CN102580105A - Polymer nanometer gel drug carrier and preparation method thereof - Google Patents
Polymer nanometer gel drug carrier and preparation method thereof Download PDFInfo
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- CN102580105A CN102580105A CN201110418924XA CN201110418924A CN102580105A CN 102580105 A CN102580105 A CN 102580105A CN 201110418924X A CN201110418924X A CN 201110418924XA CN 201110418924 A CN201110418924 A CN 201110418924A CN 102580105 A CN102580105 A CN 102580105A
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Abstract
The invention relates to a polymer nanometer gel drug carrier which is formed by self-assembling end-group modified water-soluble polymer and cyclodextrin under the action of a non-covalent bond, wherein the end-group modified water-soluble polymer is a water-soluble polymer with the end-group combined with a hydrophobic compound having a benzene ring, and the mole ratio of a repeated unit of the end-group modified water-soluble polymer to the cyclodextrin is (1:1)-(6:1). A preparation method for the polymer nanometer gel drug carrier comprises the following steps that: (1) modifying the end-group of the water-soluble polymer; (2) under the condition of normal pressure and room temperature, adopting a solvent for preparing the end-group modified water-soluble polymer into a solution with the concentration of 0.5g/l-100g/l, and then mixing the solution of the end-group modified water-soluble polymer with a saturated solution of the cyclodextrin, ultrasonically oscillating for 5-60 minutes, after ending the ultrasonically oscillating, standing for 1-24 hours, thereby forming a mixed solution containing nanometer gel; and (3) separating and purifying the nanometer gel.
Description
Technical field
The invention belongs to the pharmaceutical carrier field, particularly a kind of polymer nanocomposite gel medicine carrier and preparation method thereof.
Background technology
Nanogel (Nanogel) is a kind of gel with nanostructured and size, is the bonded product of nanotechnology and gel phase.Nanogel is cross-linked to form through strong interactions such as covalent bond or ionic bonds, can swelling in solution.Nanogel can also be avoided engulfing of reticuloendothelial system in vivo as pharmaceutical carrier Stability Analysis of Structures not only, is one type of novel nano-medicament carrier.
The research of existing nanogel pharmaceutical carrier is both at home and abroad reported.Liu Zheng obtains the nanogel of polyacrylic acid derivative through in-situ polymerization, and use it for protein molecule parcel (J.Am.Chem.Soc., 2006,128,11008-11009); Left side Ju synthesized the responsive Isopropylacrylamide nanogel of nucleocapsid structure pH (Macromolecules, 2004,37,10042-10046); Jiang Mingyong chitosan and ovalbumin prepared the responsive nanogel of pH (Langmuir, 2006,22,2754-2759); Kuckling etc. become nano-emulsion with PNIPAM emulsifying and drip, through photo-crosslinking obtain temperature sensitive property PNIPAM nanogel (Macromolecules, 2006,39,1585-1591); Lyon etc. use golden nanometer particle to be template, with the synthetic PNIPAM of precipitation polymerization method, etch away template through potassium cyanide, prepared hollow nanogel (Chemistry of Materials, 2007,19,719-726); Kabanov etc. are carrier with crosslinked PEG-PEI nanogel, the load oligonucleotide pass blood brain barrier (Blood-brain barrier) treatment brain diseases (Bioconjugate Chemistry, 2004,15,50-60); Kokufuta etc. through the interaction of positive and negative charge prepared the polyelectrolyte type nanogel (Langmuir, 2007,23,2095-2102); Smedt etc. obtain after with natural polymer glucosan emulsification and cross linked the glucosan nanogel (Macromolecules, 2005,38,8503-8511).Above-mentioned nanogel concentrates on PNIPAM (PNIPAAm), gathers ethyl imines (PEI) and natural polymer such as glucosan etc., and they as pharmaceutical carrier, are faced problems such as biocompatibility, cytotoxicity, biological degradability.
Summary of the invention
The object of the present invention is to provide one type of new type of polymer nanogel pharmaceutical carrier and preparation method thereof; This type of polymer nanocomposite gel medicine carrier not only has good stable property and dispersibility, and has excellent biological compatibility and biodegradability.
Polymer nanocomposite gel medicine carrier according to the invention; Form through the self assembly of non-covalent bond active force by terminal groups modification water-soluble polymer and cyclodextrin; Said terminal groups modification water-soluble polymer is the water-soluble polymer that end group is combined with the hydrophobic compound of band phenyl ring, and the mol ratio of terminal groups modification water-soluble polymer repetitive and cyclodextrin is 1: 1～6: 1.
