CN102977362A - Poly-amino acid block copolymer, preparation method thereof and temperature-sensitive hydrogel - Google Patents
Poly-amino acid block copolymer, preparation method thereof and temperature-sensitive hydrogel Download PDFInfo
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Abstract
The invention provides a poly-amino acid block copolymer, a preparation method thereof and a temperature-sensitive hydrogel. The block copolymer comprises a first block formed by terminal-amino polyethylene glycol or terminal-amino polyethylene glycol monomethyl ether, and a second block formed by poly(L-glutamate) containing bio-functional molecules, wherein the bio-functional molecules are galactoses, mannitose, glucoses, biotins or short peptides. The invention also provides the preparation method of the poly-amino acid block copolymer and the temperature-sensitive hydrogel. The poly-amino acid block copolymer modifies different bio-functional molecules, can effectively adjust and control biological functions of a material by changing modified groups, adjusts the interaction between the material and cells, and expands the application range of the temperature-sensitive hydrogel.
Description
Technical field
The present invention relates to technical field of polymer materials, be specifically related to a kind of polyamino acid block copolymer, its preparation method and temperature sensitive type water gel.
Background introduction
The stimulating responsive hydrogel is a kind of three-dimensional network that is comprised of hydrophilic macromolecule, can sensing external environment, subtle change such as temperature, pH value, ionic strength, biomolecules, chemical substance, photoelectricity and magnetic field etc., and the expansion/contraction of passing through own vol changes, sol/gel changes, the stimulations to external world such as cell adhesion/desorption are produced response, controls the aspects such as release, separating substances purification, biologically active substance embedding, cell cultures and organizational project at medicine and is with a wide range of applications.
Responsive to temperature type syringeability hydrogel is a kind of hydrogel of thermal stimulus response, and when being lower than body temperature, temperature-sensitive hydrogel exists with solution state, more easily mixes with biologically active substances such as medicine, polypeptide, protein, cells; After being injected into inside of human body, because the variation of temperature, volume phase transition occurs rapidly in solution, forms hydrogel; In the process that forms hydrogel, medicine wherein or biologically active substance are embedded in hydrogel inside, and then degrading by diffusion or hydrogel self slowly discharges, thereby reach the purpose of long-acting slow-release.Thermo-sensitive syringeability hydrogel also can be used as the timbering material of internal in-situ tissue culture, owing to be low viscosity solution before the injection, therefore be suitable for the wound of arbitrary shape, and can not cause new wound in the injection process.Simultaneously, temperature-sensitive hydrogel has the application conditions gentleness, need not with an organic solvent, is conducive to keep the advantages such as activity of biologically active substance, is one of study hotspot of medicine and cell release vehicle and bio-medical material.
Prior art discloses multiple Thermo-sensitive syringeability hydrogel, block copolymer hydrogel (Nature such as polyoxyethylene glycol and PLLA, 1997,388:860-862.), the block copolymer hydrogel (Macromalecule of polyoxyethylene glycol and polyamino acid, 2008,41:8204-8209, Biomacromolecules, 2009,10:2476-2481.), when temperature variation, can realize the reversible change of colloidal sol and gel.Yet these hydrogels of report all are difficult to material is carried out further chemistry and biomolecules modification at present.Especially use biologically functional molecule to the modification of hydrogel material, to improving the biological functionality of material, and significant with the interaction of cell and tissue, be that present hydrogel material field is subject to extensive concern and challenging research topic.For traditional temperature sensitive block copolymer hydrogel, polyoxyethylene glycol block wherein mainly is carbon-carbon bond and carbon-oxygen bond, all is unusual inertia, is difficult to activate; In addition traditional polyester and polyamino acid block, but also rarely have the report of modification group at present.When these polymer formation hydrogels, its surface mainly is hydrophilic polyoxyethylene glycol, is difficult to be combined with protein molecule, is unfavorable for cell adhesion, so limited to a great extent its application on cell cultures and organizational project.
Summary of the invention
The objective of the invention is to be difficult to material is carried out chemistry and the modification of biological one's share of expenses for a joint undertaking in order to solve existing hydrogel, thereby cause the narrow problem of range of application, and a kind of polyamino acid block copolymer, its preparation method and temperature sensitive type water gel are provided.The temperature sensitive type water gel that segmented copolymer provided by the invention forms contains the biological function side group, and range of application is wider.
The invention provides a kind of polyamino acid block copolymer, comprise have formula the first block of (I) or formula (II) structure and the second block with formula (III) structure:
Wherein, R is the azide biomolecules;
X is the polymerization degree, 10≤x≤227;
Y is the polymerization degree, 10≤y≤226;
M is the polymerization degree, 4≤m≤96;
N is the polymerization degree, 1≤n≤60.
Preferably, described R is semi-lactosi, seminose, glucose, vitamin H or small peptide.
Preferably, to account for the weight percentage of described polyamino acid block copolymer be 25% ~ 75% to described the second block.
The invention provides a kind of preparation method of polyamino acid block copolymer, may further comprise the steps:
Step 1: the amidized polyoxyethylene glycol of end and the γ-proyl-Pidolidone ester-N-carboxylic acid inner-acid anhydride polymerization reaction take place that have the amidized poly glycol monomethyl ether of end of formula (IV) structure or have the formula V structure obtain segmented copolymer;
Wherein, x is the polymerization degree, 10≤x≤227; Y is the polymerization degree, 10≤y≤226;
Step 2: segmented copolymer and azide biomolecular reaction with step 1 obtains obtain polyamino acid block copolymer.
