CN102525882A - Nanocomposite temperature-sensitive gel and preparation method and application thereof - Google Patents
Nanocomposite temperature-sensitive gel and preparation method and application thereof Download PDFInfo
- Publication number
- CN102525882A CN102525882A CN2012100483385A CN201210048338A CN102525882A CN 102525882 A CN102525882 A CN 102525882A CN 2012100483385 A CN2012100483385 A CN 2012100483385A CN 201210048338 A CN201210048338 A CN 201210048338A CN 102525882 A CN102525882 A CN 102525882A
- Authority
- CN
- China
- Prior art keywords
- acid
- temperature
- cancer
- preparation
- tumor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a nanocomposite temperature-sensitive gel and a preparation method and an application thereof. The preparation method comprises the following steps of: coating antitumor active substances with a high molecular polymer serving as a carrier material to obtain nanoparticles; and adding a temperature-sensitive high molecular material to obtain the nanocomposite temperature-sensitive gel. The preparation method disclosed by the invention is simple and convenient, is suitable for large-scale production, and is particularly suitable for preparing medicaments or diagnostic reagents having the characteristics of long cycle, biodegradability, slow release, passive targeting, active targeting, active substance conveying function and tumor resistance. An antitumor medicament prepared with the method disclosed by the invention is suitable for ways such as intravenous injection, intramuscular injection, hypodermic injection, intradermal injection, intratumor injection, tumor-side injection, oral administration or transdermal medicament delivery and the like, is applied to treatment and diagnosis of pancreatic cancer, liver cancer, lung cancer, gastric cancer, colorectal cancer, esophageal cancer, prostatic cancer, uterine cancer and ovarian cancer, and has a good application prospect.
Description
Technical field
The invention belongs to the targeted delivery of drugs carrier and its production and application the field, particularly a kind of nano compound temperature-sensitive gel.
Background technology
Treatment with chemotherapy Drug therapy malignant tumor has obtained certain success in many cases clinically, still, also exists some serious problems simultaneously.A main problem is that chemotherapeutics generally lacks selectivity, causes the generation of serious dose dependent toxic and side effects, has greatly limited the clinical therapeutic efficacy of chemotherapeutics.Another problem is the drug-fast quick appearance of tumor cell.Therefore, for can selectively targeted tumor cell and cause the exploitation of the Therapeutic Method of normal cell minimal, have very important significance and wide application prospect.
In recent decades, the targeted delivery carrier can effectively improve therapeutic effect, and enjoy domestic and international concern owing to its special advantages.Especially be the development rapidly that the delivery system of carrier obtains with biodegradable polymer, the targeted delivery carrier can effectively reduce the toxic and side effects of medicine, postpones medicine metabolism in vivo, improves therapeutic effect.Manyly be used as the delivery vector of medicine, gene and imaging agents widely, obtained certain effect as biodegradation materials such as polylactic acid, polylactic acid-glycolic guanidine-acetic acids.
Crinis Carbonisatus such as Duan Yourong clear " polyethylene glycol-lactic acid hydroxyacetic acid-polylysine (being called for short mPEG-PLGA-PLL) nano-delivery system, method for preparing and application thereof " (CN 200910247576.7).The preparation that this patent discloses mPEG-PLGA-PLL cationic polymer nanoparticle delivery system is used with it, and the carrier nanoparticle of polymer manufacture can be used for load organic drug, water soluble drug, water-insoluble cancer therapy drug or is used to diagnose the developing agent etc. of usefulness.
Most nano-carriers are promptly engulfed by macrophage identification before the no show target in vivo, and do not reach therapeutic effect; Domestic and international thus many scholars, with the surface of poly glycol monomethyl ether (mPEG) attached to carrier, the long-chain of mPEG can make nano-carrier effectively escape engulfing of reticuloendothelial system, thereby reaches macrocyclic purpose, and has obtained better therapeutic effect.Degradable polymer polylactic acid (PLA) or polylactic-co-glycolic acid (PLGA) can slowly be degraded in vivo, and medicine is slowly released with the degraded of material, thereby reach the therapeutic effect of long period.Cationic polymer PLL PLL, good biocompatibility, catabolite are the necessary aminoacid of human body.The poly-l-lysine complex is still positively charged, and flexible, stable, easy its molecular weight of adjustment of its structure can be modified the polymer skeleton through introducing side chain and specific target tropism group, and then adjust and improve the performance of carrier, reaches the purpose of slow releasing pharmaceutical.PLGA and PLL are combined to bring into play both advantages.Therefore be that the administration nano-drug administration system of skeleton is a kind of very excellent slow releasing pharmaceutical carrier with poly glycol monomethyl ether-polylactic acid/hydroxy acetic acid-poly-L-Lysine (mPEG-PLA/GA-PLL) cationic polymer.
Nano-carrier system diameter can remain on 1nm-10 μ m.Because the blood vessel around the normal structure does not have the slit; And the blood vessel around the tumor tissues has the slit about 100nm; So nanoparticle will infiltrate from these slits, and utilize enhanced infiltration reservation effect to be gathered in tumor locus, attack cancerous cell then; But can not damage normal cell, thereby reach the effect of passive target.
The targeting ability of drug-supplying system is the key that active substance accurately is delivered to target spot, is that the administration nano-drug administration system of skeleton can well address this problem with poly glycol monomethyl ether-polylactic acid/hydroxy acetic acid-poly-L-Lysine (mPEG-PLA/GA-PLL) cationic polymer.Valine-arginine-glycine-aspartic acid-glutamic acid cyclic peptide is called for short cRGD, is a kind of effective targeted molecular, and verified its of numerous experiments has good targeting effect to tumor neogenetic blood vessels.After nanoparticle adopted cRGD targeting base group modification; The targeting group can combine with the target spot specificity; Have the active targeting effect that receptor-mediated targeting drug delivery system forms, antitumor drug is more accurately delivered in the tumor cell, realize the targeted therapy of malignant tumor.Other targeting groups as: folic acid (Fa) can have affinity preferably to folic acid responsive type tumor cell, epidermal growth factor receptor antibody (EGFR
Ab) and hEGF (hrEGF) new vessels is had targeting, PSA antibody (PSA
Ab) can make drug-supplying system be enriched in prostate; Enhancing is for the treatment of prostate cancer effect; Transferrins (Trf) can be expressed the brain targeting that higher phenomenon strengthens drug-supplying system to the TfR of brain, and galactose (Glu) and lactobionic acid (La) have the liver targeting.
Temperature sensitive macromolecular material is one type to be changed with ambient temperature, and the material of solution-gel conversion can take place its aqueous solution.In pharmaceutics, utilize this attributes can form situ-gel, thromboembolism in vivo, or increase preparation stability etc. in external curing.Poloxamer is one type of good biocompatibility, and the temperature sensing material of extensive use, and the FDA approved is used for people's intravascular administration.When temperature raise, its aqueous solution can be transformed into hydrogel, came the speed of control drug release in vivo through degraded and corrosion, played the effect in slow release storage storehouse.Polyacrylamide and with the copolymer of esters of acrylic acid also be to study temperature sensitive polymer comparatively widely, when temperature raise, its aqueous solution formed netted gel structure, through the rate of release of variations in temperature and intraskeletal infiltration control medicine.
