, N- diformazan Amino acetamide, monomer A-3:N- acryloyl-glycine-L-Leu-N, N- dimethylaminopropylamide, monomer B-1: methyl-prop Alkene acyl-L- the third ammonia-N, N diethyl acetamide, monomer B-2: methacryl-L- the third ammonia-N, N dimethyl propionamide, monomer B- 3: methacryl-L- the third ammonia-N, N diethyl propionamide.
Further, the water-soluble azo class initiator is preferably azo dicyano valeric acid, azo diisobutyl amidine salt One of hydrochlorate；The persulfate is preferably one of potassium peroxydisulfate, ammonium persulfate.
Further, the Macromolecular chain transfer agent is preferably CTA-1: polymethylacrylic acid poly glycol monomethyl ether ester, CTA-2: poly- N,N-DMAA, CTA-3: one of poly glycol monomethyl ether ester, molecular structural formula are as follows:
。
Further, the Macromolecular chain transfer agent CTA-1: polymethylacrylic acid poly glycol monomethyl ether ester, preparation Method are as follows:
By Methylacrylic acid polyethylene glycol single armor ether ester, chain-transferring agent dithiobenzoic acid cyano isopropyl ester, initiator AIBN is added in reactor according to the ratio that molar ratio is 10 ︰, 0.2 ︰ 0.01, then dissolves added with 10 mL of solvent, and logical nitrogen removes After 15 min of oxygen, 70 DEG C of 2 h of reaction are heated to, obtain CTA-1 with petroleum ether precipitation: polymethylacrylic acid poly glycol monomethyl ether Ester.
Further, the Macromolecular chain transfer agent CTA-2: poly- N,N-DMAA, preparation method are as follows:
By N, N- dimethylacrylamide, chain-transferring agent 4- cyano -4- [[(dodecylthio) thioketones methyl] sulfenyl] penta Acid, initiator A IBN are added in reactor according to the ratio that molar ratio is 10 ︰, 0.2 ︰ 0.04, then dissolve added with 10 mL of solvent, After logical 15 min of nitrogen deoxygenation, 65 DEG C of 3 h of reaction are heated to, are precipitated to obtain CTA-2 with ether: poly- N, N- dimethyl allene acyl Amine.
Further, the Macromolecular chain transfer agent CTA-3: poly glycol monomethyl ether ester, preparation method are as follows:
By chain-transferring agent 4- cyano -4- [[(dodecylthio) thioketones methyl] sulfenyl] valeric acid, poly glycol monomethyl ether, 1- Ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride is added in reactor according to the ratio that molar ratio is 5 ︰, 2 ︰ 2.5, then It dissolves added with 10 mL of solvent, is reacted at room temperature for 24 hours under nitrogen protection；Identical 90 mL of organic solvent is added after reaction, Extracting and demixing takes organic phase successively to use 0.1 M HCL aqueous solution, 80 mL, 80 mL of saturated sodium bicarbonate aqueous solution and saturation food 80 mL of salt water washing；Then organic phase is dried, filtered with anhydrous magnesium sulfate, takes filtrate is outstanding solvent is evaporated off, obtains CTA-3: 4- cyano -4- [[(dodecylthio) thioketones methyl] sulfenyl] valeric acid poly glycol monomethyl ether ester.
Preferably, the organic solvent is toluene, benzene, tetrahydrofuran, methylene chloride, dioxane, isopropanol, first Alcohol, n,N-Dimethylformamide, one of N-Methyl pyrrolidone.
A kind of purposes of quadruple stimuli responsive polyaminoacid nanogel, it is characterised in that: can be used for controlling supporting molecular Intelligence release.
Compared with prior art, the present invention has the following advantages:
(1) present invention prepares nanogel only with the homopolymerization of ethyleneamino acid monomers, and polymeric chemical structure is bright Really；When in the prior art using various of monomer copolymerization, since each monomer reactivity is different, how many final monomer conversion At polymer, depending on the relative activity and conversion ratio of two kinds of monomers, the high monomer of activity first polymerize, the low rear polymerization of activity, There are deviations for the practical composition and design value of polymer, and this problem is not present only with a kind of monomer homopolymerization in the present invention；
(2) nanogel of the invention contains amino acid fragment, has many advantages, such as good biocompatibility and chirality；
(3) present invention prepares nanogel using the self-assembling method of aqueous polymerization induction, synthesizes and carries in nanogel Medicine process does not use organic solvent, more environmentally protective；
(4) preparation process of the present invention is simple, and step is few；
(5) nanogel is reducing ambient temperature and pH, is being passed through CO2Partial size increases after gas, molten after addition reducing agent Solution is water-soluble macromolecule, can be used for controlling the intelligence release of supporting molecular, has very high answer in drug controlled release field With value.
