CN102772356A - Taxol-based small-molecule hydrogel and preparation method thereof - Google Patents
Taxol-based small-molecule hydrogel and preparation method thereof Download PDFInfo
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Abstract
The invention relates to taxol-based small-molecule hydrogel and a preparation method thereof. The preparation method of the taxol-based small-molecule hydrogel comprises the following steps of: (1) dissolving taxol derivatives obtained by ester bond connection of taxol and hydrophilic compounds through hydroxyl groups into an aqueous medium, wherein the quality of the taxol derivatives dissolved in 1ml of aqueous medium is 5-200mg; and (2) hydrolyzing ester bonds for connecting the taxol and the hydrophilic compounds to obtain taxol, thereby forming the taxol-based small-molecule hydrogel. The degree of hydrolyzing can be defined according to specific conditions so long as the hydrogel can be formed. The invention has the following beneficial effects: the synthesis method is simple and only needs 1-2 reaction steps, and the normal saline or buffer solution of the taxol derivatives forms the small-molecule hydrogel capable of being injected through self-hydrolyzing of the ester bonds; and secondly, a slow-release system takes drug molecules as carriers, and the hydrogel can be locally injected to tumor parts, thereby improving the chemotherapy effect.
Description
Technical field
The present invention relates to a kind of micro-molecular hydrogel based on paclitaxel and preparation method thereof.
Background technology
Present a lot of hydrophobic medicines such as paclitaxel, camptothecine etc. are because its poorly water-soluble has limited its application in clinical.With the paclitaxel is example: paclitaxel is to be applied to clinical broad-spectrum anti-cancer drug of new generation the nineties in 20th century.Paclitaxel mainly is applicable to ovarian cancer and breast carcinoma, and pulmonary carcinoma, colorectal cancer, melanoma, incidence cancer, lymphoma, cerebroma are also all had certain curative effect.Because its poorly water-soluble, the formulation for paclitaxel that uses clinically at present many with polyoxyethylene castor oil (CremophorEL) and dehydrated alcohol (1: 1) mixed liquor as cosolvent.Use normal saline or 5% glucose to be diluted to final concentration before the administration and be 0.4-1.4mmolL
-1, these cosolvents can cause multiple untoward reaction, clearer and more definite anaphylaxis and the neurotoxicity of comprising.In addition, the small particle that polyoxyethylene castor oil forms in blood circulation can hinder the effect of medicine with paclitaxel molecule parcel.And need intravenously administrable during clinical use, and the time is long, and patient also can produce infusion reaction simultaneously.Having ratified new antitumoral medicine " albumin bound type nanoparticle paclitaxel " in June, 2009 China State Food and Drug Administration goes on the market in China; This medicine can save required preprocessor before the administration of conventional solvent type paclitaxel, and in 30 minutes, accomplishes infusion.This medicine of state food and drug administration approved is used to treat the breast carcinoma of recurrence in metastatic breast cancer or the NACT 6 months of combined chemotherapy failure.Because the slightly solubility of cancer therapy drug such as paclitaxel and no targeting property, it is little that many scientists have toxic and side effects in exploration always, and targeting property by force and have a pharmaceutical carrier of slow releasing function.Now the paclitaxel carrier of research mainly contains liposome, amphipathic copolymer, the macromole polymer be connected with protein; Water miscible prodrug etc., but many carriers exist envelop rate low, non-selectivity (targeting); Shortcomings such as synthetic difficulty have limited the further application of these carriers.Even reasonable pharmaceutical carrier is arranged now, many patent rights all belong to external to be owned, and from statistical data in 2008, cancer became first cause of the death of Chinese residents.The China's expense of annual flower on drug patent power may be howed a lot than the cost of medicine itself, it is very necessary therefore to develop the anti-cancer medicament carrier that belongs to Chinese property right and have good curative effect fast.Micro-molecular hydrogel was being paid close attention to as the research of pharmaceutical carrier in recent years widely, because it has good biocompatibility, was easy to degraded, synthesized advantages such as simple.Micro-molecular hydrogel since finding eighties of last century nineties, snatch domestic and international scientist's the extensive concern and the research in fields such as regenerative medicine and biomaterial.Recent years, based on the micro-molecular hydrogel of drug molecule as being expected to realize its practical application in the medicine transmission field from slow-releasing system.Yet; Existing most micro-molecular hydrogel medicament slow release system is all formed by the self assembly of drug molecule derivant; Only two examples have all obtained the FDA authentication based on the micro-molecular hydrogel of drug molecule itself, as novel pharmaceutical formulation in clinical practice.But do not find micro-molecular hydrogel as yet based on paclitaxel molecule itself.