Summary of the invention
Technical problem to be solved by this invention provides a kind of nano compound temperature-sensitive gel, and this nano compound temperature-sensitive gel is suitable for modes such as intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, intratumor injection, tumor-side injection, oral or percutaneous dosing; Method for preparing is easy, is suitable for large-scale production.
A kind of nano compound temperature-sensitive gel of the present invention wraps up anti-tumor active substance by high molecular polymer as carrier material, processes nanoparticle, adds temperature sensitive macromolecular material again, processes the nano compound temperature-sensitive gel.
Said high molecular polymer is homopolymer, copolymer or block polymer; Wherein, block is one or more in Polyethylene Glycol, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polycaprolactone, methacrylate, polyurethane, the polyamino acid, and molecular weight is 1.2 * 10
3-10.0 * 10
8The molecule mol ratio is 1-100: 100-1 between each block; When polymer or block were copolymer, the mol ratio between the monomer was 1-100: 100-1.
When said high molecular polymer contained the Polyethylene Glycol block, Polyethylene Glycol was the methylated Polyethylene Glycol of a terminal hydroxy group (poly glycol monomethyl ether mPEG), and the block molecule amount is 100-20000; When high molecular polymer contained polylactic acid, polylactic-co-glycolic acid or polycaprolactone block, the block molecule amount was 1000-100000; When high molecular polymer contained polyurethane or polyamino acid block, the block molecule amount was 500-100000.
Said high molecular polymer chemical bonding or bonding cancer target group not; Wherein, the targeting group is arginine-glycine-aspartic acid cyclic peptide (cRGD), folic acid (Fa), epidermal growth factor receptor antibody (EGFR
Ab), PSA antibody (PSA
Ab), among the hEGF (hrEGF), transferrins (Trf), lactoferrin, galactose (Glu), lactobionic acid (La) one or more.
Said anti-tumor active substance is Antioncogene, antitumor drug, antitumor diagnostic reagent or antitumor development reagent.
Said Antioncogene is siRNA, microRNA, suicide gene, antioncogene or antisensenucleic acids;
Said antitumor drug is gemcitabine, fluorouracil, paclitaxel, mitoxantrone, amycin, 9-nitrocamptothecin, cisplatin, methotrexate or vincristine;
Said antitumor diagnostic reagent is the diagnostic reagent that is used for ultrasonic, nuclear magnetic resonance, NMR, CT or PET;
Said antitumor development reagent is the development reagent that is used for NMR imaging, ultrasonic or CT.
Said temperature sensitive macromolecular material is one or more in the copolymer of poloxamer, poly-N-isopropyl acrylamide, N-Isopropylacrylamide and methacrylic acid or methacrylate;
Described poloxamer molecular weight is 1 * 10
3-1 * 10
6, wherein, polyoxy ethane block molecule amount is 1 * 10
2-6 * 10
5, polyoxy propane block molecule amount is 8 * 10
2-4 * 10
5, the molecular weight ratio of two kinds of blocks is 1-80: 1-80;
Described poly-N-isopropyl acrylamide molecular weight is 5 * 10
2-1 * 10
5
In the copolymer of described N-Isopropylacrylamide and methacrylic acid or methacrylate, polymethylacrylic acid block molecule amount is 1 * 10
2-5 * 10
4, the polymethacrylates molecular weight is 5 * 10
2-1 * 10
5, poly-N-isopropyl acrylamide and polymethylacrylic acid or polymethacrylates molecular weight ratio are 1-80: 80-1.
The method for preparing of a kind of nano compound temperature-sensitive gel according to claim 1 of the present invention comprises:
(1) adopt multi-emulsion method, membrane emulsification method, dialysis, emulsifying evaporation, interphase precipitate method or self-assembly method to make by the nanoparticle solution of high molecular polymer as carrier material parcel anti-tumor active substance;
(2) temperature sensitive macromolecular material is added in the nanoparticle solution, dissolving promptly gets;
Perhaps,, mix, promptly get with nanoparticle solution with being dissolved into solution in the temperature sensitive macromolecular material adding normal saline;
Perhaps, temperature sensitive macromolecular material is mixed with nano-granule freeze-dried powder, add the normal saline dispersing and dissolving, promptly get.
The molar concentration of the high molecular polymer in said step (1) the nanoparticle solution is 0.001-10000M, and the molar concentration of anti-tumor active substance is 0.001-10000 μ M.
The preparation of employing multi-emulsion method; Get in the mixed solvent that the 4mg high molecular polymer is dissolved in 200 μ L dichloromethane or dichloromethane and acetone, add the 0.2mg active substance solution, ultrasonic emulsification; Add 2.2mL concentration again and be in 1% the pluronic F68 water dispersion medium, once more ultrasonic emulsification.Stir 0.5-5h then under the room temperature and remove organic facies, promptly get nanoparticle solution.
Adopt the preparation of membrane emulsification method, get 4mg high molecular polymer and 0.2mg active substance and be dissolved in the 400 μ L acetone solvents, the rotary evaporation film forming adds the aqueous solution of 4mL subsequently, stirs 0.5-6h under the room temperature, promptly gets nanoparticle solution.
The preparation of employing dialysis; Getting the 4mg high molecular polymer is dissolved in the 200 μ L dimethylsulfoxide solvent; Add the 0.4mg active substance, the solution that stirs is splashed under stirring condition in the 2mL water, afterwards solution being packed into, bag filter (molecular cut off is 7000) is middle dialysed 3-72 hour; Remove organic solvent, promptly get nanoparticle solution.
Adopt the preparation of emulsifying evaporation; Get in the mixed solvent that 4mg high molecular polymer and 0.2mg active substance be dissolved in 400 μ L acetone/dichloromethane; Add 2.2mL concentration and be in 2% the water dispersion medium that contains polyvinyl alcohol (PVA), the newborn even emulsifying of ultrasonic or high pressure, emulsion at room temperature stirs 2-4h; Wave most organic solvent, promptly get nanoparticle solution.
Adopt the preparation of interphase precipitate method; Get 4mg high molecular polymer and 0.2mg active substance and be dissolved in the 400 μ L acetone solvents, under continuous stirring condition, the concentration that above-mentioned solution is injected 2.2mL is 2% PVA water dispersion medium; Acetone is removed in the pressurization volatilization, promptly gets nanoparticle solution.
The preparation of employing self-assembly method; Getting the 4mg high molecular polymer is dissolved in the 200 μ L aqueous solutions; Add the 0.4mg active substance; The solution that stirs is splashed under stirring condition in the 2mL water, with solution dialysis 3-72 hour of packing in the bag filter (molecular cut off is 7000), remove organic solvent afterwards; Promptly get nanoparticle solution.
The present invention also can be prepared into dissimilar injections, capsule, tablet preparation, pill, powder, granule, drop pill and membrane etc. with the nanometer delivery vector of bag year different pharmaceutical simultaneously.
The ultrasound intensity that the present invention is used, its scope are 10-1000W.
The bag filter molecular cut off that the present invention is used, its scope are 100-10000.
Water dispersion medium of the present invention is the various surfactants that are suitable for preparing nanoparticle such as dextran 40-70, pluronic F68, pluronic F127 or PVAC polyvinylalcohol, and disperse medium concentration is 0.01-10% (w/v).