Detailed description of the invention
Fig. 1 is a kind of quadruple stimuli responsive polyaminoacid nanogel preparation method schematic diagram of the present invention.
Fig. 2 is the hydrogen nuclear magnetic spectrogram by 1 gained Macromolecular chain transfer agent CTA-1 of the embodiment of the present invention.
Fig. 3 is the hydrogen nuclear magnetic spectrogram by 2 gained Macromolecular chain transfer agent CTA-2 of the embodiment of the present invention.
Fig. 4 is the hydrogen nuclear magnetic spectrogram by 3 gained Macromolecular chain transfer agent CTA-3 of the embodiment of the present invention.
Fig. 5 is the transmission electron microscope photo by 2 gained nanogel of the embodiment of the present invention.
Fig. 6 is the dynamic light scattering diagram by 2 gained nanogel of the embodiment of the present invention.
Fig. 7 is by 2 gained nanogel partial size of the embodiment of the present invention with temperature (a), pH value (b), CO2Gas (c) and DTT (d) variation diagram.
Fig. 8 is by the burst size curve of 2 gained nanogel of embodiment of the present invention rhodamine b at different conditions.
Specific embodiment
Technical solution of the present invention is described in detail with reference to the accompanying drawing, but implementation of the invention is not limited to This.
Embodiment 1:
It weighs 9.5 g of Methylacrylic acid polyethylene glycol single armor ether ester (being equivalent to 10 mmol), two thio phenyl first of chain-transferring agent Sour 44.2 mg of cyano isopropyl ester (being equivalent to 0.2 mmol), initiator A IBN1.64 mg (being equivalent to 0.01 mmol) set 50 In ml single port bottle, 10 mL of toluene is added to dissolve, is heated to 70 DEG C of 2 h of reaction after logical 15 min of nitrogen deoxygenation, with petroleum ether precipitation, Obtain polymethylacrylic acid poly glycol monomethyl ether ester (Macromolecular chain transfer agent CTA-1) 4.7 g.Gained polymethylacrylic acid The weight average molecular weight of poly glycol monomethyl ether esterM w=24940 g/mol, number-average molecular weightM n=23750 g/mol, polymerization degree n= 25。
It weighsNAcryloyl-glycine-L-Leu-N,N3.8 g of dimethylamino acetamide (monomer A-1) (is equivalent to 12 mmol), polymethylacrylic acid poly glycol monomethyl ether ester (Macromolecular chain transfer agent CTA-1) 0.96 g (is equivalent to 0.04 Mmol), 2.8 mg of azo dicyano valeric acid (being equivalent to 0.01 mmol), N, N '-bis- 32 mg of (acryloyl) cystamine (are equivalent to 0.12 mmol) it sets in 100 ml single port bottles, add 40 mL of deionized water, 60 DEG C of reactions are heated to after logical 15 min of argon gas deoxygenation 4 h, deionized water dialysis for 24 hours, are freeze-dried 48 h, obtain quadruple stimuli responsive polyaminoacid nanogel.
By the hydrogen nuclear magnetic spectrogram of 1 gained Macromolecular chain transfer agent CTA-1 of the embodiment of the present invention, Fig. 2 is seen.
Embodiment 2:
1. the preparation of quadruple stimuli responsive polyaminoacid nanogel
Weigh 9.9 g of N,N-DMAA (being equivalent to 100 mmol), 4- cyano -4- [[(dodecylthio) Thioketones methyl] sulfenyl] valeric acid 808 mg (being equivalent to 2 mmol), 66 mg of AIBN (being equivalent to 0.4 mmol) set 50 ml In single port bottle, 10 mL of tetrahydrofuran is added to dissolve, is heated to 65 DEG C of 3 h of reaction after logical 15 min of nitrogen deoxygenation, is precipitated with ether, Obtain poly- N, 7.8 g of N- dimethylacrylamide (Macromolecular chain transfer agent CTA-2).The poly- N of gained, N- dimethylacrylamide Weight average molecular weightM w=4320 g/mol, number-average molecular weightM n=4000 g/mol, polymerization degree n=39.