Summary of the invention
The present invention provides a kind of micro-molecular hydrogel method for preparing based on paclitaxel, can obtain the micro-molecular hydrogel based on paclitaxel molecule itself.
The micro-molecular hydrogel that the present invention also provides above-mentioned method for preparing to obtain based on paclitaxel.
The method for preparing of said micro-molecular hydrogel based on paclitaxel comprises following steps:
(1) be connected the paclitaxel derivant that obtain with hydrophilic compounds through ester bond with hydroxyl by paclitaxel and be dissolved in the aqueous medium, the said paclitaxel derivant quality that is dissolved in every milliliter of said aqueous medium is the 5-200 milligram;
(2) make the ester linkage hydrolyzing of said connection paclitaxel and hydrophilic compounds obtain paclitaxel, thereby form micro-molecular hydrogel based on paclitaxel.The degree of hydrolysis can be come fixed according to specific circumstances, as long as can form hydrogel.Generally from making full use of the angle of raw material and cost control, degree of hydrolysis (being hydrolyzed into the paclitaxel derivant and the mol ratio that adds paclitaxel derivant total in the aqueous medium of paclitaxel) should be more than 50%.
Preferred paclitaxel is connected the paclitaxel derivant that obtain with hydrophilic compounds through ester bond with 2 ' hydroxyl, to obtain satisfied esterification activity and yield.
Preferably, said aqueous medium is that normal saline or pH value are the buffer of 6.0-8.0.
In the preferred steps (2), leave standstill at 20 ℃～45 ℃ and to make the ester linkage hydrolyzing of said connection paclitaxel and hydrophilic compounds obtain paclitaxel.Time of repose was preferably more than 2 hours, more preferably 6-12 hour.
For step (2); For the hydrolysis of carrying out said ester bond of success obtains paclitaxel; The selection of aqueous medium is an important relatively factor, and the temperature and time of concrete hydrolysis can be confirmed according to the complexity of hydrolysis and speed and desired degree of hydrolysis.
Consider the medical usage of gained micro-molecular hydrogel, but said hydrophilic compounds should be selected the material of application in the body, simultaneously, the hydrophilic of said hydrophilic compounds should satisfy the dissolubility requirement of paclitaxel derivant in above-mentioned aqueous medium.That said hydrophilic compounds is preferably is hydroxyl, the hydrophilic compounds that can be used for human body of amino or carboxyl, further is preferably oxidisability glutathion (hereinafter to be referred as GSSG) or PEG (Polyethylene Glycol).The PEG here can be not carboxylated PEG (two hydroxyl structure), also can be carboxylated PEG, to satisfy the requirement that is connected with paclitaxel through ester bond.Can try the concrete structure of hydrophilic compounds selects through the method for ester bond connection; For example; Can be that esterification is carried out in the hydroxyl of 2 ' of paclitaxel and the alkyl dicarboxylic acid of C4-C6, obtain intermediate product, said intermediate product and hydroxyl or amino hydrophilic compounds reaction with a carboxyl; Obtain said paclitaxel derivant; Said hydrophilic compounds is preferably the oxidisability glutathion or number-average molecular weight is 400-20, and the not carboxylated PEG of 000g/mol, said binary acid are preferably the succinic acid (hereinafter to be referred as SA) that health is had no side effect; Perhaps said hydrophilic compounds is that number-average molecular weight is 400-20, the carboxylated PEG of 000g/mol, and hydroxyl that paclitaxel is 2 ' and carboxylated PEG carry out esterification, obtain said paclitaxel derivant.
As improvement of the present invention, what method for preparing according to the invention obtained can also be as the carrier of the drug molecule of other types based on the micro-molecular hydrogel of paclitaxel.In the step (1), when being connected the paclitaxel derivant that obtains and being dissolved in the aqueous medium through ester bond with hydroxyl and hydrophilic compounds, also add drug molecule in the said aqueous medium by paclitaxel.Behind step (2) ester linkage hydrolyzing, form the micro-molecular hydrogel of carrying medicament molecule.But said drug molecule is for micro-molecular hydrogel loaded drugs molecule commonly used, like amycin.