Organic solvent of the present invention comprises the various organic solvents that are suitable for preparing nanoparticle such as ethyl acetate, dichloromethane, chloroform, acetone, ethanol, dimethyl sulfoxine and dimethyl formamide.
The present invention preserves and uses to be prepared into lyophilized preparation, and the lyophilizing caffolding agent comprises trehalose, glucose, lactose, sucrose, dextran, sorbitol, mannitol and Polyethylene Glycol etc., and caffolding agent content is 0.01-20% (w/v).
The pharmaceutical preparation of the reagent that is applied to prepare antitumor drug targeting preparation, reverse or reduction tumor drug resistance preparation, diagnosing tumor development of said nano compound temperature-sensitive gel, transfection reagent, gene therapy medicament preparation, antisensenucleic acids and the small interference ribonucleic acid transfection reagent of DNA plasmid or antisensenucleic acids and siRNA treatment usefulness; Be applied to the treatment and the diagnosis of cancer of pancreas, hepatocarcinoma, pulmonary carcinoma, gastric cancer, colorectal cancer, the esophageal carcinoma, carcinoma of prostate, uterus carcinoma, ovarian cancer.
The high molecular polymer of targeting base group modification is specially poly glycol monomethyl ether-polylactic acid/hydroxy acetic acid-poly-L-Lysine polymer among the present invention, and polymer molecular weight is 1.2 * 10
3-10.0 * 10
8, preferred molecular weight ranges is 2.0 * 10
3-8.0 * 10
8Described polylactic acid/hydroxy acetic acid is one or more mixture of polylactic acid, polylactic-co-glycolic acid, polyglycolic acid; Described polylactic-co-glycolic acid monomer ratio is a lactic acid: hydroxyacetic acid 1-100: 100-1; The mol ratio of described poly glycol monomethyl ether and polylactic acid/hydroxy acetic acid is 1-50: 100-1, and the ratio of optimization is 5-25: 60-15; The mol ratio of described poly glycol monomethyl ether-polylactic-co-glycolic acid and poly-L-Lysine is 1-50: 99-1, and the ratio of optimization is 5-25: 60-15; The mol ratio of described poly glycol monomethyl ether, polylactic-co-glycolic acid and poly-L-Lysine is 0.1-30: 0.1-80: 1-99, and the ratio of optimization is 5-20: 10-45: 15-65.
The active substance that bag of the present invention carries comprises that medicine, gene, diagnosis are with developing agent, probe.Medicine comprises any antitumor drug that is fit to process the nanoparticle drug-supplying system; Can be organic drug, water soluble drug or water-insoluble drug anticarcinogen; Like anti-folic acid class (like methotrexate), anti-purine class (like mercaptopurine), anti-miazines (like fluorouracil, ftorafur), nucleotide reducing enzyme inhibitor (like hydroxyurea), deoxyribonucleotide polymerase depressant (like ancitabine), directly influence and destroy dna structure and function thereof medicine (like chlormethine, cyclophosphamide, formylmerphalan, cisplatin, mitomycin, camptothecine), the synthetic medicine of CKIs matter (like amycin, L-asparaginase, daunorubicin, mithramycin), influence the medicine (vincristine, etoposide) that microtubular protein assembling and spindle fiber form and be used for used developing agent active medicine or the diagnostic reagents of Image-forming instrument such as NMR imaging, ultrasonic or CT, diagnostic reagent is divided into the diagnostic reagent that is used for ultrasonic, nuclear magnetic resonance, NMR, CT and PET.Gene comprises the gene that siRNA, microRNA, suicide gene, antioncogene, antisensenucleic acids etc. are used to treat.
The present invention be a kind of be skeleton with the high molecular polymer, be the nanometer drug administration carrier system of substrate with temperature sensitive macromolecule.Through the molecular weight and the composition of control skeleton polymer each block, can make carrier have the function of better biocompatibility, higher drug loading and stronger cancer target.Regulate temperature sensitive high molecular kind and form the temperature-sensitive that to regulate gel.This gel at room temperature is a liquid, can be used in the body through injection, through temperature sensitive effect, under body temperature, forms gel storage storehouse, localized slow release targeted nano granule, and initiatively targeting is in tumor cell.This nano-carrier system has functions such as the active substance of transporting, oncotherapy and diagnosis, ultrasonic development, reverse or reduction drug resistance.It is mainly used in (1) preparation antitumor drug targeting preparation; (2) preparation reverses or reduction tumor drug resistance preparation; (3) reagent of preparation diagnosing tumor development; (4) transfection reagent of preparation DNA (DNA) plasmid; (5) prepare the gene therapy medicament preparation that oncotherapy is used; (6) preparation is used for antisensenucleic acids and small interference ribonucleic acid (siRNA) transfection reagent; (7) pharmaceutical preparation of preparation antisensenucleic acids and siRNA (RNA interference) treatment usefulness.
Beneficial effect
Method for preparing of the present invention is easy, is suitable for large-scale production, is adapted to preparation especially and has long circulation, biodegradable, slow controlled release, passive target, active targeting, transports active substance, anti-tumor drug or diagnostic reagent.The anti-tumor drug that adopts method of the present invention to obtain is suitable for modes such as intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, intratumor injection, tumor-side injection, oral or percutaneous dosing, has a good application prospect.
Description of drawings
Fig. 1 is 5Fu-PLGA-PLL-cRGD nanoparticle (A), GEM-mPEG-PLGA-PLL-cRGD nanoparticle (B), siRNA-mPEG-PLGA-PLL nanoparticle (C), PTX-mPEG-PLA-FA (D), DNA-mPEG-PCL-PLL-Trf (E), ADM-mPEG-PLGA-PLL-PSAab nanoparticle (F), DHAQ-mPEG-PLGA-PU nanoparticle (G), cisPt-PCL-PU-cRGD (H), 9-NC-mPEG-PLA-PLAs-FA nanoparticle (I) particle size distribution figure.
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.Should be understood that in addition those skilled in the art can do various changes or modification to the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Bag carries the preparation and the application of the temperature sensitive pluralgel agent of PLGA-PLL-cRGD of 5-fluorouracil (5Fu)
The preparation of employing multi-emulsion method: get 8mg PLGA-PLL-cRGD and be dissolved in 400 μ L dichloromethane, adding 40 μ L concentration is 5-fluorouracil (5-Fu) solution of 20mg/mL, after the ultrasonic emulsification, adds in the poloxamer F68 aqueous solution of 4.4mL 2wt% again, ultrasonic once more.Stir 3h then under the room temperature and remove organic facies, promptly get the nanoparticle suspension.The above-mentioned nanoparticle particle diameter that makes is controlled at 10-1000nm (Figure 1A).
In above nanoparticle aqueous dispersion, adding F-127, to make concentration be 15%, promptly gets the pluralgel agent.
Hepar Leporis seu Oryctolagi cancer model is opened abdomen and is exposed tumor, and gel is injected 10-50 μ l in tumor, with the biological fibrin glue sealing, sews up.2 weeks back inspection tumor has the trend of dwindling.
Embodiment 2
Bag carries the preparation and the application of the temperature sensitive pluralgel agent of mPEG-PLGA-PLL-cRGD of gemcitabine hydrochloride (GEM)
The preparation of employing multi-emulsion method: get 8mg mPEG-PLGA-PLL-cRGD and be dissolved in 400 μ L dichloromethane, adding 20 μ L concentration is the GEM solution of 40mg/mL, after the ultrasonic emulsification, adds in the poloxamer F68 aqueous solution of 4.4mL 2wt% again, ultrasonic once more.Stir 3h then under the room temperature and remove organic facies, promptly get the nanoparticle suspension.The above-mentioned nanoparticle particle diameter that makes is controlled at 10-1000nm (Figure 1B).