Weigh the third ammonia of methacryl-L--N,N3.83 g of diethyl acetamide (monomer B-1) (is equivalent to 15 mmol), Poly- N, N- dimethylacrylamide (Macromolecular chain transfer agent CTA-2) 1.2 g (being equivalent to 0.3 mmol), azo dicyano penta It is mono- that 28 mg of acid (being equivalent to 0.1 mmol), N, N '-bis- 200 mg (being equivalent to 0.75mmol) of (acryloyl) cystamine set 50 ml In mouth bottle, add 21 mL of deionized water, be heated to 70 DEG C of reactions 2 h, 16 h of deionized water dialysis after logical 15 min of nitrogen deoxygenation, 48 h are freeze-dried, quadruple stimuli responsive polyaminoacid nanogel is obtained.
2. carrying medicine and release experiment:
The guest molecule release of 2.1 pH induction
50 mg rhodamine b(RhB), 1.0 g are mixed by 2 gained nanogel of embodiment and 99 g deionized waters, After 24 h are stirred at room temperature, it is classified as two equal portions and dialyses in 1000 mL water respectively 24 h.Test the outer aqueous solution of bag filter UV absorption (characteristic absorption peak of RhB molecule in aqueous solution) under 554 nm wavelength come determine it is unsupported enter nanometer it is solidifying The amount of the RhB of glue.With the RhB mass of addition subtract it is unsupported enter nanogel its available load capacity of RhB mass (24%).Then two bag filters are respectively put into 100 mL water (room temperature, t=25 DEG C) again and in pH=9.5 and pH=4.0 Under the conditions of carry out release experiment.Interval 4h takes out the outer aqueous solution of 2 mL bag filters and tests it in the absorption of 554 nm wavelength and fill into The aqueous solution of 2 mL same pH is to guarantee aqueous solution constant volume outside bag filter.The concentration of RhB in solution is taken out in measurement, calculates Drug release rate.Experimental results are shown in figure 8: in pH=9.5, the preparation of drug only has 26.2 %(to see figure when 24 h 8-e)；And pH when being reduced to 4.0 RhB reached 72.8 %(in release rate for 24 hours and see attached drawing 8-b).This is because poly- (methyl-prop The third ammonia of alkene acyl-L--N,NDiethyl acetamide) tertiary amine protonates in acidic aqueous solution on side chain, and RhB is in acid condition Positively charged, electrostatic repulsion causes release rate to increase.
2.2 temperature-induced guest molecule releases
50 mg rhodamine b(RhB), 1.0 g are mixed by 2 gained nanogel of embodiment and 99 g deionized waters, After 24 h are stirred at room temperature, it is classified as two equal portions and dialyses in 1000 mL water respectively 24 h.Test the outer aqueous solution of bag filter UV absorption (characteristic absorption peak of RhB molecule in aqueous solution) under 554 nm wavelength come determine it is unsupported enter nanometer it is solidifying The amount of the RhB of glue.With the RhB mass of addition subtract it is unsupported enter nanogel its available load capacity of RhB mass (24%).Then two bag filters are respectively put into 100 mL and the water of pH=9.5 again, are lower than phase transition temperature in t=25oC() And release experiment is carried out under t=60 DEG C (being higher than phase transition temperature).Interval 4h take out the outer aqueous solution of 2 mL bag filters test its The absorption of 554 nm wavelength simultaneously fills into the aqueous solution of 2 pH=9.5 mL to guarantee aqueous solution constant volume outside bag filter.Measurement takes Out in solution RhB concentration, calculate drug release rate.Experimental results are shown in figure 8: as can be seen that be 25 DEG C in temperature, accumulation Release rate is that 26.2 %(are shown in Fig. 8-e)；And temperature be 60 DEG C when, preparation be 42.8%(see Fig. 8-d).This is because warm When degree is increased to phase transition temperature or more, poly- (the third ammonia of methacryl-L--N,NDiethyl acetamide) become hydrophobic from hydrophilic and led It causes nanogel partial size sharply to shrink the RhB being wrapped in (see attached drawing 7-a) in gel to be extruded, therefore release rate increases.
2.3 CO2The guest molecule of induction discharges
PH=9.5 described in " 2.2 temperature-induced guest molecule release " experiment of embodiment 2, the nanometer of t=25 DEG C are solidifying In the aqueous solution of glue packet RhB, it is passed through CO2Gas 5min, the preparation of rhodamine b increases to 63.6%(and sees when placing 24 h Fig. 8-c), this is because the CO being passed through2Solution becomes acid after gas, with poly- (the third ammonia of methacryl-L--N,NDiethyl second Amide) side chain reactive tertiary amine protonation, RhB is also positively charged in acid condition, and electrostatic repulsion causes release rate to increase.