In the polymer nanocomposite gel medicine carrier according to the invention, said water-soluble polymer is a kind of in PEO-PPO-PEO, polyethylene glycol oxide, the polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer; The hydrophobic compound of said band phenyl ring is a kind of in dinitro cinnamic acid, lauric acid, coumarin, half coumarin, carboxyl half coumarin, the carboxyl coumarin.
In the polymer nanocomposite gel medicine carrier of the present invention, said cyclodextrin is a kind of in alpha-cyclodextrin, beta-schardinger dextrin-, the gamma-cyclodextrin.
Polymer nanocomposite gel medicine carrier of the present invention, its particle diameter is 20nm～450nm.
The method for preparing of polymer nanocomposite gel medicine carrier according to the invention, processing step is following:
(1) terminal groups modification of water-soluble polymer
Raw material comprises the hydrophobic compound and the condensing agent of water-soluble polymer, band phenyl ring, and water-soluble polymer, the hydrophobic compound of band phenyl ring, the mol ratio of condensing agent are 1: 2: 2～1: 10: 10;
To be dispersed in the solvent with the hydrophobic compound and the water-soluble polymer of phenyl ring normal pressure ,-20 ℃～50 ℃; The consumption of solvent is that 0.5 grams per liter～20 grams per liters exceed with the concentration of water-soluble polymer in the mixed liquor; Adding condensing agent then under agitation reacted 0.5 hour～24 hours; After response time expires, with reacting liquid filtering and concentrate, concentrated solution is put into the precipitant post precipitation wash hydrophobic compound, condensing agent and by-product to remove free band phenyl ring; With the product vacuum drying after the washing, promptly obtain the terminal groups modification water-soluble polymer that end group is combined with the hydrophobic compound of band phenyl ring;
(2) the terminal groups modification water-soluble polymer penetrates cyclodextrin
Raw material comprises that (solvent of preparing the cyclodextrin saturated solution is dimethyl sulfoxine, N with the cyclodextrin saturated solution for the terminal groups modification water-soluble polymer of step (1) preparation; Dinethylformamide or deionized water); Terminal groups modification water-soluble polymer 10 mass parts～500 mass parts; Cyclodextrin saturated solution 5 parts by volume～20 parts by volume; The mass unit of terminal groups modification water-soluble polymer is that the volume unit of milligram, cyclodextrin saturated solution is milliliter, or the mass unit of terminal groups modification water-soluble polymer for the volume unit of gram, cyclodextrin saturated solution for rising;
Under room temperature, normal pressure; Use solvent to be made into the solution that concentration is 0.5 grams per liter～100 grams per liters the terminal groups modification water-soluble polymer of step (1) preparation; Then said terminal groups modification water-soluble polymer solution is mixed with the cyclodextrin saturated solution, sonic oscillation 5 minutes～60 minutes is after the sonic oscillation time expires; Left standstill 1 hour～24 hours, i.e. formation contains the nanogel mixed liquor;
(3) isolation and purification of nanogel
The nanogel mixed liquor that contains that step (2) is obtained passes through filtering with microporous membrane; The centrifugalize (rotating speed is 3000 rev/mins～50000 rev/mins) of will filtrating then; The isolated nanogel of institute is removed free cyclodextrin postlyophilization (temperature-50 ℃ to 25 ℃, be at least drying time 12 hours) through washing and is promptly obtained polymer nanocomposite gel medicine carrier.
The relevant raw material that the method for preparing of polymer nanocomposite gel medicine carrier according to the invention is related:
Said water-soluble polymer is a kind of in PEO-PPO-PEO, polyethylene glycol oxide, the polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer; The hydrophobic compound of said band phenyl ring is a kind of in dinitro cinnamic acid, lauric acid, coumarin, half coumarin, carboxyl half coumarin, the carboxyl coumarin.
Said cyclodextrin is a kind of in alpha-cyclodextrin, beta-schardinger dextrin-, the gamma-cyclodextrin.
Said condensing agent is a kind of in carbodicyclo hexylimide, 1-ethyl-(3-dimethyl aminopropyl) carbodiimide, 1-ethyl-(3-dimethyl aminopropyl) carbodiimide hydrochloride.