In above solution, adding F-127, to make its concentration be 13%, promptly gets gel.
Nude mice cancer of pancreas primary tumor model is opened left abdomen, exposes tumor, and above gel injection 2-5 μ l in tumor, with the biological fibrin glue sealing, is sewed up.2 weeks back inspection tumor has the trend of dwindling.
Embodiment 3
Bag carries the preparation and the application of the temperature sensitive pluralgel agent of mPEG-PLGA-PLL of siRNA
The preparation of employing multi-emulsion method; Get in the mixed solvent that 20mg material mPEG-PLGA-PLL is dissolved in 1000 μ L dichloromethane or dichloromethane and acetone, add 4nmoL siRNA solution, ultrasonic emulsification (300W or 500W; 10s * 4); Add 6mL concentration again and be in 0.5% the pluronic F68 water dispersion medium, once more ultrasonic emulsification (300W or 500W, 10s * 4).Stir 0.5-5h then under the room temperature and remove organic facies, promptly getting particle diameter is the nanoparticle solution (Fig. 1 C) of 100-800nm, lyophilizing.
In above nanoparticle aqueous dispersion, add polyacrylamide, making its concentration is 5%, and lyophilizing promptly gets the composite xerogel agent.
Nude mice liver primary tumor model is opened abdomen, exposes tumor.Dry gels is disperseed with an amount of normal saline, and injection 2-5 μ l sews up in tumor.2 weeks back inspection tumor has the trend of dwindling.
Embodiment 4
Bag carries the preparation and the application of the temperature sensitive pluralgel agent of mPEG-PLA-FA of paclitaxel (PTX)
Adopt the preparation of emulsifying evaporation: get 8mg mPEG-PLGA-FA and be dissolved in 400 μ L dichloromethane, add 0.4mg PTX, after the ultrasonic emulsification, add again in the poloxamer F68 aqueous solution of 4.4mL 1wt%, ultrasonic once more.Stir 3h then under the room temperature and remove organic facies, promptly get the nanoparticle suspension.The above-mentioned nanoparticle particle diameter that makes is controlled at 10-1000nm (Fig. 1 D).
F-127 is added in the above nanoparticle aqueous dispersion, and making its concentration is 15%, and lyophilizing promptly gets the composite xerogel agent.
Nude mice pancreas primary tumor model is opened abdomen, exposes tumor.Dry gels is disperseed with an amount of normal saline, and injection 2-5 μ l with the biological fibrin glue sealing, sews up in tumor.2 weeks back inspection tumor has the trend of dwindling.
Embodiment 5
Bag carries the preparation and the application of the temperature sensitive pluralgel agent of mPEG-PCL-PLL-Trf of DNA
Emulsion-liquid drying method is also claimed solvent evaporation method, is about to gene and is dissolved in water as interior water, and 8mgmPEG-PCL-PLL-Trf is dissolved in 400 μ L dichloromethane as oil phase; After both are ultrasonic, form the colostrum of Water-In-Oil (W/O), pouring 4mL concentration then into is the 2wt% polyvinyl alcohol water solution; Be emulsified into the emulsion (W/O/W) of W/O/W once more; Stirring boils off the organic solvent solidified microsphere, centrifuge washing, behind the vacuum drying with the 60Co irradiation sterilization.
Nano-granule freeze-dried powder and polyacrylamide acrylic acid methyl ester. powder are mixed, get the composite xerogel agent.
Nude mice lung primary tumor model is cut off tumor pleurobranch portion skin, and dry gels is disperseed with an amount of normal saline, with insulin needle the nanoparticle aqueous dispersion is aimed at knub position injection 5-10 μ l, sews up.2 week back inspection tumors have not have in the model group contrast and rise appreciably.
Embodiment 6
Bag carries the preparation and the application of the temperature sensitive pluralgel agent of PLGA-PLG-EGFRab of siRNA and DHAQ
Adopt the preparation of emulsifying evaporation: get 8mg PLGA-PLG-EGFRab and be dissolved in the 400 μ L dichloromethane; Add the aqueous solution that 40 μ L concentration are the mitoxantrone hydrochloride (DHAQ) of 10mg/mL; After the ultrasonic emulsification, add again in the F68 aqueous solution of 4.4mL 1wt%, ultrasonic once more.Stirred 3 hours under the room temperature then, remove organic facies, promptly get the nanoparticle suspension.An amount of PLGA-PLG-EGFRab nanoparticle solution is dropwise added in isopyknic siRNA solution under fully stirring, and low temperature was hatched 30 minutes, promptly obtained carrying the nanoparticle (Fig. 1 E) of gene and medicine.
In above nanoparticle aqueous dispersion, add and gather methyl-N, the N-dimethylaminoethyl, making its concentration is 2%, promptly gets the pluralgel agent.
Nude mice stomach primary tumor model is opened abdomen, exposes tumor, and the pluralgel agent 5-10 μ l that is enclosed with siRNA and DHAQ is injected into tumor, with the biological fibrin glue sealing, sews up.2 weeks back inspection tumor is not seen obvious increase.
Embodiment 7
Bag carries the preparation and the application of the temperature sensitive pluralgel agent of mPEG-PLGA-PLL-PSAab of amycin (ADM)
Adopt thin film aquation legal system to be equipped with: to get 8mg mPEG-PLGA-PLL-PSAab and 0.4mg amycin (ADM) and be dissolved in the 400 μ L acetone solvents; The rotary evaporation film forming; Add the 4mL aqueous solution subsequently, stir 3h under the room temperature, promptly get ADM-mPEG-PLGA-PLL-PSAab nanoparticle suspension.The above-mentioned nanoparticle particle diameter that makes is controlled at 10-1000nm (Fig. 1 F).Lyophilizing.
Above nano-granule freeze-dried powder and F-123 are mixed, promptly get the composite xerogel agent.
Nude mice carcinoma of prostate subcutaneous tumors model disperses above dry gels with an amount of normal saline, divide multi-point injection to go in the tumor every some 5-10 μ l.2 weeks back inspection tumor has the trend of dwindling.
Bag carries the preparation and the application of the temperature sensitive pluralgel agent of mPEG-PLGA-PU of mitoxantrone hydrochloride (DHAQ) medicine
Adopt the preparation of emulsifying evaporation: get 8mg mPEG-PLGA-PU and be dissolved in 400 μ L dichloromethane; Adding 40 μ L concentration is mitoxantrone hydrochloride (DHAQ) aqueous solution of 10mg/mL; After the ultrasonic emulsification, add again in the poloxamer F68 aqueous solution of 4.4mL 1wt%, ultrasonic once more.Stir 3h then under the room temperature and remove organic facies, promptly get the nanoparticle suspension.The above-mentioned nanoparticle particle diameter that makes is controlled at 10-1000nm (Fig. 1 G).
In above nanoparticle aqueous dispersion, add polyacrylamide methacrylic acid-N, N-dimethylaminoethyl and F-127, making its concentration is 4% and 6%, promptly gets the pluralgel agent.