The invention has the beneficial effects as follows: at first the used raw material of the present invention is paclitaxel and hydrophilic oxidized form of glutathione or PEG; Be the medicine of clinical use; Synthetic method is simple; Only need 1-2 step reaction; Said paclitaxel derivant is purified also simple (as purifying through recrystallization), and productive rate can reach 85%, and the normal saline of the most outstanding is this paclitaxel derivant molecule or buffer all can form the micro-molecular hydrogel that can inject through ester bond from hydrolysis at 20 ℃～45 ℃; Secondly such slow-releasing system uses drug molecule itself as carrier; Need not again the safety of carrier to be estimated; This hydrogel can local injection improves the lethality of tumor and alleviates the toxic and side effects to other normal structures, the raising chemotherapy effect to tumor locus; Simultaneously; The drug molecule of other type also can be wrapped in wherein in the process that forms the paclitaxel micro-molecular hydrogel with the form of physics parcel; Such slow-releasing system is slow release multiple medications molecule simultaneously, and perhaps other needs the effect of the treatment (like rheumatic arthritis) of taxol drug to improve chemotherapy.
Description of drawings
Fig. 1: chemical compound 1
1The HNMR spectrogram;
The PBS solution (pH=7.4) of Fig. 2: Taxol-SA-GSSG and be placed on the LC-MS chromatogram of the micro-molecular hydrogel that forms after 37 ℃ by it; Wherein 2a is the LC-MS chromatogram of the PBS solution (pH=7.4) of Taxol-SA-GSSG, and 2b is that the PBS solution (pH=7.4) of Taxol-SA-GSSG is at 37 ℃ of LC-MS chromatograms of placing the micro-molecular hydrogel that forms behind the 12h;
Fig. 3: with the three-dimensional appearance structure of atomic force microscope observation micro-molecular hydrogel.
The specific embodiment
Embodiment 1:
(1) synthetic (reference literature J.Med.Chem., 1989,32 (4), the pp 788-792) of Taxol-SA, the structural formula of Taxol-SA is as follows:
(2) Taxol-SA-GSSG's (chemical compound 1) is synthetic, and step is as follows:
Take by weighing 100mg (104.8 μ mol) Taxol-SA; Be dissolved in the anhydrous methylene chloride (DCM) of 20mL, add following material: 13.3mg (115.3 μ mol) N-hydroxy-succinamide (NHS) and 25.7mg (125.4 μ mol) N, N '-dicyclohexylcarbodiimide (DCC) simultaneously successively; The room temperature lucifuge stirred three hours; Filter, collect filtrating, revolve dried.Add 10mL acetone (Acetone), (content of oxidized form of glutathione is 96.2mg, adds NaHCO to add the aqueous solution of 6mL oxidized form of glutathione (GSSG) simultaneously
3About 40mg adjustment pH value is to pH=7.4), dry acetone is revolved in lucifuge reaction 12 hours, lyophilizing then, HPLC separates, productive rate 83.2%.
1HNMR(400MHz，DMSO-d
6)δ7.99(d，J＝7.62，2H)，7.86(d，J＝7.07，2H)，7.67-7.75(m，3H)，7.44-7.58(m，6H)，7.10-7.22(m，2H)，6.21(s，1H)，5.81-5.85(m，1H)，5.53-5.55(m，1H)，5.35-5.44(m，2H)，4.90-4.95(m，2H)，4.55-4.66(m，3H)，4.02-4.18(m，4H)，3.75-3.77(m，3H)，3.57-3.60(m，1H)，3.09-3.13(m，3H)，2.81-2.84(m，2H)，2.54-2.85(m，2H)，2.34(m，4H)，2.18-2.25(m，5H)，2.11(s，3H)，1.90-2.01(m，4H)，1.79(s，5H)，1.58-1.68(m，2H)，1.50(s，4H).MS：calc.M
+＝1545.5，obsvd.(M+1)
+＝1547.8.
Embodiment 2:
Taxol-SA-PEG2000's (chemical compound 2) is synthetic
Take by weighing 200mg (209.6 μ mol) Taxol-SA, add 10mL anhydrous methylene chloride (DCM), add following material on the ice bath successively: 98.4 μ L (628.8 μ mol) N; N '-dicyclohexylcarbodiimide (DIC) and 10mg DMAP add the PEG2000 of 482mg (241.04 μ mol) at last, return to room temperature afterwards; Lucifuge stirred 12 hours, revolved driedly, washed one time with 0.1N hydrochloric acid (10mL); The isopropyl alcohol crystallization, productive rate 83.5%.