Said solvent is distilled water, deionized water, oxolane, ether, ethanol, 1,4-dioxane, dichloromethane, acetone, Methanamide, acetamide, N, a kind of in dinethylformamide, DMAC N,N, the dimethyl sulfoxine.
Said precipitant is absolute ether or deionized water.
A kind of as in acetone, Methanamide, acetamide, deionized water, ethanol, the ether of the washing liquid that said washing the time is used.
The aperture of said microporous filter membrane is 0.45 micron～0.80 micron.
The present invention has following beneficial effect:
1, the invention provides one type of new type of polymer nanogel pharmaceutical carrier, enlarged the type of pharmaceutical carrier.
2, the present invention's main constituent of being nanogel with the water-soluble polymer and the cyclodextrin of good biocompatibility, the nanogel that obtains has good biocompatibility as pharmaceutical carrier, no cytotoxicity.
3, the present invention with the water-soluble polymer chain of modification penetrate cyclodextrin and with end group on contain the weak interaction force of phenyl ring molecule through non-covalent bond and drive self assembly and form nanogel, make nanogel have favorable biological degradability.
4, the present invention utilizes the terminal groups modification of water-soluble polymer to introduce strong hydrophobic group, and the nanogel that non-covalent bond is formed has good stable property and dispersibility.
5, the present invention can be through changing the type of water-soluble polymer, and the kind of the hydrophobic compound of band phenyl ring is regulated the degradation time of nanogel.
Description of drawings
Fig. 1 is the stereoscan photograph of polymer nanocomposite gel medicine carrier according to the invention, and A figure and B figure are the photos of different amplification, and the minimum scale of scale is 500 nanometers among the A figure, and the minimum scale of scale is 100 nanometers among the B figure.
Fig. 2 is the transmission electron microscope photo of polymer nanocomposite gel medicine carrier according to the invention, and A figure and B figure are the photos of different amplification, and scale is 500 nanometers among the A figure, and scale is 100 nanometers among the B figure.
Fig. 3 is the AFM photo of polymer nanocomposite gel medicine carrier according to the invention.
Fig. 4 is the particle size distribution figure of polymer nanocomposite gel medicine carrier according to the invention, records with the dynamic light scattering particle size appearance.
Fig. 5 is the cytotoxicity experiment figure as a result of polymer nanocomposite gel according to the invention, adopts the MTT method to record.
The specific embodiment
Through embodiment polymer nanocomposite gel medicine carrier according to the invention and preparation method thereof is described further below.Among the following embodiment, hydrophobic compound, condensing agent, solvent, the cyclodextrin of various water-soluble polymers, band phenyl ring are all selected analytical pure for use, can buy through market.
Embodiment 1
(1) terminal groups modification of water-soluble polymer
Water-soluble polymer is a polyethylene glycol oxide; The hydrophobic compound of band phenyl ring is a lauric acid; Condensing agent is 1-ethyl-(3-dimethyl aminopropyl) carbodiimide (EDC); Solvent is 1, the 4-dioxane, and the mol ratio of polyethylene glycol oxide, lauric acid and 1-ethyl-(3-dimethyl aminopropyl) carbodiimide is 1: 4: 10;
Normal pressure, 50 ℃ lauric acid and polyethylene glycol oxide are dispersed in 1, in the 4-dioxane, 1; The consumption of 4-dioxane is that 0.5 grams per liter exceeds with the concentration of polyethylene glycol oxide in the mixed liquor, adds 1-ethyl-(3-dimethyl aminopropyl) carbodiimide then and under agitation reacts 0.5 hour, after the response time expires; With reacting liquid filtering and concentrate; Concentrated solution is put into after the absolute ether deposition three times with washing with acetone three times, with product vacuum drying (negative pressure 0.1MPa, 30 ℃ of the baking temperatures after washing; 24 hours drying times), promptly obtain the terminal groups modification polyethylene glycol oxide that end group is combined with the lauric acid molecule;
(2) water-soluble polymer of terminal groups modification penetrates cyclodextrin
The terminal groups modification polyethylene glycol oxide 25mg of metrology steps (1) preparation, 20 milliliters of the alpha-cyclodextrin saturated solutions of alpha-cyclodextrin and dimethyl sulfoxine preparation;
Terminal groups modification polyethylene glycol oxide with step (1) preparation under room temperature, normal pressure is dissolved in the distilled water; Be mixed with the solution that concentration is 0.5 grams per liter; Then said terminal groups modification polyethylene oxide solutions is mixed with the alpha-cyclodextrin saturated solution, sonic oscillation 60 minutes is after the sonic oscillation time expires; Left standstill 24 hours, i.e. formation contains the nanogel mixed liquor;
(3) isolation and purification of nanogel
To use the aperture be 0.80 micron membrane filtration to the nanogel mixed liquor that contains that step (2) is obtained; To filtrate then 30000 rev/mins of following centrifugalize;-20 ℃ of lyophilizations 36 hours, obtain Powdered nanogel pharmaceutical carrier after isolated nanogel respectively washs three times with ether, ethanol successively, the mol ratio of terminal groups modification polyethylene glycol oxide repetitive and alpha-cyclodextrin is 4: 1; Form is seen Fig. 1～Fig. 3, and its particle diameter is seen Fig. 4.Nanogel pharmaceutical carrier degradation time is about 10 days.