The guest molecule release of 2.4 DTT induction
PH=9.5 described in " 2.2 temperature-induced guest molecule release " experiment of embodiment 2, the nanometer of t=25 DEG C are solidifying Glue coats in RhB aqueous solution, and 10 mM DTT are added, and the preparation of RhB increases to 87.8%(and sees attached drawing 8- when placing 24 h A).This is because DTT is reducing substances, it, which can destroy disulfide bond, makes nanogel be decomposed into linear polymeric (see attached drawing 7-d), increase RhB release rate.
By the hydrogen nuclear magnetic spectrogram of 2 gained Macromolecular chain transfer agent CTA-2 of the embodiment of the present invention, Fig. 3 is seen.
By the transmission electron microscope photo of 2 gained nanogel of the embodiment of the present invention, Fig. 5 is seen.
By the dynamic light scattering diagram of 2 gained nanogel of the embodiment of the present invention, Fig. 6 is seen.
By 2 gained nanogel partial size of the embodiment of the present invention with temperature (a), pH value (b), CO2Gas (c) and DTT's (d) Variation diagram is shown in Fig. 7.
By the burst size curve of 2 gained nanogel of embodiment of the present invention rhodamine b at different conditions, Fig. 8 is seen.
Embodiment 3:
2.0 g (being equivalent to 5 mmol) of 4- cyano -4- [[(dodecylthio) thioketones methyl] sulfenyl] valeric acid is weighed, is gathered Glycol monoethyl ether (2000 g/mol of average molecular weight) 4.0 g (being equivalent to 2 mmol), 1- ethyl-(3- dimethylamino third Base) carbodiimide hydrochloride 0.48 g (being equivalent to 2.5 mmol) set in 50 ml single port bottles, add 10 mL of anhydrous methylene chloride It dissolves, is reacted at room temperature for 24 hours under nitrogen protection.After reaction, add methylene chloride 90 mL, and extracting and demixing takes organic phase successively to use 0.1 M HCL aqueous solution, saturated sodium bicarbonate aqueous solution and each 80 mL washing of saturated salt solution.It is dry with anhydrous magnesium sulfate Organic phase, filtering take filtrate is outstanding organic solvent is evaporated off, obtain 4- cyano -4- [[(dodecylthio) thioketones methyl] sulfenyl] Valeric acid poly glycol monomethyl ether ester (Macromolecular chain transfer agent CTA-3) 5.6 g.
It weighsNMethacryl-glycine-L-Leu-N,N4.83 g (phase of dimethylamino acetamide (monomer A-2) When in 15 mmol), 4- cyano -4- [[(dodecylthio) thioketones methyl] sulfenyl] valeric acid poly glycol monomethyl ether ester (macromolecular Chain-transferring agent CTA-3) 0.3 g (being equivalent to 0.15 mmol), 12 mg of azo dicyano valeric acid (is equivalent to 0.04 Mmol), N, N '-bis- 106 mg of (acryloyl) cystamine (being equivalent to 0.4 mmol) are set in 50 ml single port bottles, and deionized water 30 is added 65 DEG C of reactions 3 h, 20 h of deionized water dialysis are heated to after mL, logical 15 min of nitrogen deoxygenation, 70 h is freeze-dried, obtains quadruple Stimuli responsive polyaminoacid nanogel.
By the hydrogen nuclear magnetic spectrogram of 3 gained Macromolecular chain transfer agent CTA-3 of the embodiment of the present invention, Fig. 4 is seen.
The above is only presently preferred embodiments of the present invention, the interest field being not intended to limit the invention.Using ability The molar ratio of domain prior art, change monomer and chain-transferring agent can be convenient the molecular weight and molecular weight distribution of regulation polymer. Technical solution that any interest field for being covered with the application the scope of the patents is implemented any is familiar with those skilled in the art Member, the scheme of many possible changes and modifications is made using the method content of the disclosure above, belongs to protection model of the invention It encloses.