Human breast cancer in nude mice subcutaneous tumors model divides multi-point injection to go in the tumor above nanoparticle aqueous dispersion, every some 5-10 μ l.2 weeks back inspection tumor has the trend of dwindling.
Embodiment 9
Bag carries the preparation and the application of the temperature sensitive pluralgel agent of PCL-PU-cRGD of cisplatin
Adopt the preparation of emulsifying evaporation: get 8mg PCL-PU-cRGD and be dissolved in 400 μ L dichloromethane, adding 40 μ L concentration is the cisplatin solution of 20mg/mL, after the ultrasonic emulsification, adds in the poloxamer F68 aqueous solution of 4.4mL 2wt% again, ultrasonic once more.Stir 3h then under the room temperature and remove organic facies, promptly get the nanoparticle suspension.The above-mentioned nanoparticle particle diameter that makes is controlled at 10-1000nm (Fig. 1 H).
In above-mentioned nanoparticle aqueous dispersion, add F-123 and F-68, making its concentration is 15% and 2%, promptly gets the pluralgel agent.
Nude mice colorectal cancer primary tumor model is opened abdomen, exposes tumor, and above gel 5-10 μ l is injected into tumor, with the biological fibrin glue sealing, sews up.2 weeks back inspection tumor is compared in model group and is not seen obvious increase.
Bag carries the preparation and the application of the temperature sensitive pluralgel agent of mPEG-PLA-PLAs-FA of 9-nitrocamptothecin (9-NC)
Adopt the preparation of emulsifying evaporation: get 8mg mPEG-PLA-PLAs-FA and be dissolved in the dichloromethane that 400 μ L contain 9-NC 1mg/ml, add in the poloxamer F68 aqueous solution of 4.4mL 2wt% ultrasonic emulsification.Stir 3h then under the room temperature and remove organic facies, promptly get the nanoparticle suspension.The above-mentioned nanoparticle particle diameter that makes is controlled at 10-1000nm (Fig. 1 I).
In above-mentioned nanoparticle aqueous dispersion, adding F-127, to make its concentration be 14%, and lyophilizing promptly gets the composite xerogel agent.
Nude mice human oral cavity epithelial cancer subcutaneous tumors model adds an amount of normal saline with above dry gels and disperses, and divides multi-point injection to go into tumor, every some 5-10 μ l.2 weeks back inspection tumor has atrophy trend.
The mPEG-PLA-PLL-La bag carries the preparation and the application of the temperature sensitive pluralgel agent of cy5
Get 8mg mPEG-PLA-PLL-La and be dissolved in the 400 μ L dichloromethane, add 400 μ g cy5 dissolving, add in the F68 aqueous solution of 4.4mL 1wt% ultrasonic emulsification.Stir 3h then under the room temperature and remove organic facies, promptly get cy5-mPEG-PLA-PLL-La nanoparticle suspension.
F-127 is added in the above nanoparticle aqueous dispersion, and making its concentration is 10%, promptly gets the pluralgel agent.
Nude mice cancer of pancreas primary tumor model is opened left abdomen, and above gel 5-10 μ l is injected into the tumor body, with the biological fibrin glue sealing, sews up.In the small animal imaging system, observe after 4 hours, the tumor body shows fluorescence.Constantly put to death animal respectively at the injection back is different, get band tumor pancreas, do the pathology section, laser co-focusing is observed fluorescence distribution in tumor cell, does not almost have fluorescence in the normal cell.
Embodiment 12
The mPEG-PLA-Glu bag carries the preparation and the application of the temperature sensitive pluralgel agent of Docetaxel (DTX)
Get 8mg mPEG-PLA-Glu and be dissolved in the 400 μ L dichloromethane, add 400 μ g DTX dissolving, add in the F68 aqueous solution of 4.4mL 1wt% ultrasonic emulsification.Stir 3h then under the room temperature and remove organic facies, promptly get DTX-mPEG-PLA-Glu nanoparticle suspension.
In above nanoparticle aqueous dispersion, add F-127 and F-123, making its concentration is 10% and 3%, and lyophilizing promptly gets the composite xerogel agent.
Nude mice liver cancer in situ model is opened abdomen and is exposed tumor, and above dry gels is disperseed with an amount of normal saline, is injected into tumor 5-10 μ l, with the biological fibrin glue sealing, sews up.Observe tumor group after 10 days and be woven with atrophy trend.
Embodiment 13
The mPEG-PCL-PLS-LA bag carries the preparation of the temperature sensitive pluralgel agent of vincristine
Solvent diffusion method is dissolved in 8mg mPEG-PCL-PLS-LA and 0.4mg vincristine in the 1ml methanol, under agitation splashes among the 0.5%F-68 solution 4ml, and methanol is removed in decompression, and lyophilizing promptly gets the mPEG-PCL-PLS-LA nano-granule freeze-dried powder that carries vincristine.
With above lyophilized powder and Methacrylamide powder mixes, promptly get the composite xerogel agent.
Embodiment 14
The own ester of mPEG-polymethylacrylic acid (HMA)-hrEGF bag carries the preparation of the temperature sensitive pluralgel agent of imatinib
Thin film aquation method is dissolved in 8mg mPEG-PHMA-hrEGF and 0.4mg imatinib in the 2ml dehydrated alcohol, revolve to steam to make into uniform thin film, and drying under vacuum overnight is to eliminate ethanol.Add 0.5%F-127 solution 4ml, 40 ℃ of following aquations promptly get the mPEG-PHMA-hrEGF nanoparticle that carries imatinib.
In above nanoparticle aqueous dispersion, add F-127, making its concentration is 10%, promptly gets the pluralgel agent.
Embodiment 15
The PGA-PLL-cRGD bag carries the preparation and the application of the temperature sensitive pluralgel agent of developing agent
Emulsion process is dissolved in 8mg PGA-PLL-cRGD and 0.4mg iohexol in the 0.5ml dichloromethane, adds 4ml F-68 solution, ultrasonic emulsification, and stirring at room is removed dichloromethane, promptly gets the PGA-PLL-cRGD nanoparticle that carries developing agent.
In above nanoparticle, adding F-127, to make its concentration be 10%, promptly gets the pluralgel agent.
Above gel is injected into hepatocarcinoma nude mice tumor locus, the visible tumor imaging of a week back X-ray check.
Embodiment 16
The preparation of the temperature sensitive pluralgel agent of mPEG-poly hydroxy ethyl acrylate (PHEMA)-PLL-cRGD bag carrying mitomycin C
Multi-emulsion method; 8mg mPEG-PHEMA-PLL-cRGD is dissolved in the 0.5ml ethyl acetate, adds 50 μ l 10mg/ml mitomycin c solutions, ultrasonic emulsification; Add 4ml 0.5%F-127 solution; Ultrasonic emulsification once more, stirring at room is removed organic solvent, promptly gets the mPEG-PHEMA-PLL-cRGD nanoparticle of carrying mitomycin C.
In above nanoparticle aqueous dispersion, add F-127 and PVP K30, making its concentration is 15% and 0.5%, lyophilizing, and the irradiation under ultraviolet ray sterilization promptly gets the composite xerogel agent.