Embodiment 2
(1) terminal groups modification of water-soluble polymer
Water-soluble polymer is a PEO-PPO-PEO; The hydrophobic compound of band phenyl ring is half coumarin; Condensing agent is 1-ethyl-(3-dimethyl aminopropyl) carbodiimide hydrochloride; Solvent is N, dinethylformamide, and the mol ratio of PEO-PPO-PEO, half coumarin and 1-ethyl-(3-dimethyl aminopropyl) carbodiimide hydrochloride is 1: 5: 5;
Normal pressure ,-20 ℃ half coumarin and PEO-PPO-PEO are dispersed in N; In the dinethylformamide, N, the consumption of dinethylformamide is that 20 grams per liters exceed with the concentration of PEO-PPO-PEO in the mixed liquor; Adding 1-ethyl-(3-dimethyl aminopropyl) carbodiimide hydrochloride then under agitation reacted 10 hours; After response time expires, with reacting liquid filtering and concentrate, concentrated solution is put into after the absolute ether deposition three times with Methanamide washing three times; With product vacuum drying (the negative pressure 0.1MPa after the washing; 30 ℃ of baking temperatures, 24 hours drying times), promptly obtain the terminal groups modification PEO-PPO-PEO that end group is combined with half coumarin molecule;
(2) water-soluble polymer of terminal groups modification penetrates cyclodextrin
The terminal groups modification PEO-PPO-PEO 20mg of metrology steps (1) preparation, beta-schardinger dextrin-and N, 10 milliliters of the beta-schardinger dextrin-saturated solutions of dinethylformamide preparation;
Terminal groups modification PEO-PPO-PEO with step (1) preparation under room temperature, normal pressure is dissolved in the distilled water; Be mixed with the solution that concentration is 2 grams per liters; Then said terminal groups modification PEO-PPO-PEO solution is mixed with the beta-schardinger dextrin-saturated solution, sonic oscillation 30 minutes is after the sonic oscillation time expires; Left standstill 10 hours, i.e. formation contains the nanogel mixed liquor;
(3) isolation and purification of nanogel
To use the aperture be 0.45 micron membrane filtration to the nanogel mixed liquor that contains that step (2) is obtained; To filtrate then 10000 rev/mins of following centrifugalize; Isolated nanogel with after the washing with alcohol three times-50 ℃ of lyophilizations 48 hours, obtain Powdered nanogel pharmaceutical carrier, the mol ratio of terminal groups modification PEO-PPO-PEO repetitive and beta-schardinger dextrin-is 3: 1; Form is similar to Fig. 1～Fig. 3, and particle diameter is in the said scope of Fig. 4.Nanogel pharmaceutical carrier degradation time is about 20 days.