Preferably, the amidized polyoxyethylene glycol of described end or hold amidized poly glycol monomethyl ether and the mol ratio of γ-proyl-Pidolidone ester-N-carboxylic acid inner-acid anhydride is 1:(5 ~ 120);
Preferably, the alkynyl of segmented copolymer and azide biomolecules mol ratio are 1:(0.8 ~ 1.2 in the described step 2).
Preferably, described azide biomolecules is semi-lactosi, seminose, glucose, vitamin H or small peptide.
The present invention also provides a kind of responsive to temperature type block copolymer hydrogel, comprises the described polyamino acid block copolymer of technique scheme and solvent.
Preferably, described solvent is water, physiological saline, buffered soln, tissue culture medium or body fluid.
Preferably, the massfraction of described poly-amino segmented copolymer is 2% ~ 30%.
Beneficial effect of the present invention
The invention provides a kind of polyamino acid block copolymer, comprise the amidized polyoxyethylene glycol of end or hold the first block of amidized poly glycol monomethyl ether formation and second block that gathers (γ-proyl-Pidolidone ester) formation of biological function base group modification.The first block of described polyamino acid block copolymer all has the different polymerization degree with the second block, can obtain the polyamino acid block copolymer of different molecular weight, thereby forms the temperature sensitive type water gel with different transformation temperatures; And the second block of polyamino acid block copolymer provided by the invention, namely contain the alkynyl substituted base on the side chain of poly-(γ-proyl-Pidolidone ester), can react by click chemistry, obtain containing the segmented copolymer of different biological molecules, thereby be conducive to the further biologic applications of material; Segmented copolymer provided by the invention has different biological function side groups, has significantly strengthened material to biological functions such as sticking of cell, has expanded the temperature sensitive type water gel range of application, is conducive to temperature sensitive type water gel in the application of biomedical aspect.
Temperature sensitive type water gel with functional group provided by the invention has good biocompatibility, the functional group of modifying adapts to organizational project more, experimental result shows, hydrogel provided by the invention, help to a great extent cell in the adhesion of gel surface, be conducive to promote cell and the cultivation that is organized in the material.In addition, the present invention receives the different biological molecules of azide on the second block by click chemistry, can obtain functionality block copolymer, the preparation method is simple to operate, and raw material is simple and easy to, and reaction conditions is gentle.
Description of drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of the polyamino acid block copolymer of the embodiment of the invention 6 preparations;
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of the polyamino acid block copolymer of the embodiment of the invention 9 preparations;
The temperature variant phasor of the polyamino acid block copolymer aqueous solution of the different concns that Fig. 3 provides for the embodiment of the invention 41;
The temperature variant phasor of the polyamino acid block copolymer aqueous solution of the different concns that Fig. 4 provides for the embodiment of the invention 42.
The temperature variant phasor of the segmented copolymer aqueous solution of the different concns that Fig. 5 provides for the embodiment of the invention 43;
The temperature variant phasor of the segmented copolymer aqueous solution of the different concns that Fig. 6 provides for the embodiment of the invention 44.
Embodiment
The invention provides a kind of polyamino acid block copolymer, comprise have formula the first block of (I) or formula (II) structure and the second block with formula (III) structure:
Wherein, R is the azide biomolecules; Be preferably semi-lactosi, seminose, glucose, vitamin H or small peptide;
X is the polymerization degree, 10≤x≤227; Be preferably 20≤x≤185, more preferably 30≤x≤115;
Y is the polymerization degree, 10≤y≤226; Be preferably 20≤y≤180, more preferably 30≤y≤112;
M is the polymerization degree, 4≤m≤96; Be preferably 6≤m≤92; 8≤m≤90 more preferably;
N is the polymerization degree, 1≤n≤60.Be preferably 2≤n≤32; 2≤n≤24 more preferably;
Preferably, the weight percentage that described the second block accounts for described segmented copolymer is 25% ~ 75%, more preferably 30% ~ 65%, most preferably be 35% ~ 60%.
The invention provides a kind of preparation method of polyamino acid block copolymer, may further comprise the steps:
Step 1: the amidized polyoxyethylene glycol of end and the γ-proyl-Pidolidone ester-N-carboxylic acid inner-acid anhydride polymerization reaction take place that have the amidized poly glycol monomethyl ether of end of formula (IV) structure or have the formula V structure obtain segmented copolymer;
Wherein, x is the polymerization degree, 10≤x≤227; Y is the polymerization degree, 10≤y≤226;
Step 2: segmented copolymer and azide biomolecular reaction with step 1 obtains obtain polyamino acid block copolymer.
Described γ-the proyl of step 1 of the present invention-Pidolidone ester-N-carboxylic acid anhydride prepares in accordance with the following methods:
Pidolidone and propiolic alcohol generation esterification obtain γ-proyl-Pidolidone ester;
Described γ-proyl-Pidolidone ester carries out condensation reaction with two (trichloromethyl) carbonic ethers, obtains γ-proyl-Pidolidone ester-N-carboxylic acid anhydride.
