CN103006535A - Methotrexate (MTX)-Pluronic copolymer mixed micelle carrying indissoluble medicament and preparation method thereof - Google Patents
Methotrexate (MTX)-Pluronic copolymer mixed micelle carrying indissoluble medicament and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of biological medicine and relates to a novel methotrexate (MTX)-Pluronic copolymer mixed micelle carrying an indissoluble medicament and a preparation method thereof. The method comprises the following steps of: performing chemical connection and copolymerization on Pluronic and MTX to obtain an MTX-Pluronic copolymer; and mixing the MTX-Pluronic copolymer with Pluronic-kind matters to prepare an MTX-Pluronic copolymer mixed micelle system, wherein a hydrophobic core of the mixed micelle carries the indissoluble medicament. Tests prove that the mixed micelle can improve the medicament-loading capacity of the indissoluble medicament, effectively reverses the medicament tolerance of tumors and has the medicament-delivery characteristic targeting folate receptors.
Description
Technical field
The invention belongs to the biological medicine technology field, be specifically related to a kind of novel bag and carry pluronic (Pluronic) copolymer mixed micelle that the methotrexate (MTX) of insoluble drug modifies and preparation method thereof.
Background technology
Along with the continuous appearance of chemotherapeutics and preparation thereof, chemotherapy has become the important means for the treatment of malignant tumor.It is reported, large and poor selectivity is seriously restricting antineoplastic agent use clinically owing to most of antitumor drug poorly water-solubles, untoward reaction.Studies show that, the phenomenon of the malignant tumor chemotherapy failures such as breast carcinoma, ovarian cancer, pulmonary carcinoma, hepatocarcinoma, nasopharyngeal carcinoma, esophageal carcinoma, gastric cancer and leukemia is of common occurrence clinically at present, and its main cause is exactly the formed tumor multi-medicine drug-resistant of prolonged application antitumor drug (MDR).MDR becomes a great problem of current oncotherapy, estimates according to American Cancer Society, and the tumor patient more than 90% is died from drug resistance in various degree.Therefore, the multidrug resistance of solution insoluble anti-tumor medicament becomes the hot issue in the drug delivery system research.
In recent years, drug delivery system such as liposome, nanoparticle and copolymer micelle etc. have obtained increasing concern for overcoming tumor MDR.Selecting suitable carrier material is the basis that successfully makes up the copolymer micelle drug delivery system, and desirable micelle carrier should only not have the effect of inertia carrying, also need possess himself potential biological activity.Pluronic (Pluronic) is a kind of multi-functional pharmaceutic adjuvant, and it is made of polyoxyethylene-poly-oxypropylene polyoxyethylene (PEO-PPO-PEO) three blocks.Studies show that, Pluronic series has good biocompatibility, and when concentration during greater than CMC, its PPO chain can form the hydrophobic inner core bag and carry insoluble anti-tumor medicament; The PEO chain can form hydrophilic outer shell, has Steric stabilization and EPR effect, avoids engulfing of RES system, and the extension body circulation time strengthens the passive target ability.Pluronic can suppress P-glycoprotein (P-gp) and and the effluxing of multidrug-associated protein (MRP), the reason of its reversion MDR is that Pluronic can effectively reduce the film micro-viscosity, make the structure disturbance of cytolipin plasma membrane, adenosine triphosphate (ATP) and the affinity of P-gp binding site are significantly reduced, disturbed simultaneously the ATP enzyme activity; Its hydrophobic part can interact with intracellular mitochondrial membrane, reduces the electronics transmission, effectively reduces the ability that mitochondrion is produced ATP; Reduce the level of Intracellular Glutathione, and suppress the activity of glutathione transferase; Change apoptosis signal transduction in the cell, promote the mdr cell apoptosis; Suppress pharmaceutical carrier and enter kytoplasm inner acidic vesicle etc.