Embodiment 3
(1) terminal groups modification of water-soluble polymer
Water-soluble polymer is polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer; The hydrophobic compound of band phenyl ring is a coumarin; Condensing agent is 1-ethyl-(3-dimethyl aminopropyl) carbodiimide hydrochloride; Solvent is N, dinethylformamide, and the mol ratio of polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer, coumarin and 1-ethyl-(3-dimethyl aminopropyl) carbodiimide hydrochloride is 1: 5: 5;
Normal pressure, 20 ℃ coumarin and polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer are dispersed in N; In the dinethylformamide, N, the consumption of dinethylformamide is that 10 grams per liters exceed with the concentration of polyethylene glycol oxide-polypropylene glycol in the mixed liquor-polyoxyethylene alkene copolymer; Adding 1-ethyl-(3-dimethyl aminopropyl) carbodiimide hydrochloride then under agitation reacted 5 hours; After response time expires, with reacting liquid filtering and concentrate, concentrated solution is put into after the deionized water deposition three times with deionized water wash three times; With product vacuum drying (the negative pressure 0.1MPa after the washing; 30 ℃ of baking temperatures, 24 hours drying times), promptly obtain terminal groups modification polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer that end group is combined with the coumarin group;
(2) water-soluble polymer of terminal groups modification penetrates cyclodextrin
Terminal groups modification polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer the 500mg of metrology steps (1) preparation, 20 milliliters of the beta-schardinger dextrin-saturated solutions of beta-schardinger dextrin-and deionized water preparation;
Terminal groups modification polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer with step (1) preparation under room temperature, normal pressure is dissolved in N; In the dinethylformamide, be mixed with the solution that concentration is 10 grams per liters, then said terminal groups modification polyethylene glycol oxide-polypropylene glycol-polyethylene glycol oxide copolymer solution mixed with the beta-schardinger dextrin-saturated solution; Sonic oscillation 15 minutes; After the sonic oscillation time expires, left standstill 1 hour, i.e. formation contains the nanogel mixed liquor;
(3) isolation and purification of nanogel
To use the aperture be 0.80 micron membrane filtration to the nanogel mixed liquor that contains that step (2) is obtained; To filtrate then 20000 rev/mins of following centrifugalize; Isolated nanogel spends behind the ion-cleaning three times-40 ℃ of lyophilizations 12 hours, obtains Powdered nanogel pharmaceutical carrier, and the mol ratio of terminal groups modification polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer repetitive and beta-schardinger dextrin-is 2: 1; Form is similar to Fig. 1～Fig. 3, and particle diameter is in the said scope of Fig. 4.
Embodiment 4
(1) terminal groups modification of water-soluble polymer
Water-soluble polymer is a polyethylene glycol oxide; The hydrophobic compound of band phenyl ring is carboxyl half coumarin; Condensing agent is 1-ethyl-(3-dimethyl aminopropyl) carbodiimide hydrochloride, and solvent is a deionized water, and the mol ratio of polyethylene glycol oxide, carboxyl half coumarin and 1-ethyl-(3-dimethyl aminopropyl) carbodiimide hydrochloride is 1: 2: 5;
Normal pressure, 25 ℃ carboxyl half coumarin and polyethylene glycol oxide are dispersed in the deionized water; The consumption of deionized water is that 2 grams per liters exceed with the concentration of polyethylene glycol oxide in the mixed liquor, adds 1-ethyl-(3-dimethyl aminopropyl) carbodiimide hydrochloride then and under agitation reacts 20 hours, after the response time expires; With reacting liquid filtering and concentrate; Concentrated solution is put into after the absolute ether deposition three times with washing with alcohol three times, with product vacuum drying (negative pressure 0.1MPa, 30 ℃ of the baking temperatures after washing; 24 hours drying times), promptly obtain the terminal groups modification polyethylene glycol oxide that end group is combined with carboxyl half coumarin group;
(2) water-soluble polymer of terminal groups modification penetrates cyclodextrin
Terminal groups modification polyethylene glycol oxide-polypropylene glycol-polyethylene glycol oxide copolymer 1 the 0mg of metrology steps (1) preparation, 5 milliliters of the alpha-cyclodextrin saturated solutions of alpha-cyclodextrin and deionization preparation;
Terminal groups modification polyethylene glycol oxide with step (1) preparation under room temperature, normal pressure is dissolved in the deionized water; Be mixed with the solution that concentration is 0.5 grams per liter; Then said terminal groups modification polyethylene oxide solutions is mixed with the alpha-cyclodextrin saturated solution, sonic oscillation 45 minutes is after the sonic oscillation time expires; Left standstill 20 hours, i.e. formation contains the nanogel mixed liquor;
(3) isolation and purification of nanogel
To use the aperture be 0.80 micron membrane filtration to the nanogel mixed liquor that contains that step (2) is obtained; To filtrate then 50000 rev/mins of following centrifugalize; Isolated nanogel spends behind the ion-cleaning three times-30 ℃ of lyophilizations 72 hours, obtains Powdered nanogel pharmaceutical carrier, and the mol ratio of terminal groups modification polyethylene glycol oxide repetitive and alpha-cyclodextrin is 5: 1; Form is similar to Fig. 1～Fig. 3, and particle diameter is in the said scope of Fig. 4.