1HNMR(300MHz，DMSO-d
6)δ1.94-7.97(m，2H)，7.81-7.84(m，2H)，7.58-7.66(m，4H)，7.41-7.50(m，7H)，6.27(s，1H)，5.80-5.81(m，1H)，5.53(t，1H)，5.31-5.41(m，3H)，4.87-4.91(m，2H)，4.54-4.63(m，5H)，3.99-4.05(m，6H)，3.71-3.75(m，4H)，3.43-3.65(s，PEG)，3.37-3.41(m，8H)，3.22-3.28(m，3H)，2.55-2.66(m，3H)，2.23(s，3H)，2.05-2.11(m，3H)，1.75-1.77(m，3H)，1.49(s，3H)，1.09-1.15(m，3H)，0.99-1.02(m，6H).
Embodiment 3:
Taxol-PEG 600 (chemical compound 3) synthetic (reference literature J.Med.Chem.1996,39,424-431) draw the carboxylated PEG 600 (Polyethylene Glycol dicarboxylic acids) in 120 μ L two ends with liquid-transfering gun; In ice bath, add the dichloromethane of 10mL, add 79uL N simultaneously; N '-dicyclohexylcarbodiimide (DIC) and 10mg DMAP add the 200mg paclitaxel then, make it slowly return to room temperature; Lucifuge room temperature reaction 12 hours revolves driedly, washes one time with 0.1N hydrochloric acid (10mL); Lyophilizing, isopropyl alcohol crystallization, productive rate 80.2%.
1HNMR(300MHz，CHCl
3-d
6)δ8.10-8.14(m，2H)，7.75-7.77(m，3H)，7.26-7.53(m，13H)，6.20-6.28(m，2H)，5.99-6.03(m，1H)，5.67-5.70(d，1H)，5.50-5.53(m，1H)，4.95-4.98(d，1H)，4.17-4.31(m，7H)，4.07-4.12(m，4H)，3.50-3.67(m，PEG)，3.43-3.51(m，5H)，2.47(s，3H)，2.23(s，2H)，2.14-2.17(m，2H)，1.96(d，J＝13.5，3H)，1.80(s，2H)，1.68(s，2H)，1.12-1.23(m，11H)
Embodiment 4:
By chemical compound 1 set out the paclitaxel micro-molecular hydrogel that obtains with through its three-dimensional appearance of atomic force microscope observation
Take by weighing the chemical compound 1 that 4.0mg obtains; PBS (pH=7.4) buffer that adds 0.4mL; Carefully regulate pH to 7.4 with sodium carbonate, room temperature (20-25 ℃) or 37 ℃ were placed respectively 8 hours or more than 6 hours, were inverted bottle and can observe the jellylike micro-molecular hydrogel of similar fruit.Can learn through the variation of LCMS (LC-MS chromatograph) analysis of compounds 1 in forming the colloid process; Chemical compound 1 forms micro-molecular hydrogel (like Fig. 2) through the ester linkage breaking at 2 ' hydroxyl place; After 12 hours, about 90% chemical compound 1 becomes paclitaxel and oxidized form of glutathione through ester linkage hydrolyzing.
The hydrogel of drawing about about 15uL with liquid-transfering gun is added drop-wise on the silicon chip of surface clean, makes it even with nitrogen treatment, with atomic force microscope observation pattern (like Fig. 3).Its pattern is netted nanofibrous structures.
Embodiment 5:
Load the formation of paclitaxel micro-molecular hydrogel of amycin
Take by weighing the chemical compound 1 that 10.0mg obtains, add PBS (pH=7.4) buffer of 0.5mL, carefully regulate pH to 7.4 with sodium carbonate; Room temperature (22-25 ℃) was placed after 12 hours, when chemical compound when about 90% 1 becomes paclitaxel through ester linkage hydrolyzing, and the vortex colloid; Add doxorubicin hydrochloride 3.3mg; Vortex one minute, room temperature was placed about 10 minutes afterwards, was inverted bottle and can observes the jellylike red hydrogel of similar fruit.