At first with Pidolidone and propiolic alcohol preferably at-5 ℃ ~ 5 ℃, more preferably in the time of 0 ℃, mix, drip the vitriol oil under the agitation condition, after the vitriol oil dropwises, be warming up to 20 ℃ ~ 30 ℃ reaction 10h ~ 30h, reaction neutralizes reaction mixture with sodium bicarbonate after finishing, through obtaining γ-proyl-Pidolidone ester after filtration, washing, recrystallization, the freeze-drying.Wherein, the mol ratio of described Pidolidone and propiolic alcohol is preferably 1:(1 ~ 6), 1:(2 ~ 5 more preferably), most preferably be 1:(3 ~ 4); The mol ratio of described Pidolidone and the described vitriol oil is preferably 1:(0.8 ~ 3), 1:(1 ~ 2.5 more preferably), most preferably be 1:(1.2 ~ 2); The mol ratio of described sodium bicarbonate and the described vitriol oil is preferably 2:1.
Described γ-proyl-Pidolidone ester and two (trichloromethyl) carbonic ethers are mixed under anhydrous, 20 ℃ ~ 30 ℃ conditions, add tetrahydrofuran (THF), be warming up to 40 ℃ ~ 60 ℃ reaction 1h ~ 3h, after reaction finishes, with reaction mixture sedimentation in excessive sherwood oil, with product separation, through obtaining γ-proyl-Pidolidone ester-N-carboxylic acid inner-acid anhydride after washing, recrystallization, the drying.Wherein, described γ-proyl-Pidolidone ester is preferably 1:0.3 ~ 1 with the mol ratio of two (trichloromethyl) carbonic ethers, more preferably 1:0.5 ~ 0.8.
In step 1 of the present invention, the amidized polyoxyethylene glycol of end and the γ-proyl-Pidolidone ester-N-carboxylic acid inner-acid anhydride polymerization reaction take place that have the amidized poly glycol monomethyl ether of end of formula (IV) structure or have the formula V structure obtain segmented copolymer;
The amidized polyoxyethylene glycol of end that has the amidized poly glycol monomethyl ether of end of formula (IV) structure or have a formula V structure is dissolved in the first organic solvent, obtains the first solution;
γ-proyl-Pidolidone ester-N-carboxylic acid inner-acid anhydride is dissolved in the second organic solvent, obtains the second solution;
Above-mentioned the first solution and the second solution are mixed, namely obtain segmented copolymer;
Among the present invention, with described have the amidized poly glycol monomethyl ether of end of formula (IV) structure or have the amidized polyoxyethylene glycol of end of formula V structure and the dry toluene azeotropic water removing after continue to remove toluene, then it is dissolved in the first solvent, obtain the first solution, the present invention does not have particular restriction to the concentration of described the first solution, described the first solvent is preferably DMF, N,N-dimethylacetamide or trichloromethane; Described have the amidized poly glycol monomethyl ether of end of formula (IV) structure or have the amidized polyoxyethylene glycol of end of formula V structure and the volume ratio of dry toluene is preferably 1g:(10ml ~ 50ml), 1g:(15ml ~ 45ml) more preferably, most preferably be 1g:(25ml ~ 35ml), described azeotropic temperature is preferably 110 ℃ ~ 150 ℃, more preferably 115 ℃ ~ 140 ℃, most preferably be 125 ℃ ~ 135 ℃, the described azeotropic time is preferably 1h ~ 3h, more preferably 1.5h ~ 2.5h most preferably is 1.8h ~ 2.2h.
Described γ-proyl-Pidolidone ester-N-carboxylic acid inner-acid anhydride is dissolved in the second organic solvent, obtain the second solution, the present invention does not have particular restriction to the concentration of described the second solution, described the second solvent is preferably N, dinethylformamide, N,N-dimethylacetamide or trichloromethane.
With the first solution and the second solution under nitrogen atmosphere, mix and constantly stirring, obtain mixing solutions, the amidized polyoxyethylene glycol of end and the γ-proyl-Pidolidone ester-N-carboxylic acid inner-acid anhydride polymerization reaction take place that namely have the amidized poly glycol monomethyl ether of end of formula (IV) structure or have the formula V structure obtain segmented copolymer; Describedly have the amidized poly glycol monomethyl ether of end of formula (IV) structure or have the amidized polyoxyethylene glycol of end of formula V structure and the mol ratio of γ-proyl-Pidolidone ester-N-carboxylic acid inner-acid anhydride is 1:(5 ~ 120), be preferably 1:(10 ~ 100), 1:(15 ~ 90 more preferably); The temperature of described polyreaction is 20 ℃ ~ 40 ℃, and more preferably 25 ℃ ~ 35 ℃, described polymerization reaction time is 24h ~ 72h, more preferably 30h ~ 70h.
Reaction is preferably drained the organic solvent in the reaction solution that obtains with the method for decompressing and extracting after finishing, and obtains solid with the chloroform dissolving, then carries out sedimentation with ether, and the sediment that obtains is carried out suction filtration, washing, vacuum-drying, obtains segmented copolymer.
In step 2 of the present invention, segmented copolymer and azide biomolecular reaction with step 1 obtains obtain polyamino acid block copolymer.