Embodiment 5
(1) terminal groups modification of water-soluble polymer
Water-soluble polymer is polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer; The hydrophobic compound of band phenyl ring is the dinitro cinnamic acid; Condensing agent is carbodicyclo hexylimide (DCC); Solvent is a dichloromethane, and the mol ratio of polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer, dinitro cinnamic acid and carbodicyclo hexylimide is 1: 2: 2;
Normal pressure ,-10 ℃ dinitro cinnamic acid and polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer are dispersed in the dichloromethane; The consumption of dichloromethane is that 5 grams per liters exceed with the concentration of polyethylene glycol oxide-polypropylene glycol in the mixed liquor-polyoxyethylene alkene copolymer, adds carbodicyclo hexylimide then.Under agitation reacted 24 hours; After response time expires, with reacting liquid filtering and concentrate, concentrated solution is put into after the absolute ether deposition three times with acetamide washing three times; With product vacuum drying (the negative pressure 0.1MPa after the washing; 30 ℃ of baking temperatures, 24 hours drying times), promptly obtain terminal groups modification polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer that end group is combined with the dinitro cinnamic acid;
(2) water-soluble polymer of terminal groups modification penetrates cyclodextrin
With the terminal groups modification polyethylene glycol oxide-polypropylene glycol-polyethylene glycol oxide copolymer 1 00mg of step (1) preparation, 40 milliliters of the gamma-cyclodextrin saturated solutions of gamma-cyclodextrin and DMAC N,N preparation;
Terminal groups modification polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer with step (1) preparation under room temperature, normal pressure is dissolved in the distilled water; Be mixed with the solution that concentration is 100 grams per liters; Then said terminal groups modification polyethylene glycol oxide-polypropylene glycol-polyethylene glycol oxide copolymer solution is mixed with the gamma-cyclodextrin saturated solution, sonic oscillation 5 minutes is after the sonic oscillation time expires; Left standstill 24 hours, i.e. formation contains the nanogel mixed liquor;
(3) isolation and purification of nanogel
To use the aperture be 0.45 micron membrane filtration to the nanogel mixed liquor that contains that step (2) is obtained; To filtrate then 10000 rev/mins of following centrifugalize; Isolated nanogel is used behind the deionized water wash three times-25 ℃ of lyophilizations 36 hours successively, obtains Powdered nanogel pharmaceutical carrier, and the mol ratio of terminal groups modification polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer repetitive and gamma-cyclodextrin is 6: 1; Form is similar to Fig. 1～Fig. 3, and particle diameter is in the said scope of Fig. 4.
Embodiment 6
(1) terminal groups modification of water-soluble polymer
Water-soluble polymer is a PEO-PPO-PEO; The hydrophobic compound of band phenyl ring is the carboxyl coumarin; Condensing agent is 1-ethyl-(3-dimethyl aminopropyl) carbodiimide hydrochloride; Solvent is an oxolane, and the mol ratio of PEO-PPO-PEO, carboxyl coumarin and 1-ethyl-(3-dimethyl aminopropyl) carbodiimide hydrochloride is 1: 10: 10;
Normal pressure, 0 ℃ carboxyl coumarin and PEO-PPO-PEO are dispersed in the oxolane; The consumption of oxolane is that 15 grams per liters exceed with the concentration of PEO-PPO-PEO in the mixed liquor, adds 1-ethyl-(3-dimethyl aminopropyl) carbodiimide hydrochloride then.Under agitation reacted 4 hours; After response time expires, with reacting liquid filtering and concentrate, concentrated solution is put into after the absolute ether deposition three times with washing with acetone three times; With product vacuum drying (the negative pressure 0.1MPa after the washing; 30 ℃ of baking temperatures, 24 hours drying times), promptly obtain the terminal groups modification PEO-PPO-PEO that end group is combined with the carboxyl coumarin;
(2) water-soluble polymer of terminal groups modification penetrates cyclodextrin
With the terminal groups modification PEO-PPO-PEO 200mg of step (1) preparation, 20 milliliters of the gamma-cyclodextrin saturated solutions of gamma-cyclodextrin and deionized water preparation;
Terminal groups modification PEO-PPO-PEO with step (1) preparation under room temperature, normal pressure is dissolved in the deionized water; Be mixed with the solution that concentration is 1 grams per liter; Then said terminal groups modification PEO-PPO-PEO solution is mixed with the gamma-cyclodextrin saturated solution, sonic oscillation 30 minutes is after the sonic oscillation time expires; Left standstill 24 hours, i.e. formation contains the nanogel mixed liquor;
(3) isolation and purification of nanogel
To use the aperture be 0.80 micron membrane filtration to the nanogel mixed liquor that contains that step (2) is obtained; To filtrate then 50000 rev/mins of following centrifugalize;-50 ℃ of lyophilizations 48 hours, obtain Powdered nanogel pharmaceutical carrier after isolated nanogel respectively washs three times with ether and ethanol successively, the mol ratio of terminal groups modification PEO-PPO-PEO repetitive and gamma-cyclodextrin is 5: 1; Form is similar to Fig. 1～Fig. 3, and particle diameter is in the said scope of Fig. 4.