Embodiment 6:
The paclitaxel micro-molecular hydrogel that sets out and obtain by chemical compound 2
Take by weighing the chemical compound 2 that 5.0mg obtains; PBS (pH=7.4) buffer that adds 0.2mL; Carefully regulate pH to 7.4 with sodium carbonate, room temperature (20-25 ℃) or 37 ℃ were placed respectively 8 hours or 6 hours, were inverted bottle and can observe the jellylike micro-molecular hydrogel of similar fruit.This moment, chemical compound 2 nearly 65% was hydrolyzed into paclitaxel (along with prolong standing time, percent hydrolysis can reach 95%, approximately takes more than 120 hours).
Embodiment 7:
The paclitaxel micro-molecular hydrogel that sets out and obtain by chemical compound 3
Take by weighing the chemical compound 3 that 5.0mg obtains; PBS (pH=7.4) buffer that adds 0.5mL; Carefully regulate pH to 7.4 with sodium carbonate, room temperature (20-25 ℃) or 37 ℃ were placed respectively 8 hours or 6 hours, were inverted bottle and can observe the jellylike micro-molecular hydrogel of similar fruit.This moment, chemical compound 3 nearly 60% was hydrolyzed into paclitaxel (along with prolong standing time, percent hydrolysis can reach 95%, approximately takes more than 120 hours).
Embodiment 8:
The paclitaxel micro-molecular hydrogel that sets out and obtain by chemical compound 1
Take by weighing the chemical compound 1 that 100.0mg obtains; PBS (pH=7.4) buffer that adds 0.5mL; Carefully regulate pH to 7.4 with sodium carbonate, room temperature (20-25 ℃) or 37 ℃ were placed respectively 4 hours or 2 hours, were inverted bottle and can observe the jellylike micro-molecular hydrogel of similar fruit.This moment, chemical compound 1 nearly 58% was hydrolyzed into paclitaxel (along with prolong standing time, percent hydrolysis can reach 95%, approximately takes more than 120 hours)
Embodiment 9:
The paclitaxel micro-molecular hydrogel that sets out and obtain by chemical compound 2
Take by weighing the chemical compound 2 that 100.0mg obtains; PBS (pH=7.4) buffer that adds 0.5mL; Carefully regulate pH to 7.4 with sodium carbonate, room temperature (20-25 ℃) or 37 ℃ were placed respectively 4 hours or 2 hours, were inverted bottle and can observe the jellylike micro-molecular hydrogel of similar fruit.This moment, chemical compound 2 nearly 72% was hydrolyzed into paclitaxel (along with prolong standing time, percent hydrolysis can reach 95%, approximately takes more than 120 hours)
Embodiment 10:
The paclitaxel micro-molecular hydrogel that sets out and obtain by chemical compound 3
Take by weighing the chemical compound 3 that 100.0mg obtains; PBS (pH=7.4) buffer that adds 0.5mL; Carefully regulate pH to 7.4 with sodium carbonate, room temperature (20-25 ℃) or 37 ℃ were placed respectively 4 hours or 2 hours, were inverted bottle and can observe the jellylike micro-molecular hydrogel of similar fruit.This moment, chemical compound 3 nearly 68% was hydrolyzed into paclitaxel (along with prolong standing time, percent hydrolysis can reach 95%, approximately takes more than 120 hours)
Embodiment 11:
The paclitaxel micro-molecular hydrogel that sets out and obtain by chemical compound 3
Take by weighing the chemical compound 3 that 100.0mg obtains; PBS (pH=7.4) buffer that adds 0.5mL; Carefully regulate pH to 7.4 with sodium carbonate, room temperature (20-25 ℃) or 37 ℃ were placed respectively 2.5 hours or 1 hour 20 minutes, were inverted bottle and can observe the jellylike micro-molecular hydrogel of similar fruit.This moment, chemical compound 3 nearly 52% was hydrolyzed into paclitaxel (along with prolong standing time, percent hydrolysis can reach 95%, approximately takes more than 120 hours)
Claims (10)
1. the method for preparing based on the micro-molecular hydrogel of paclitaxel is characterized in that, comprises following steps:
(1) be connected the paclitaxel derivant that obtain with hydrophilic compounds through ester bond with hydroxyl by paclitaxel and be dissolved in the aqueous medium, the said paclitaxel derivant quality that is dissolved in every milliliter of said aqueous medium is the 5-200 milligram;
(2) make the ester linkage hydrolyzing of said connection paclitaxel and hydrophilic compounds obtain paclitaxel, thereby form micro-molecular hydrogel based on paclitaxel.