Adopting mixed micelle is the developing direction of copolymer micelle drug-supplying system, and single micelle medicine carrying amount is low because it can remedy, poor stability and the shortcoming such as anti-dilution not.In addition, the different block copolymer that forms mixed micelle also can be worked in coordination with performance features and effect.MTX is widely used in treating the malignant tumor such as lymphoma, chorionic epithelioma and small cell lung cancer clinically.But tumor cell has become a key factor that limits its clinical practice to the drug resistance of MTX.The Pluronic outer end connects MTX, and the hydrophobic inner core bag carries other slightly solubility cancer therapy drug, not only can improve the MTX anti-tumor activity and but also can increase the drug loading of micelle.MTX is the analog of folic acid, has the affinity of folacin receptor, so the Pluronic micelle that MTX modifies also has the targeting of folacin receptor.
Therefore, the research of relevant MTX-Pluronic copolymer mixed micelle becomes the focus of this area.
Summary of the invention
The purpose of this invention is to provide pluronic (Pluronic) copolymer mixed micelle of a kind of methotrexate (MTX) modification of carrying insoluble drug newly and preparation method thereof.The mixed micelle that the present invention makes can improve the drug loading to insoluble drug, and the effective drug resistance of reversing tumor has the folacin receptor targeting passed the medicine characteristic.
The present invention adopts pluronic Pluronic to be connected by chemistry with methotrexate MTX, after the hydroxyl of Pluronic one or both ends activates into amino, after obtaining the MTX-Pluronic copolymer with the carboxyl reaction of MTX, mix with pluronic Pluronic class material, make MTX-Pluronic copolymer mixed micelle system, as drug administration carrier, have effect and the targeting of reversing tumor MDR.The hydrophobic core of described MTX-Pluronic mixed micelle can wrap and carry hydrophobic drug PTX simultaneously, has improved the drug loading of micellar system integral body.
Mixed micelle of the present invention is to be selected from Pluronic class material L35, L43, L44, L61, L62, L64, F68, L81, P84, P85, F87, F88, L92, F98, L101, P103, P104, P105, F108, L121, P123 and F127 be the mixed micelles of any one or two kinds and MTX-Pluronic preparation wherein, among the present invention, and preferred F68, L101, P104, P105, P123 or F127 be the mixed micelles of any one or two kinds and MTX-Pluronic preparation wherein.Described arbitrarily both quality is 0.01 than scope: 1-1: 100.
. among the present invention, prepare in the described MTX-Pluronic copolymer, adopt acetone, normal hexane and ether purification Pluronic, take anhydrous acetonitrile and anhydrous dimethyl sulphoxide as solvent, ethylenediamine; Carbonyl dimidazoles (CDI), N-hydroxyl-butanimide (NHS), N, N '-dicyclohexylcarbodiimide (DCC) is reaction reagent, lucifuge, room temperature, nitrogen protection, response time 4-12hr; Adopt dialysis and ultrafiltration to remove impurity.
The present invention adopts the standby MTX-Pluronic copolymer mixed micelle system of thin film aquation legal system: with MTX-Pluronic, Pluronic and insoluble drug are dissolved in the organic solvents such as methanol, acetonitrile, triethylamine, oxolane, ethanol or chloroform in proportion, after evaporated under reduced pressure is removed organic solvent, the water or the aqueous solution that add the pH scope 0.1-14 of 1-50ml, aquation, hydration temperature 40-70 ℃.
In one embodiment of the present of invention, prepare as follows MTX-Pluronic copolymer mixed micelle (MPF-PTX):
With a certain amount of PTX, P123, F127, F127-MTX, place round-bottomed flask, add the 5mL acetonitrile, it is fully dissolved, at 50 ℃ of lower rotary evaporation 40min, with the organic solvent evaporate to dryness, vacuum drying spends the night under the room temperature, adds the 5mL deionized water, constant speed stirs 30min in 60 ℃ of water-baths of 700rpm rotating speed, be cooled to room temperature, with 0.22 μ m acetyl cellulose membrane filtration, namely get the MTX-Pluronic copolymer mixed micelle (MPF-PTX) that carries PTX.