Embodiment 7
With density is 1 * 10
5The L929 cell suspension 0.1mL of individual/mL is inoculated in 96 well culture plates, and every hole adds 0.1mL complete medium (DMEM culture medium+10% hyclone+antibiotic) again, puts 37 ℃, 5%CO
2, saturated humidity the cell constant incubator in hatched 24 hours.The nanogel (being numbered embodiment 1～6) that embodiment 1～6 is prepared; Dilute with normal saline; Every hole adds 100 μ L nanogel solution and 100 μ L complete mediums respectively as test group, and the final concentration that makes nanogel is 0.05mg/mL, 0.10mg/mL, 0.30mg/mL and 0.50mg/mL.Negative control group is that normal saline 100 μ L add 100 μ L complete medium culture fluid.Each test group and negative control group are all established 3 of parallel sample.Put and continue in the cell constant incubator to cultivate, in the 48h abandoning supernatant, PBS washing 2 times.Every then hole adds 200 μ L PBS; The MTT liquid that adds 20 μ L 5mg/mL again continues to cultivate 4h, exhausts supernatant then; Add 100 μ L DMSO; Vibration 10min measures the OD value (OD) of 570nm wavelength with enzyme-linked immunosorbent assay instrument, through relatively obtaining the relative rate of increase of experimental group with matched group OD value.Cell toxicity test result sees Fig. 5, and as can beappreciated from fig. 5, embodiment 1～6 prepared nanogel pharmaceutical carrier does not all have obvious cytotoxicity.
Claims (10)
1. polymer nanocomposite gel medicine carrier; It is characterized in that this gel medicine carrier is formed through the self assembly of non-covalent bond active force by terminal groups modification water-soluble polymer and cyclodextrin; Said terminal groups modification water-soluble polymer is the water-soluble polymer that end group is combined with the hydrophobic compound of band phenyl ring, and the mol ratio of terminal groups modification water-soluble polymer repetitive and cyclodextrin is 1: 1～6: 1.
2. polymer nanocomposite gel medicine carrier according to claim 1 is characterized in that said water-soluble polymer is a kind of in PEO-PPO-PEO, polyethylene glycol oxide, the polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer; The hydrophobic compound of said band phenyl ring is a kind of in dinitro cinnamic acid, lauric acid, coumarin, half coumarin, carboxyl half coumarin, the carboxyl coumarin.
3. polymer nanocomposite gel medicine carrier according to claim 1 and 2 is characterized in that said cyclodextrin is a kind of in alpha-cyclodextrin, beta-schardinger dextrin-, the gamma-cyclodextrin.
4. polymer nanocomposite gel medicine carrier according to claim 1 and 2 is characterized in that particle diameter is 20nm～450nm.