Embodiment 17
MPEG-Vinalac 5920 methyl methacrylate (PBMA-MMA)-PLL bag carries the preparation of the temperature sensitive pluralgel agent of methotrexate
Multi-emulsion method; 8mg mPEG-PBMA-MMA-PLL is dissolved in the 0.5ml ether, adds 50 μ l 10mg/ml methotrexate solution, ultrasonic emulsification; Add 4ml 0.5%F-68 solution; Ultrasonic emulsification once more, stirring at room is removed organic solvent, promptly gets the mPEG-PBMA-MMA-PLL nanoparticle that carries methotrexate.
In above nanoparticle aqueous dispersion, add F-127 and PVP K30, making its concentration is 17% and 1%, lyophilizing, and the irradiation under ultraviolet ray sterilization promptly gets the composite xerogel agent.
Claims (10)
1. a nano compound temperature-sensitive gel is characterized in that: wrap up anti-tumor active substance by high molecular polymer as carrier material, process nanoparticle, add temperature sensitive macromolecular material again, process the nano compound temperature-sensitive gel.
2. a kind of nano compound temperature-sensitive gel according to claim 1 is characterized in that: said high molecular polymer is homopolymer, copolymer or block polymer; Wherein, block is one or more in Polyethylene Glycol, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polycaprolactone, methacrylate, polyurethane, the polyamino acid, and molecular weight is 1.2 * 10
3-10.0 * 10
8The molecule mol ratio is 1-100: 100-1 between each block; When polymer or block were copolymer, the mol ratio between the monomer was 1-100: 100-1.
3. a kind of nano compound temperature-sensitive gel according to claim 2 is characterized in that: when said high molecular polymer contained the Polyethylene Glycol block, Polyethylene Glycol was the methylated Polyethylene Glycol of a terminal hydroxy group, and the block molecule amount is 100-20000; When high molecular polymer contained polylactic acid, polylactic-co-glycolic acid or polycaprolactone block, the block molecule amount was 1000-100000; When high molecular polymer contained polyurethane or polyamino acid block, the block molecule amount was 500-100000.
4. a kind of nano compound temperature-sensitive gel according to claim 1 is characterized in that: said high molecular polymer chemical bonding or bonding cancer target group not; Wherein, the targeting group is one or more in arginine-glycine-aspartic acid cyclic peptide, folic acid, epidermal growth factor receptor antibody, PSA antibody, hEGF, transferrins, lactoferrin, galactose, the lactobionic acid.
5. a kind of nano compound temperature-sensitive gel according to claim 1 is characterized in that: said anti-tumor active substance is Antioncogene, antitumor drug, antitumor diagnostic reagent or antitumor development reagent.
6. a kind of nano compound temperature-sensitive gel according to claim 5 is characterized in that: said Antioncogene is siRNA, microRNA, suicide gene, antioncogene or antisensenucleic acids;
Said antitumor drug is gemcitabine, fluorouracil, paclitaxel, mitoxantrone, amycin, 9-nitrocamptothecin, cisplatin, methotrexate or vincristine;
Said antitumor diagnostic reagent is the diagnostic reagent that is used for ultrasonic, nuclear magnetic resonance, NMR, CT or PET;
Said antitumor development reagent is the development reagent that is used for NMR imaging, ultrasonic or CT.
7. a kind of nano compound temperature-sensitive gel according to claim 1 is characterized in that: said temperature sensitive macromolecular material is one or more in the copolymer of poloxamer, poly-N-isopropyl acrylamide, N-Isopropylacrylamide and methacrylic acid or methacrylate;
Described poloxamer molecular weight is 1 * 10
3-1 * 10
6, wherein, polyoxy ethane block molecule amount is 1 * 10
2-6 * 10
5, polyoxy propane block molecule amount is 8 * 10
2-4 * 10
5, the molecular weight ratio of two kinds of blocks is 1-80: 1-80;
Described poly-N-isopropyl acrylamide molecular weight is 5 * 10
2-1 * 10
5
In the copolymer of described N-Isopropylacrylamide and methacrylic acid or methacrylate, polymethylacrylic acid block molecule amount is 1 * 10
2-5 * 10
4, the polymethacrylates molecular weight is 5 * 10
2-1 * 10
5, poly-N-isopropyl acrylamide and polymethylacrylic acid or polymethacrylates molecular weight ratio are 1-80: 80-1.
8. the method for preparing of a nano compound temperature-sensitive gel according to claim 1 comprises:
(1) adopt multi-emulsion method, membrane emulsification method, dialysis, emulsifying evaporation, interphase precipitate method or self-assembly method to make by the nanoparticle solution of high molecular polymer as carrier material parcel anti-tumor active substance;
(2) temperature sensitive macromolecular material is added in the nanoparticle solution, dissolving promptly gets;
Perhaps,, mix, promptly get with nanoparticle solution with being dissolved into solution in the temperature sensitive macromolecular material adding normal saline;
Perhaps, temperature sensitive macromolecular material is mixed with nano-granule freeze-dried powder, add the normal saline dispersing and dissolving, promptly get.
9. the method for preparing of a kind of nano compound temperature-sensitive gel according to claim 8; It is characterized in that: the molar concentration of the high molecular polymer in said step (1) the nanoparticle solution is 0.001-10000M, and the molar concentration of anti-tumor active substance is 0.001-10000 μ M.