Segmented copolymer and azide biomolecules are dissolved in the organic solvent, for the oxygen in the desolventizing, use nitrogen bubble 15 ~ 60 minutes, preferred 20 ~ 40 minutes, more preferably 30 minutes, then add CuSO
45H
2O continued bubbling after 1 ~ 10 minute minute, and preferred 2 ~ 8 minutes, more preferably 5 minutes, add sodium ascorbate, sealing is reacted under nitrogen atmosphere, namely obtains polyamino acid block copolymer.The alkynyl of described segmented copolymer, azide biomolecules, CuSO
45H
2The mol ratio of O and sodium ascorbate is 1:0.8 ~ 2:0.3 ~ 2:0.8 ~ 2, be preferably 1:1 ~ 1.5:0.4 ~ 1.6:1 ~ 1.5,1:1.2:0.5:1.2 more preferably, described azide biomolecules is semi-lactosi, seminose, glucose, vitamin H or small peptide, described organic solvent is preferably N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE or dimethyl sulfoxide (DMSO), described temperature of reaction is 30 ℃ ~ 50 ℃, be preferably 35 ℃ ~ 45 ℃, more preferably 40 ℃, the described reaction times is 36 ~ 120h, be preferably 48 ~ 96h, more preferably 72h.
Reaction adds reaction solution in the dialysis tubing after finishing, and uses distill water dialysis three days, and then freeze-drying namely obtains the polyamino acid block polymer.
Biological functional polyamino acid block copolymer provided by the invention, because it contains and has bioactive semi-lactosi, seminose, glucose, vitamin H or small peptide, they and cell have specific effect, can improve the adhesive power of cell, thereby be conducive to regulate the interaction of material and cell, thereby enlarge the range of application of hydrogel.
The present invention also provides a kind of responsive to temperature type block copolymer hydrogel, comprises the described polyamino acid block copolymer of technique scheme and solvent.After described responsive to temperature type block copolymer hydrogel at room temperature mixes polyamino acid block copolymer and solvent, can obtain the hydrogel of responsive to temperature type, described churning time is preferably 5 ~ 48h, 10 ~ 36h more preferably,, most preferably being 24h, described solvent is preferably water, physiological saline, buffered soln, tissue culture medium or body fluid, more preferably buffered soln or physiological saline most preferably are buffered soln.The quality optimization of described polyamino acid block copolymer is 2% ~ 30% of described polyamino acid block copolymer and solvent total mass, more preferably 4% ~ 20%, most preferably be 5% ~ 15%.
Above-mentioned block copolymer hydrogel is temperature-sensitive hydrogel, and when lesser temps, it is the aqueous solution, and this solution viscosity is lower; In the time of near temperature is increased to human body temperature, the aqueous solution can be transformed into gel.In addition, hydrogel provided by the invention has good biocompatibility and biological degradability, and its degradation cycle was about for 2 week ~ 15 weeks, and degraded product is amino acid and polyoxyethylene glycol, can directly excrete by kidney, and is harmless.
In order to further specify the present invention, below in conjunction with embodiment segmented copolymer provided by the invention, its preparation method and temperature sensitive type water gel are described in detail.
Embodiment 1
Add 8.8g, number-average molecular weight in the reaction flask of drying and be 550 the amidized poly glycol monomethyl ether of end, with the 200mL dry toluene behind 130 ℃ of lower azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The dissolution of solid that obtains in the DMF of 100mL drying, is obtained the first solution; 16.44g γ-proyl-Pidolidone ester-N-carboxylic acid anhydride is dissolved in the DMF of 100mL drying, obtains the second solution; In nitrogen atmosphere, the first solution is mixed with the second solution, under the nitrogen protection condition, stir 40
oC reacts 24h; After reaction finishes, the decompressing and extracting DMF, then with the dissolution of solid that obtains in chloroform, carry out sedimentation with ether again, suction filtration after the drying, obtains poly glycol monomethyl ether-poly-(γ-proyl-Pidolidone ester) di-block copolymer;
The semi-lactosi 0.5g of the poly glycol monomethyl ether that obtains-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.3g and azide is dissolved in the DMF of 20mL, then used nitrogen bubble 30 minutes, add 0.1gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.4g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of semi-lactosi functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of semi-lactosi success, connects 1.2 semi-lactosis on each polymkeric substance simultaneously.
The seminose 0.5g of the poly glycol monomethyl ether that obtains among the embodiment 1-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.4g and azide is dissolved in the DMF of 20mL, then used nitrogen bubble 30 minutes, add 0.1gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.4g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of seminose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of seminose success, connects 1.4 seminoses on each polymkeric substance simultaneously.
Embodiment 3
The glucose 0.5g of the poly glycol monomethyl ether that obtains among the embodiment 1-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.4g and azide is dissolved in the DMF of 20mL, then used nitrogen bubble 30 minutes, add 0.1gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.4g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days.After reaction finishes, reaction solution is added in the dialysis tubing, with distill water dialysis three days, then freeze-drying, namely obtain the polyamino acid block polymer of glucose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of glucose success, connects 1.2 glucose on each polymkeric substance simultaneously.
The vitamin H 0.7g of the poly glycol monomethyl ether that obtains among the embodiment 1-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.4g and azide is dissolved in the DMF of 20mL, then used nitrogen bubble 30 minutes, add 0.1gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.4g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days.After reaction finishes, reaction solution is added in the dialysis tubing, with distill water dialysis three days, then freeze-drying, namely obtain the polyamino acid block polymer of vitamin H functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of vitamin H success, connects 1.1 vitamin Hs on each polymkeric substance simultaneously.
The small peptide 1.0g of the poly glycol monomethyl ether that obtains among the embodiment 1-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.4g and azide is dissolved in the DMF of 20mL, then used nitrogen bubble 30 minutes, add 0.1gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.4g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days.After reaction finishes, reaction solution is added in the dialysis tubing, with distill water dialysis three days, then freeze-drying, namely obtain the polyamino acid block polymer of small peptide functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of small peptide success, connects 1.3 small peptides on each polymkeric substance simultaneously.