5. the method for preparing of a polymer nanocomposite gel medicine carrier is characterized in that processing step is following:
(1) terminal groups modification of water-soluble polymer
Raw material comprises the hydrophobic compound and the condensing agent of water-soluble polymer, band phenyl ring, and water-soluble polymer, the hydrophobic compound of band phenyl ring, the mol ratio of condensing agent are 1: 2: 2～1: 10: 10;
To be dispersed in the solvent with the hydrophobic compound and the water-soluble polymer of phenyl ring normal pressure ,-20 ℃～50 ℃; The consumption of solvent is that 0.5 grams per liter～20 grams per liters exceed with the concentration of water-soluble polymer in the mixed liquor; Adding condensing agent then under agitation reacted 0.5 hour～24 hours; After response time expires, with reacting liquid filtering and concentrate, concentrated solution is put into the precipitant post precipitation wash hydrophobic compound, condensing agent and by-product to remove free band phenyl ring; With the product vacuum drying after the washing, promptly obtain the terminal groups modification water-soluble polymer that end group is combined with the hydrophobic compound of band phenyl ring;
(2) the terminal groups modification water-soluble polymer penetrates cyclodextrin
Raw material comprises the terminal groups modification water-soluble polymer and the cyclodextrin saturated solution of step (1) preparation; Terminal groups modification water-soluble polymer 10 mass parts～500 mass parts; Cyclodextrin saturated solution 5 parts by volume～20 parts by volume; The mass unit of terminal groups modification water-soluble polymer is that the volume unit of milligram, cyclodextrin saturated solution is milliliter, or the mass unit of terminal groups modification water-soluble polymer for the volume unit of gram, cyclodextrin saturated solution for rising;
Under normal pressure, room temperature; Use solvent to be made into the solution that concentration is 0.5 grams per liter～100 grams per liters the terminal groups modification water-soluble polymer of step (1) preparation; Then said terminal groups modification water-soluble polymer solution is mixed with the cyclodextrin saturated solution, sonic oscillation 5 minutes～60 minutes is after the sonic oscillation time expires; Left standstill 1 hour～24 hours, i.e. formation contains the nanogel mixed liquor;
(3) isolation and purification of nanogel
Contain the nanogel mixed liquor through filtering with microporous membrane with what step (2) obtained, the centrifugalize of will filtrating then, the isolated nanogel of institute is removed free cyclodextrin postlyophilization through washing and is promptly obtained polymer nanocomposite gel medicine carrier.
6. according to the method for preparing of the said polymer nanocomposite gel medicine of claim 5 carrier, it is characterized in that said water-soluble polymer is a kind of in PEO-PPO-PEO, polyethylene glycol oxide, the polyethylene glycol oxide-polypropylene glycol-polyoxyethylene alkene copolymer; The hydrophobic compound of said band phenyl ring is a kind of in dinitro cinnamic acid, lauric acid, coumarin, half coumarin, carboxyl half coumarin, the carboxyl coumarin.
7. according to the method for preparing of claim 5 or 6 said polymer nanocomposite gel medicine carriers, it is characterized in that said cyclodextrin is a kind of in alpha-cyclodextrin, beta-schardinger dextrin-, the gamma-cyclodextrin.
8. according to the method for preparing of claim 5 or 6 said polymer nanocomposite gel medicine carriers, it is characterized in that said condensing agent is a kind of in carbodicyclo hexylimide, 1-ethyl-(3-dimethyl aminopropyl) carbodiimide, 1-ethyl-(3-dimethyl aminopropyl) carbodiimide hydrochloride.
9. according to the method for preparing of claim 5 or 6 said polymer nanocomposite gel medicine carriers; It is characterized in that said solvent is distilled water, deionized water, oxolane, ether, ethanol, 1; 4-dioxane, dichloromethane, acetone, Methanamide, acetamide, N; A kind of in dinethylformamide, DMAC N,N, the dimethyl sulfoxine.
10. according to the method for preparing of claim 5 or 6 said polymer nanocomposite gel medicine carriers, it is characterized in that said precipitant is absolute ether or deionized water; A kind of as in acetone, Methanamide, acetamide, deionized water, ethanol, the ether of the washing liquid of using during the washing of step (1) and step (3).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108324682A (en) * | 2018-04-11 | 2018-07-27 | 上海交通大学 | A kind of multivalence key nanogel and its purposes in cervical carcinoma situ treatment drug |
| CN114948863A (en) * | 2022-06-15 | 2022-08-30 | 四川大学 | Medicine for treating atherosclerosis |
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| CN101284885A (en) * | 2008-05-09 | 2008-10-15 | 浙江大学 | Amphipathic cyclodextrin polymers, preparation method and use |
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| 《中国科学：化学》 20101231 李媛，等 alpha-环糊精/聚乙二醇自组装超分子纳米药物载体 第247-254页 1-10 第40卷, 第3期 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108324682A (en) * | 2018-04-11 | 2018-07-27 | 上海交通大学 | A kind of multivalence key nanogel and its purposes in cervical carcinoma situ treatment drug |
| CN108324682B (en) * | 2018-04-11 | 2020-11-17 | 上海交通大学 | Multivalent bond nanogel and application thereof in cervical cancer in-situ treatment drug |
| CN114948863A (en) * | 2022-06-15 | 2022-08-30 | 四川大学 | Medicine for treating atherosclerosis |
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