2. the method for preparing of the micro-molecular hydrogel based on paclitaxel as claimed in claim 1 is characterized in that said aqueous medium is that normal saline or pH value are the buffer of 6.0-8.0.
3. the method for preparing of the micro-molecular hydrogel based on paclitaxel as claimed in claim 1; It is characterized in that; In the step (2); Leave standstill at 20 ℃～45 ℃ and to make the ester linkage hydrolyzing of said connection paclitaxel and hydrophilic compounds obtain paclitaxel more than 2 hours, preferably leave standstill and made the ester linkage hydrolyzing of said connection paclitaxel and hydrophilic compounds obtain paclitaxel in 6-12 hour at 20 ℃～45 ℃.
4. the method for preparing of the micro-molecular hydrogel based on paclitaxel as claimed in claim 1 is characterized in that paclitaxel is connected the paclitaxel derivant that obtains with 2 ' hydroxyl with hydrophilic compounds through ester bond.
5. the method for preparing of the micro-molecular hydrogel based on paclitaxel as claimed in claim 1 is characterized in that, said hydrophilic compounds is the hydrophilic compounds of hydroxyl, amino or carboxyl.
6. the method for preparing of the micro-molecular hydrogel based on paclitaxel as claimed in claim 5; It is characterized in that; Esterification is carried out in the alkyl dicarboxylic acid of hydroxyl that paclitaxel is 2 ' and C4-C6, obtains the intermediate product with a carboxyl, said intermediate product and hydroxyl or amino hydrophilic compounds reaction; Obtain said paclitaxel derivant, said binary acid is preferably succinic acid.
7. the method for preparing of the micro-molecular hydrogel based on paclitaxel as claimed in claim 6 is characterized in that said hydrophilic compounds is that oxidisability glutathion or number-average molecular weight are 400-20, the not carboxylated PEG of 000g/mol.
8. the method for preparing of the micro-molecular hydrogel based on paclitaxel as claimed in claim 5; It is characterized in that; Said hydrophilic compounds is that number-average molecular weight is 400-20; The carboxylated PEG of 000g/mol, hydroxyl that paclitaxel is 2 ' and carboxylated PEG carry out esterification, obtain said paclitaxel derivant.
9. like the method for preparing of each described micro-molecular hydrogel based on paclitaxel among the claim 1-8; It is characterized in that; In the step (1); When being connected the paclitaxel derivant that obtains and being dissolved in the aqueous medium through ester bond with hydroxyl and hydrophilic compounds by paclitaxel, also add drug molecule in the said aqueous medium, said drug molecule is preferably amycin.
10. the micro-molecular hydrogel that each said method for preparing obtains among the claim 1-9 based on paclitaxel.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108033996A (en) * | 2017-12-01 | 2018-05-15 | 南方医科大学 | A kind of controllable preparation paclitaxel nano fiber and its preparation method and application |
| CN114315956A (en) * | 2022-01-10 | 2022-04-12 | 北京工商大学 | Method for preparing multiple response type gel by using oxidized glutathione derivative |
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| CN102120756A (en) * | 2010-12-07 | 2011-07-13 | 南开大学 | Taxol-based small molecule hydrogel-nanosphere transmission system and preparation method thereof |
| CN102349868A (en) * | 2011-10-18 | 2012-02-15 | 南开大学 | Preparation method of targeting folic acid-hydrophobic anticancer drug hydrogel |
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| CN102120756A (en) * | 2010-12-07 | 2011-07-13 | 南开大学 | Taxol-based small molecule hydrogel-nanosphere transmission system and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108033996A (en) * | 2017-12-01 | 2018-05-15 | 南方医科大学 | A kind of controllable preparation paclitaxel nano fiber and its preparation method and application |
| CN114315956A (en) * | 2022-01-10 | 2022-04-12 | 北京工商大学 | Method for preparing multiple response type gel by using oxidized glutathione derivative |
| CN114315956B (en) * | 2022-01-10 | 2023-11-21 | 北京工商大学 | Method for preparing multiple response type gel by using oxidized glutathione derivative |
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Application publication date: 20121114 |