Add 10g, number-average molecular weight in the reaction flask of drying and be 2000 the amidized poly glycol monomethyl ether of end, with the 100mL dry toluene behind 130 ℃ of lower azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The dissolution of solid that obtains in the DMF of 100mL drying, is obtained the first solution; 12.65g γ-proyl-Pidolidone ester-N-carboxylic acid anhydride is dissolved in the DMF of 100mL drying, obtains the second solution; In nitrogen atmosphere, the first solution is mixed with the second solution, under the nitrogen protection condition, stir 20
oC reacts 72h; After reaction finishes, the decompressing and extracting DMF, then with the dissolution of solid that obtains in chloroform, carry out sedimentation with ether again, suction filtration after the drying, obtains poly glycol monomethyl ether-poly-(γ-proyl-Pidolidone ester) segmented copolymer;
The semi-lactosi 0.4g of the poly glycol monomethyl ether that obtains-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.835g and azide is dissolved in the DMF of 20mL, then used nitrogen bubble 30 minutes, add 0.08gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.32g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of semi-lactosi functionalization.
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of the polyamino acid block polymer that obtains of the embodiment of the invention 6, and experimental result shows that receiving on the polymkeric substance of semi-lactosi success connects 1.2 semi-lactosis on each polymkeric substance simultaneously.
Embodiment 7
The seminose 0.4g of the poly glycol monomethyl ether that obtains among the embodiment 6-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.835g and azide is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.08gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.32g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of seminose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of seminose success, connects 2.1 seminoses on each polymkeric substance simultaneously.
The glucose 0.4g of the poly glycol monomethyl ether that obtains among the embodiment 6-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.835g and azide is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.08gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.32g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of glucose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of glucose success, connects 1.7 glucose on each polymkeric substance simultaneously.
Embodiment 9
The vitamin H 0.5g of the poly glycol monomethyl ether that obtains among the embodiment 6-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.835g and azide is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.08CuSO
45H
2O continued bubbling after 5 minutes, added 0.32 sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of vitamin H functionalization.
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of the polyamino acid block polymer that obtains of the embodiment of the invention 9, and experimental result shows: receiving on the polymkeric substance of vitamin H success connects 1.3 vitamin Hs on each polymkeric substance simultaneously.
The small peptide 0.7g of the poly glycol monomethyl ether that obtains among the embodiment 6-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.835g and azide is dissolved in the DMF of 20mL, then used nitrogen bubble 30 minutes, add 0.08gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.32g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of small peptide functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of small peptide success, connects 1.5 small peptides on each polymkeric substance simultaneously.
Embodiment 11
Add 10g, number-average molecular weight in the reaction flask of drying and be 5000 the amidized poly glycol monomethyl ether of end, with the 100mL dry toluene behind 130 ℃ of lower azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The dissolution of solid that obtains in the DMF of 100mL drying, is obtained the first solution; 10.54g γ-proyl-Pidolidone ester-N-carboxylic acid anhydride is dissolved in the DMF of 100mL drying, obtains the second solution; In nitrogen atmosphere, the first solution is mixed with the second solution, under the nitrogen protection condition, stir 40
oC reacts 72h; After reaction finishes, the decompressing and extracting DMF, then with the dissolution of solid that obtains in chloroform, carry out sedimentation with ether again, suction filtration after the drying, obtains poly glycol monomethyl ether-poly-(γ-proyl-Pidolidone ester) segmented copolymer;
The semi-lactosi 0.2g of the poly glycol monomethyl ether that obtains-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.668g and azide is dissolved in the dimethyl sulfoxide (DMSO) of 20mL, then used nitrogen bubble 30 minutes, add 0.04gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.16g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of semi-lactosi functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of semi-lactosi success, connects 2.9 semi-lactosis on each polymkeric substance simultaneously.
Embodiment 12
The seminose 0.2g of the poly glycol monomethyl ether that obtains among the embodiment 11-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.668g and azide is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.04gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.16g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of seminose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of seminose success, connects 2.4 seminoses on each polymkeric substance simultaneously.
Embodiment 13
The glucose 0.2g of the poly glycol monomethyl ether that obtains among the embodiment 11-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.668g and azide is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.04gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.16g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of glucose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of glucose success, connects 3.0 glucose on each polymkeric substance simultaneously.
Embodiment 14
The vitamin H 0.26g of the poly glycol monomethyl ether that obtains among the embodiment 11-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.668g and azide is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.04gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.16g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of vitamin H functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of vitamin H success, connects 3.2 vitamin Hs on each polymkeric substance simultaneously.
The small peptide 0.38g of the poly glycol monomethyl ether that obtains among the embodiment 11-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.668g and azide is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.04gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.16g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of small peptide functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of small peptide success, connects 2.5 small peptides on each polymkeric substance simultaneously.