Claims (8)

1. a kind of quadruple stimuli responsive polyaminoacid nanogel, it is characterised in that: the polyaminoacid nanogel is by big Molecular chain transfer agent, N, bis- (acryloyl) cystamines of N '-, water soluble starter, amino acid monomer are polymerized in water；Wherein, The Macromolecular chain transfer agent is the water soluble polymer that thiocarbonic acid ester structure is contained in end；The amino acid monomer is Vinyl amino acid；
The vinyl amino acid is one of following amino acid monomers, the monomer A-1:N- acryloyl-bright ammonia of glycine-L- Acid-N, N- dimethylamino acetamide, monomer A-2:N- methacryl-glycine-L-Leu-N, N- dimethylamino acetyl Amine, monomer A-3:N- acryloyl-glycine-L-Leu-N, N- dimethylaminopropylamide, monomer B-1: methacryl-L- Alanine-N, N diethyl acetamide, monomer B-2: methacryl-l-Alanine-N, N dimethyl propionamide, monomer B-3: first Base acryloyl-l-Alanine-N, N diethyl propionamide, molecular structure are respectively as follows:
。
2. a kind of quadruple stimuli responsive polyaminoacid nanogel as described in claim 1, the polyaminoacid nanometer are solidifying Glue is reducing ambient temperature, is reducing pH, is passed through CO2Partial size increases after gas, is dissolved as water-soluble big point after reducing agent is added Son.
3. a kind of preparation method of quadruple stimuli responsive polyaminoacid nanogel, which comprises the following steps:
S1, by Macromolecular chain transfer agent, N, bis- (acryloyl) cystamines of N '-, water soluble starter, amino acid monomer according to mole Than for 1 ︰, 1~6 ︰, 0.1~0.6 ︰ 20~500 ratio be added reactor in, then plus deionized water make solid content 8~30 wt%；
S2, it being passed through inert gas deoxygenation, the deoxygenation time is 10~30min, then it polymerize under the conditions of temperature is 50~80 DEG C, Polymerization time is 1~7 h；
S3, dialysis remove the impurity in solution, and freeze-drying obtains quadruple stimuli responsive polyaminoacid nanogel；
Wherein, in step S1, the Macromolecular chain transfer agent is the water soluble polymer that thiocarbonic acid ester structure is contained in end, The amino acid monomer is vinyl amino acid, and the water soluble starter is water-soluble azo class initiator or persulfuric acid Salt；The vinyl amino acid is one of following amino acid monomers, the monomer A-1:N- acryloyl-bright ammonia of glycine-L- Acid-N, N- dimethylamino acetamide, monomer A-2:N- methacryl-glycine-L-Leu-N, N- dimethylamino acetyl Amine, monomer A-3:N- acryloyl-glycine-L-Leu-N, N- dimethylaminopropylamide, monomer B-1: methacryl-L- Alanine-N, N diethyl acetamide, monomer B-2: methacryl-l-Alanine-N, N dimethyl propionamide, monomer B-3: first Base acryloyl-l-Alanine-N, N diethyl propionamide.
4. a kind of preparation method of quadruple stimuli responsive polyaminoacid nanogel as claimed in claim 3, it is characterised in that: In step S1, by the Macromolecular chain transfer agent, N, bis- (acryloyl) cystamines of N '-, water soluble starter, amino acid monomer are pressed It is added in reactor according to the ratio that molar ratio is 1 ︰, 2~5 ︰, 0.2~0.5 ︰ 30~400；The solid content is 10~25 wt%.
5. a kind of preparation method of quadruple stimuli responsive polyaminoacid nanogel as claimed in claim 3, it is characterised in that: In step S2, the deoxygenation time is 15~20min；The temperature is 55~75 DEG C；The polymerization time is 1~6 h；In step S3, the dialysis is to dialyse in distilled water, and dialysis time is 12~36 h；The time of the freeze-drying For 36~72 h.
6. a kind of preparation method of quadruple stimuli responsive polyaminoacid nanogel as claimed in claim 3, it is characterised in that: In step S1, the water-soluble azo class initiator is azo dicyano valeric acid, one in azo diisobutyl amidine hydrochloride Kind, the persulfate is one of potassium peroxydisulfate, ammonium persulfate.
7. a kind of preparation method of quadruple stimuli responsive polyaminoacid nanogel as claimed in claim 3, it is characterised in that: In step S1, the Macromolecular chain transfer agent is one of CTA-1, CTA-2 and CTA-3, and molecular structural formula is respectively as follows:
。
8. a kind of purposes of quadruple stimuli responsive polyaminoacid nanogel as described in claim 1, it is characterised in that: available In the intelligence release of control supporting molecular.
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