10. the application of a nano compound temperature-sensitive gel as claimed in claim 1 is characterized in that: the reagent that is applied to prepare antitumor drug targeting preparation, reverse or reduction tumor drug resistance preparation, diagnosing tumor development of said nano compound temperature-sensitive gel, transfection reagent, gene therapy medicament preparation, antisensenucleic acids, small interference ribonucleic acid transfection reagent or the antisensenucleic acids of DNA plasmid and the pharmaceutical preparation of siRNA treatment usefulness; Be applied to the treatment and the diagnosis of cancer of pancreas, hepatocarcinoma, pulmonary carcinoma, gastric cancer, colorectal cancer, the esophageal carcinoma, carcinoma of prostate, uterus carcinoma, ovarian cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100483385A CN102525882A (en) | 2012-02-28 | 2012-02-28 | Nanocomposite temperature-sensitive gel and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100483385A CN102525882A (en) | 2012-02-28 | 2012-02-28 | Nanocomposite temperature-sensitive gel and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102525882A true CN102525882A (en) | 2012-07-04 |
Family
ID=46334716
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012100483385A Pending CN102525882A (en) | 2012-02-28 | 2012-02-28 | Nanocomposite temperature-sensitive gel and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102525882A (en) |
Cited By (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103110567A (en) * | 2013-03-11 | 2013-05-22 | 上海中医药大学附属普陀医院 | Preparation method of nanometer drug delivery system carrying tanshinone IIA and application thereof |
| CN103432632A (en) * | 2013-09-16 | 2013-12-11 | 姚静 | Temperature-sensitive gel composition and preparation method thereof |
| CN103555767A (en) * | 2013-10-28 | 2014-02-05 | 北京工业大学 | Preparation method and applications of microRNA nano-carrier self-assembled layer by layer |
| CN103735501A (en) * | 2014-02-18 | 2014-04-23 | 长沙晶易医药科技有限公司 | CS/GP/MAX (Methotrexate-loaded Chitosan-based Thermosensitive Hydrogel) and application thereof |
| WO2014108076A1 (en) * | 2013-01-10 | 2014-07-17 | 北京大学 | Gel composition of insoluble drug and preparation method therefor |
| CN104083321A (en) * | 2014-07-04 | 2014-10-08 | 上海市肿瘤研究所 | Composite nano-temperature-sensitive gel agent and application thereof |
| CN104721131A (en) * | 2015-04-09 | 2015-06-24 | 泸州医学院附属医院 | Gel preparation used for tumor in-situ treatment and preparation method |
| CN105561334A (en) * | 2014-10-11 | 2016-05-11 | 中国人民解放军第二军医大学 | Temperature targeting-based nanogel gene delivery compound, and preparation method and application thereof |
| CN105982845A (en) * | 2015-02-17 | 2016-10-05 | 复旦大学 | Thermotropic hydrogel hypoglycemic drug preparation and preparing method thereof |
| CN106994117A (en) * | 2016-01-25 | 2017-08-01 | 上海市肿瘤研究所 | A kind of medicament nano compound temperature-sensitive gel for treating biliary tract neoplasms |
| CN107281502A (en) * | 2016-04-05 | 2017-10-24 | 上海市肿瘤研究所 | The compound development thermo-sensitive gel suppository of one kind, preparation method and applications |
| CN107496382A (en) * | 2017-09-04 | 2017-12-22 | 上海交通大学 | Composite Nano capsule injection aquagel dual drug-loading slow-releasing system and preparation method |
| WO2018000423A1 (en) * | 2016-06-29 | 2018-01-04 | 安徽美科迪智能微胶囊科技有限公司 | Thermosensitive nano-capsule and preparation method therefor |
| CN108272771A (en) * | 2018-03-01 | 2018-07-13 | 中南民族大学 | A kind of temperature control administration microvesicle patch and preparation method |
| CN108778252A (en) * | 2016-03-22 | 2018-11-09 | 高丽大学校世宗产学协力团 | Temperature sensitivity compound and preparation method thereof |
| CN109206612A (en) * | 2017-07-06 | 2019-01-15 | 香港理工大学深圳研究院 | Bionical spider silk polyaminoacid bioelastomer material and preparation method thereof |
| CN109364239A (en) * | 2018-10-29 | 2019-02-22 | 深圳职业技术学院 | A kind of YGLF that contains receives the preparation method of rouge body |
| CN111298195A (en) * | 2019-11-13 | 2020-06-19 | 长春圣博玛生物材料有限公司 | Composite micron material, dermal filler, and preparation method and application thereof |
| CN114073666A (en) * | 2020-08-11 | 2022-02-22 | 武汉科福新药有限责任公司 | Nadolol slow release injection and preparation method thereof |
| CN114272201A (en) * | 2021-12-13 | 2022-04-05 | 贵州中医药大学 | Chelerythrine mPEG-PLGA nano gel composite preparation and detection methods and application thereof |
| CN114377192A (en) * | 2021-12-28 | 2022-04-22 | 广东粤港澳大湾区国家纳米科技创新研究院 | Preparation method of embolism material |
| CN114907661A (en) * | 2022-06-13 | 2022-08-16 | 南京林业大学 | Hydrogel for flexible strain sensor and preparation method and application thereof |
| CN116509794A (en) * | 2023-05-19 | 2023-08-01 | 上海市肿瘤研究所 | Oral thermosensitive gel preparation and preparation method and application thereof |
| US11730826B2 (en) | 2016-05-02 | 2023-08-22 | Massachusetts Institute Of Technology | Amphiphilic nanoparticles for delivery of CRISPR based therapy |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101732723A (en) * | 2009-12-30 | 2010-06-16 | 上海市肿瘤研究所 | Polyethylene glycol-poly(lactic-co-glycolic acid)-polylysine nano-delivery system, preparation method and application thereof |
| CN102321242A (en) * | 2011-08-22 | 2012-01-18 | 上海市肿瘤研究所 | Polyethylene glycol-polylactic acid-poly-L-lysine copolymer, preparation method thereof and application thereof as gene or drug vector |
-
2012
- 2012-02-28 CN CN2012100483385A patent/CN102525882A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101732723A (en) * | 2009-12-30 | 2010-06-16 | 上海市肿瘤研究所 | Polyethylene glycol-poly(lactic-co-glycolic acid)-polylysine nano-delivery system, preparation method and application thereof |
| CN102321242A (en) * | 2011-08-22 | 2012-01-18 | 上海市肿瘤研究所 | Polyethylene glycol-polylactic acid-poly-L-lysine copolymer, preparation method thereof and application thereof as gene or drug vector |
Non-Patent Citations (4)
| Title |
|---|
| 仇海镇 等: "原位凝胶的研究进展及其在药剂学中的应用", 《医学信息》 * |
| 宋燕青 等: "胰岛素纳米粒温敏凝胶的制备及体外释药性能", 《中国医院药学杂志》 * |
| 张翠霞 等: "新型的药物传递系统-原位凝胶的研究进展", 《中国医院药学杂志》 * |
| 沈承武 等: "环境敏感性水凝胶的研究进展及其在给药系统中的应用", 《齐鲁药事》 * |
Cited By (36)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014108076A1 (en) * | 2013-01-10 | 2014-07-17 | 北京大学 | Gel composition of insoluble drug and preparation method therefor |
| CN103110567A (en) * | 2013-03-11 | 2013-05-22 | 上海中医药大学附属普陀医院 | Preparation method of nanometer drug delivery system carrying tanshinone IIA and application thereof |
| CN103432632A (en) * | 2013-09-16 | 2013-12-11 | 姚静 | Temperature-sensitive gel composition and preparation method thereof |
| CN103432632B (en) * | 2013-09-16 | 2015-11-25 | 姚静 | A kind of thermosensitive in situ gel compositions and preparation method |
| CN103555767A (en) * | 2013-10-28 | 2014-02-05 | 北京工业大学 | Preparation method and applications of microRNA nano-carrier self-assembled layer by layer |
| CN103555767B (en) * | 2013-10-28 | 2016-07-13 | 北京工业大学 | The preparation method of the microRNA nano-carrier of a kind of LBL self-assembly and application thereof |
| CN103735501A (en) * | 2014-02-18 | 2014-04-23 | 长沙晶易医药科技有限公司 | CS/GP/MAX (Methotrexate-loaded Chitosan-based Thermosensitive Hydrogel) and application thereof |
| CN103735501B (en) * | 2014-02-18 | 2016-01-13 | 长沙晶易医药科技有限公司 | Methotrexate chitosan thermosensitive hydrogel and application thereof |