Embodiment 16
Add 10g, number-average molecular weight in the reaction flask of drying and be 2000 the amidized polyoxyethylene glycol of end, with the 100mL dry toluene behind 130 ℃ of lower azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The dissolution of solid that obtains in the DMF of 100mL drying, is obtained the first solution; 11.6g γ-proyl-Pidolidone ester-N-carboxylic acid anhydride is dissolved in the DMF of 100mL drying, obtains the second solution; In nitrogen atmosphere, the first solution is mixed with the second solution, under the nitrogen protection condition, stir 40 ℃ of reaction 72h; After reaction finishes, the decompressing and extracting DMF, then with the dissolution of solid that obtains in chloroform, carry out sedimentation, suction filtration with ether again, after the drying, gathered (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer;
The triblock copolymer 1.835g that obtains and the semi-lactosi 0.4g of azide are dissolved in the DMF of 20mL, then used nitrogen bubble 30 minutes, add 0.08gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.32g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days; After reaction finishes, reaction solution is added in the dialysis tubing, with distill water dialysis three days, then freeze-drying, namely obtain the polyamino acid block polymer of semi-lactosi functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of semi-lactosi success, connects 1.9 semi-lactosis on each polymkeric substance simultaneously.
Embodiment 17
The seminose 0.4g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.835g and azide that obtains among the embodiment 16 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.08gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.32g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of seminose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of seminose success, connects 2.2 seminoses on each polymkeric substance simultaneously.
Embodiment 18
The glucose 0.4g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.835g and azide that obtains among the embodiment 16 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.08gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.32g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of glucose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of glucose success, connects 2.1 glucose on each polymkeric substance simultaneously.
Embodiment 19
The vitamin H 0.5g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.835g and azide that obtains among the embodiment 16 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.08gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.32g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of vitamin H functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of vitamin H success, connects 1.6 vitamin Hs on each polymkeric substance simultaneously.
The small peptide 0.7g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.835g and azide that obtains among the embodiment 16 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.08gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.32g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of small peptide functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of small peptide success, connects 1.8 small peptides on each polymkeric substance simultaneously.
Embodiment 21
Add 10g, number-average molecular weight in the reaction flask of drying and be 5000 the amidized polyoxyethylene glycol of end, with the 100mL dry toluene behind 130 ℃ of lower azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The dissolution of solid that obtains in the DMF of 100mL drying, is obtained the first solution; 9.7g γ-proyl-Pidolidone ester-N-carboxylic acid anhydride is dissolved in the DMF of 100mL drying, obtains the second solution; In nitrogen atmosphere, the first solution is mixed with the second solution, under the nitrogen protection condition, stir 40 ℃ of reaction 72h; After reaction finishes, the decompressing and extracting DMF, then with the dissolution of solid that obtains in chloroform, carry out sedimentation, suction filtration with ether again, after the drying, gathered (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) segmented copolymer;
The semi-lactosi 0.2g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.668g and azide that obtains is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.04gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.16g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of semi-lactosi functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of semi-lactosi success, connects 2.6 semi-lactosis on each polymkeric substance simultaneously.
Embodiment 22
The seminose 0.2g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.668g and azide that obtains among the embodiment 21 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.04gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.16g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of seminose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of seminose success, connects 2.9 seminoses on each polymkeric substance simultaneously.
Embodiment 23
The glucose 0.2g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.668g and azide that obtains among the embodiment 21 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.04gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.16g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of glucose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of glucose success, connects 3.3 glucose on each polymkeric substance simultaneously.
Embodiment 24
The vitamin H 0.26g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.668g and azide that obtains among the embodiment 21 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.04gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.16g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of vitamin H functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of vitamin H success, connects 2.4 vitamin Hs on each polymkeric substance simultaneously.
The small peptide 0.38g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.668g and azide that obtains among the embodiment 21 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.04gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.16g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of small peptide functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of small peptide success, connects 2.2 small peptides on each polymkeric substance simultaneously.
Embodiment 26
The semi-lactosi 0.5g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.668g and azide that obtains among the embodiment 21 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.1gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.4g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of semi-lactosi functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of semi-lactosi success, connects 5.2 semi-lactosis on each polymkeric substance simultaneously.
Embodiment 27
The seminose 0.5g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.668g and azide that obtains among the embodiment 21 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.1gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.4g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of seminose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of seminose success, connects 5 seminoses on each polymkeric substance simultaneously.
Embodiment 28
The glucose 0.5g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.668g and azide that obtains among the embodiment 21 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.1gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.4g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of glucose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of glucose success, connects 6.3 glucose on each polymkeric substance simultaneously.
Embodiment 29
The vitamin H 0.7g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.668g and azide that obtains among the embodiment 21 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.1gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.4g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of vitamin H functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of vitamin H success, connects 6.5 vitamin Hs on each polymkeric substance simultaneously.
The small peptide 1.0g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.668g and azide that obtains among the embodiment 21 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.1gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.4g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of small peptide functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of small peptide success, connects 4.8 small peptides on each polymkeric substance simultaneously.
Embodiment 31
Add 10g, number-average molecular weight in the reaction flask of drying and be 10000 the amidized poly glycol monomethyl ether of end, with the 100mL dry toluene behind 130 ℃ of lower azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The dissolution of solid that obtains in the DMF of 100mL drying, is obtained the first solution; 13.08g γ-proyl-Pidolidone ester-N-carboxylic acid anhydride is dissolved in the DMF of 100mL drying, obtains the second solution; In nitrogen atmosphere, the first solution is mixed with the second solution, under the nitrogen protection condition, stir 40 ℃ of reaction 72h; After reaction finishes, the decompressing and extracting DMF, then with the dissolution of solid that obtains in chloroform, carry out sedimentation with ether again, suction filtration after the drying, obtains poly glycol monomethyl ether-poly-(γ-proyl-Pidolidone ester) di-block copolymer;
The semi-lactosi 0.2g of the poly glycol monomethyl ether that obtains-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.001g and azide is dissolved in the DMF of 20mL, then used nitrogen bubble 30 minutes, add 0.04gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.16g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of semi-lactosi functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of semi-lactosi success, connects 11.3 semi-lactosis on each polymkeric substance simultaneously.
Embodiment 32
The seminose 0.2g of the poly glycol monomethyl ether that embodiment 31 is obtained-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.001g and azide is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.04gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.16g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of seminose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of seminose success, connects 12.8 seminoses on each polymkeric substance simultaneously.
Embodiment 33
The glucose 0.2g of the poly glycol monomethyl ether that embodiment 31 is obtained-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.001g and azide is dissolved in the DMF of 20mL, then uses nitrogen bubble 30 minutes, adds 0.04CuSO
45H
2O continued bubbling after 5 minutes, added the 0.16g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of glucose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of glucose success, connects 10.5 glucose on each polymkeric substance simultaneously.
Embodiment 34
The vitamin H 0.25g of the poly glycol monomethyl ether that embodiment 31 is obtained-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.001g and azide is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.04CuSO
45H
2O continued bubbling after 5 minutes, added the 0.16g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of vitamin H functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of vitamin H success, connects 11.9 vitamin Hs on each polymkeric substance simultaneously.
Embodiment 35
The small peptide 0.36g of the poly glycol monomethyl ether that embodiment 31 is obtained-poly-(γ-proyl-Pidolidone ester) di-block copolymer 1.001g and azide is dissolved in the DMF of 20mL, then uses nitrogen bubble 30 minutes, adds 0.04CuSO
45H
2O continued bubbling after 5 minutes, added the 0.16g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of small peptide functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of small peptide success, connects 10.9 small peptides on each polymkeric substance simultaneously.
Embodiment 36
Add 10g, number-average molecular weight in the reaction flask of drying and be 10000 the amidized polyoxyethylene glycol of end, with the 100mL dry toluene behind 130 ℃ of lower azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The dissolution of solid that obtains in the DMF of 100mL drying, is obtained the first solution; 26g γ-proyl-Pidolidone ester-N-carboxylic acid anhydride is dissolved in the DMF of 100mL drying, obtains the second solution; In nitrogen atmosphere, the first solution is mixed with the second solution, under the nitrogen protection condition, stir 40 ℃ of reaction 72h; After reaction finishes, the decompressing and extracting DMF, then with the dissolution of solid that obtains in chloroform, carry out sedimentation, suction filtration with ether again, after the drying, gathered (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer;
The semi-lactosi 0.4g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.001g and azide that obtains is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.08gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.32g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days; After reaction finishes, reaction solution is added in the dialysis tubing, with distill water dialysis three days, then freeze-drying, namely obtain the polyamino acid block polymer of semi-lactosi functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of semi-lactosi success, connects 21.8 semi-lactosis on each polymkeric substance simultaneously.
Embodiment 37
The seminose 0.4g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.001g and azide that obtains among the embodiment 36 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.08gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.32g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of seminose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of seminose success, connects 23.5 seminoses on each polymkeric substance simultaneously.
Embodiment 38
The glucose 0.4g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.001g and azide that obtains among the embodiment 36 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.08gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.32g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of glucose functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of glucose success, connects 18.2 glucose on each polymkeric substance simultaneously.
Embodiment 39
The vitamin H 0.5g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.001g and azide that obtains among the embodiment 36 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.08gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.32g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of vitamin H functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of vitamin H success, connects 24.9 vitamin Hs on each polymkeric substance simultaneously.
The small peptide 0.72g that gathers (γ-proyl-Pidolidone ester)-polyethylene glycol-(γ-proyl-Pidolidone ester) triblock copolymer 1.001g and azide that obtains among the embodiment 36 is dissolved in the N of 20mL, in the dinethylformamide, then use nitrogen bubble 30 minutes, and added 0.08gCuSO
45H
2O continued bubbling after 5 minutes, added the 0.32g sodium ascorbate, sealing, and under nitrogen atmosphere, 40
oC reaction three days, reaction adds reaction solution in the dialysis tubing after finishing, and with distill water dialysis three days, then freeze-drying, namely obtains the polyamino acid block polymer of small peptide functionalization.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows receiving on the polymkeric substance of small peptide success, connects 26.5 small peptides on each polymkeric substance simultaneously.
Embodiment 41
It is 5% ~ 20% the aqueous solution that the polyamino acid block copolymer of embodiment 6 preparation is mixed with mass concentration, adopting the tubule inverted type to observe its viscosity at 5 ℃ ~ 80 ℃ changes, when being inverted with tubule, do not occur in the 30s to flow is gelation, balance 10min under each temperature, temperature rise rate is 2 ℃/min, the result is referring to Fig. 3, the temperature variant phasor of the polyamino acid block copolymer aqueous solution of the different concns that Fig. 3 provides for the embodiment of the invention 41, in Fig. 3, Regional Representative's solution of straight line below, Regional Representative's gel of straight line top, this gelation process is reversible, as seen from Figure 3, when the polyamino acid block copolymer concentration of aqueous solution was 10% ~ 15%, it was 30 ℃ ~ 40 ℃ by the temperature that the aqueous solution forms hydrogel.