| CN104083321A (en) * | 2014-07-04 | 2014-10-08 | 上海市肿瘤研究所 | Composite nano-temperature-sensitive gel agent and application thereof |
| CN105561334A (en) * | 2014-10-11 | 2016-05-11 | 中国人民解放军第二军医大学 | Temperature targeting-based nanogel gene delivery compound, and preparation method and application thereof |
| CN105982845A (en) * | 2015-02-17 | 2016-10-05 | 复旦大学 | Thermotropic hydrogel hypoglycemic drug preparation and preparing method thereof |
| CN104721131A (en) * | 2015-04-09 | 2015-06-24 | 泸州医学院附属医院 | Gel preparation used for tumor in-situ treatment and preparation method |
| CN104721131B (en) * | 2015-04-09 | 2017-07-04 | 泸州医学院附属医院 | A kind of gel preparation and preparation method for neoplasm in situ treatment |
| CN106994117A (en) * | 2016-01-25 | 2017-08-01 | 上海市肿瘤研究所 | A kind of medicament nano compound temperature-sensitive gel for treating biliary tract neoplasms |
| CN106994117B (en) * | 2016-01-25 | 2020-05-05 | 上海市肿瘤研究所 | A nanometer composite temperature-sensitive gel for treating biliary tumor |
| CN108778252A (en) * | 2016-03-22 | 2018-11-09 | 高丽大学校世宗产学协力团 | Temperature sensitivity compound and preparation method thereof |
| CN107281502B (en) * | 2016-04-05 | 2021-05-04 | 上海市肿瘤研究所 | Composite developing temperature-sensitive gel suppository, preparation method and application thereof |
| CN107281502A (en) * | 2016-04-05 | 2017-10-24 | 上海市肿瘤研究所 | The compound development thermo-sensitive gel suppository of one kind, preparation method and applications |
| US11730826B2 (en) | 2016-05-02 | 2023-08-22 | Massachusetts Institute Of Technology | Amphiphilic nanoparticles for delivery of CRISPR based therapy |
| US10543471B2 (en) | 2016-06-29 | 2020-01-28 | Anhui Microdelivery Smart Microcapsule Sci & Tech Co. Ltd | Thermosensitive nanocapsules and preparing method thereof |
| WO2018000423A1 (en) * | 2016-06-29 | 2018-01-04 | 安徽美科迪智能微胶囊科技有限公司 | Thermosensitive nano-capsule and preparation method therefor |
| CN109206612B (en) * | 2017-07-06 | 2021-06-04 | 香港理工大学深圳研究院 | Bionic spider silk polyamino acid biological elastomer material and preparation method thereof |
| CN109206612A (en) * | 2017-07-06 | 2019-01-15 | 香港理工大学深圳研究院 | Bionical spider silk polyaminoacid bioelastomer material and preparation method thereof |
| CN107496382A (en) * | 2017-09-04 | 2017-12-22 | 上海交通大学 | Composite Nano capsule injection aquagel dual drug-loading slow-releasing system and preparation method |
| CN108272771A (en) * | 2018-03-01 | 2018-07-13 | 中南民族大学 | A kind of temperature control administration microvesicle patch and preparation method |
| CN108272771B (en) * | 2018-03-01 | 2020-12-01 | 中南民族大学 | Temperature-controlled administration microbubble patch and preparation method thereof |
| CN109364239A (en) * | 2018-10-29 | 2019-02-22 | 深圳职业技术学院 | A kind of YGLF that contains receives the preparation method of rouge body |
| CN111298195A (en) * | 2019-11-13 | 2020-06-19 | 长春圣博玛生物材料有限公司 | Composite micron material, dermal filler, and preparation method and application thereof |
| CN114073666A (en) * | 2020-08-11 | 2022-02-22 | 武汉科福新药有限责任公司 | Nadolol slow release injection and preparation method thereof |
| CN114272201A (en) * | 2021-12-13 | 2022-04-05 | 贵州中医药大学 | Chelerythrine mPEG-PLGA nano gel composite preparation and detection methods and application thereof |
| CN114272201B (en) * | 2021-12-13 | 2024-01-26 | 贵州中医药大学 | Chelidonine mPEG-PLGA nano gel composite preparation, and preparation method, detection method and application thereof |
| CN114377192A (en) * | 2021-12-28 | 2022-04-22 | 广东粤港澳大湾区国家纳米科技创新研究院 | Preparation method of embolism material |
| CN114907661A (en) * | 2022-06-13 | 2022-08-16 | 南京林业大学 | Hydrogel for flexible strain sensor and preparation method and application thereof |
| CN114907661B (en) * | 2022-06-13 | 2023-08-22 | 南京林业大学 | Hydrogel applicable to flexible strain sensor and preparation method and application thereof |
| CN116509794A (en) * | 2023-05-19 | 2023-08-01 | 上海市肿瘤研究所 | Oral thermosensitive gel preparation and preparation method and application thereof |
| CN116509794B (en) * | 2023-05-19 | 2024-03-15 | 上海市肿瘤研究所 | Oral thermosensitive gel preparation and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102525882A (en) | Nanocomposite temperature-sensitive gel and preparation method and application thereof | |
| CN101732723B (en) | Polyethylene glycol-poly(lactic-co-glycolic acid)-polylysine nano-delivery system, preparation method and application thereof | |
| Anajafi et al. | Polymersome-based drug-delivery strategies for cancer therapeutics | |
| Kim et al. | The delivery of doxorubicin to 3-D multicellular spheroids and tumors in a murine xenograft model using tumor-penetrating triblock polymeric micelles | |
| Chen et al. | Targeting tumor microenvironment with PEG-based amphiphilic nanoparticles to overcome chemoresistance | |
| Dong et al. | Thermosensitive hydrogel loaded with chitosan-carbon nanotubes for near infrared light triggered drug delivery | |
| You et al. | Polymeric nanoparticles for colon cancer therapy: overview and perspectives | |
| Chen et al. | Lipid/PLGA hybrid microbubbles as a versatile platform for noninvasive image-guided targeted drug delivery | |
| Gupta et al. | Recent trends in biodegradable polyester nanomaterials for cancer therapy | |
| Son et al. | Echogenic nanoparticles for ultrasound technologies: Evolution from diagnostic imaging modality to multimodal theranostic agent | |
| CN102321242A (en) | Polyethylene glycol-polylactic acid-poly-L-lysine copolymer, preparation method thereof and application thereof as gene or drug vector | |
| CN100577209C (en) | Magnetic tumor double-target polymer nano micelle and preparation thereof | |
| CN105147615B (en) | The tumour cell and double targeted nano granules of tumor vessel, construction method and application | |
| Wang et al. | Ultrasound-responsive microbubbles for sonography-guided siRNA delivery | |
| Sohail et al. | Nanocarrier-based drug delivery system for cancer therapeutics: a review of the last decade | |
| AU2017226517B2 (en) | Ovarian cancer specifically targeted biodegradable amphiphilic polymer, polymer vesicle prepared thereby and use thereof | |
| CN107233577A (en) | A kind of pH responses and the double medicine-carried nano particles and preparation method of cancer target and application | |
| CN106905519B (en) | Biodegradable amphiphilic polymers, polymer vesicle prepared therefrom and preparing the application in targeted therapy of lung cancer drug | |
| CN104888235A (en) | pH sensitive nanoparticles prodrug with capacity of co-delivering multiple drugs, preparation method and application thereof | |
| CN102600474A (en) | Application of polyethylene glycol-polylactic-co-glycolic acid-poly-L-lysine block polymer in delivery drugs or genes | |
| CN106994117A (en) | A kind of medicament nano compound temperature-sensitive gel for treating biliary tract neoplasms | |
| CN107875140A (en) | A kind of double targeted drug delivery systems and its application in oncotherapy preparation is prepared | |
| Janrao et al. | Recent advances of polymer based nanosystems in cancer management | |
| CN102302783A (en) | Bufalin-loaded cyclic peptide-modified polyethylene glycol-polylactic acid hydroxyl glycolic acid-polylysine nanoparticles | |
| Sahakyan et al. | Personalized nanoparticles for cancer therapy: a call for greater precision |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20120704 |