Embodiment 42
It is 5% ~ 20% the aqueous solution that the polyamino acid block copolymer of embodiment 9 preparation is mixed with mass concentration, adopting the tubule inverted type to observe its viscosity at 5 ℃ ~ 80 ℃ changes, when being inverted with tubule, do not occur in the 30s to flow is gelation, balance 10min under each temperature, temperature rise rate is 2 ℃/min, the result is referring to Fig. 4, the temperature variant phasor of the segmented copolymer aqueous solution of the different concns that Fig. 4 provides for the embodiment of the invention 42, as shown in Figure 4, when the polyamino acid block copolymer concentration of aqueous solution was 8% ~ 16%, it was 30 ℃ ~ 40 ℃ by the temperature that the aqueous solution forms hydrogel.
Embodiment 43
It is 6% ~ 12% the aqueous solution that the polyamino acid block copolymer of embodiment 17 preparation is mixed with mass concentration, adopts the tubule inverted type to observe its viscosity at 5 ℃ ~ 80 ℃ and changes, and when being inverted with tubule, not occuring in the 30s to flow is gelation.Balance 10min under each temperature, temperature rise rate are 2 ℃/min, and the result is referring to Fig. 5, the temperature variant phasor of the segmented copolymer aqueous solution of the different concns that Fig. 5 provides for the embodiment of the invention 43.As shown in Figure 5, when the polyamino acid block copolymer concentration of aqueous solution was 7% ~ 9%, it was 30 ℃ ~ 40 ℃ by the temperature that the aqueous solution forms hydrogel.
Embodiment 44
It is 10% ~ 25% the aqueous solution that the polyamino acid block copolymer of embodiment 21 preparation is mixed with mass concentration, adopting the tubule inverted type to observe its viscosity at 5 ℃ ~ 80 ℃ changes, when being inverted with tubule, do not occur in the 30s to flow is gelation, balance 10min under each temperature, temperature rise rate is 2 ℃/min, and the result is referring to Fig. 6, the temperature variant phasor of the segmented copolymer aqueous solution of the different concns that Fig. 6 provides for the embodiment of the invention 44.As shown in Figure 6, when the polyamino acid block copolymer concentration of aqueous solution was 15% ~ 22%, it was 30 ℃ ~ 40 ℃ by the temperature that the aqueous solution forms hydrogel.
Embodiment 45
It is 12% the aqueous solution that the polyamino acid block copolymer of embodiment 6 preparation is mixed with mass concentration, and the 0.5mL aqueous solution is placed 10min in 37 ℃ constant temperature oscillation case, forms hydrogel; Be that 7.4 phosphoric acid salt (PBS) buffered soln joins in the above-mentioned hydrogel with 3mL pH value, obtain solution to be measured; Get 2.5mL solution to be measured, with freeze-drying behind the liquid nitrogen flash freezer, that then adds equivalent in the described solution to be measured contains enzyme PBS solution at every turn.Adopt weighting method and gel permeation chromatography (GPC) that the sample that each freeze-drying obtains is analyzed, the result shows that the degradation cycle of described polyamino acid block copolymer was 12 weeks, and degraded product is polyoxyethylene glycol and Pidolidone.
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. a polyamino acid block copolymer is characterized in that, comprises have formula the first block of (I) or formula (II) structure and the second block with formula (III) structure:
Wherein, R is the azide biomolecules;
X, y, m and n are the polymerization degree, 10≤x≤227,10≤y≤226,4≤m≤96,1≤n≤60.
2. a kind of polyamino acid block copolymer according to claim 1 is characterized in that, described R is semi-lactosi, seminose, glucose, vitamin H or small peptide.
3. a kind of polyamino acid block copolymer according to claim 1 is characterized in that, the weight percentage that described the second block accounts for described polyamino acid block copolymer is 25% ~ 75%.
4. the preparation method of a polyamino acid block copolymer is characterized in that, may further comprise the steps:
Step 1: the amidized polyoxyethylene glycol of end and the γ-proyl-Pidolidone ester-N-carboxylic acid inner-acid anhydride polymerization reaction take place that have the amidized poly glycol monomethyl ether of end of formula (IV) structure or have the formula V structure obtain segmented copolymer;
Wherein, x is the polymerization degree, 10≤x≤227; Y is the polymerization degree, 10≤y≤226;
Step 2: segmented copolymer and azide biomolecular reaction with step 1 obtains obtain polyamino acid block copolymer.
5. the preparation method of a kind of polyamino acid block copolymer according to claim 4, it is characterized in that, the amidized polyoxyethylene glycol of described end or hold amidized poly glycol monomethyl ether and the mol ratio of γ-proyl-Pidolidone ester-N-carboxylic acid inner-acid anhydride is 1:(5 ~ 120).
6. the preparation method of a kind of polyamino acid block copolymer according to claim 4 is characterized in that, the alkynyl of segmented copolymer and azide biomolecules mol ratio are 1:(0.8 ~ 1.2 in the described step 2).
7. the preparation method of a kind of polyamino acid block copolymer according to claim 4 is characterized in that, described azide biomolecules is semi-lactosi, seminose, glucose, vitamin H or small peptide.
8. a responsive to temperature type block copolymer hydrogel is characterized in that, comprises the described polyamino acid block copolymer of claim 1 ~ 7 any one and solvent.
9. a kind of responsive to temperature type block copolymer hydrogel according to claim 8 is characterized in that, described solvent is water, physiological saline, buffered soln, tissue culture medium or body fluid.
10. a kind of responsive to temperature type block copolymer hydrogel according to claim 8 is characterized in that, the massfraction of described poly-amino segmented copolymer is 2% ~ 30%.
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