Among the present invention, described insoluble drug comprises hydrophobic drug paclitaxel (PTX) and Docetaxel (Docetaxel), also comprises the medicine that can be transformed into after treatment hydrophobic form, such as amycin (DOX) and doxorubicin hydrochloride.
Methotrexate of the present invention-pluronic copolymer mixed micelle has carried out experiment in vivo and vitro, experimental result shows: there is the competitive binding effect in MPF-PTX to folacin receptor, MTX-Pluronic copolymer mixed micelle has the targeting of reversion MDR effect and folacin receptor, and treatment multidrug resistance of tumor effect is more obvious; And the toxicity of MPF-PTX is little.
Description of drawings
Fig. 1: Pluronic F127 and MTX-Pluronic F127 polymer
1The H-NMR nuclear magnetic spectrum, the result shows and synthesizes successfully.
Fig. 2: Pluronic mixed micelle (PF-PTX) particle size distribution (A) and the form (C) of carrying PTX; The particle size distribution of MPF-PTX (B) form (D).
Fig. 3: the apoptosis of cells were tested by flow cytometry KBv cell,
As shown in the figure, negative control group nucleus rule rounding shows that apoptosis does not occur; Karyomorphism after the Taxol group is processed is compared substantially with negative control group and is not changed, and only individual cells is slight accordion; PF-PTX group parts of fine karyon is corrugated or is the crease sample, namely is in apoptotic early stage; And the cell after the MPF-PTX processing, the nuclear chromatin height cohesion of part, marginalisation, and have some nucleus to be cracked into fragment, produce apoptotic body, namely existing part cell is in apoptotic late period.
The folacin receptor blocking experiment result of Fig. 4: MPF-PTX,
Wherein show, for sensitive strain KB cell and the persister KBv cell of folacin receptor expressed in abundance, the equal significance of the picked-up of MPF-PTX is higher than free PTX, and more obvious for the effect of persister cell; Under the free folic acid existence condition of 1mM, the ingestion of medicines of MPF-PTX all significantly reduces (P＜0.01), show that there is the competitive binding effect in MPF-PTX to folacin receptor, MTX-Pluronic copolymer mixed micelle has the targeting of reversion MDR effect and folacin receptor.
Anti-KBv tumor effect in the body of Fig. 5: MPF-PTX,
Wherein, (a) anti-KBv tumor effect in the body of MPF-PTX; (b) subcutaneous lotus KBv tumor nude mice body weight temporal evolution; (c) tumor photo of each group the 22nd day the time; The tumor weight that takes out when (d) putting to death, * p＜0.05, * * p＜0.01, compared with Taxol (n=5).
Fig. 6: through the hepatic pathology tissue slice of h and E dyeing,
Wherein show: the MPF-PTX group is compared with the normal saline group does not have obvious toxic and side effects, illustrates that the carrier toxicity of MPF-PTX group is less.
Fig. 7: through the cancer pathology tissue slice of h and E dyeing,
Wherein show: normal saline group tumor cell is abundant, and nuclear is large, engrain, and out-of-shape has more karyokinesis phase; Behind different PTX preparation for treating, necrosis in various degree appears in tumor tissues, showing as tumor cell quantity reduces, the nuclear shrinkage, the area of pale red endochylema increases, MPF-PTX group tumor tissue necrosis area is maximum, and the result shows, MTX-Pluronic copolymer mixed micelle treatment tumor effect is remarkable.
The specific embodiment
Further specify technical scheme of the present invention by following embodiment, but protection scope of the present invention is not limited to this.
Synthetic Pluronic-MTX
1. synthesize Pluronic-CDI
At first carry out the purification of Pluronic: an amount of Pluronic is dissolved in acetone, and the normal hexane that then adds pre-cooling is separated out Pluronic, vacuum drying and get final product.Pluronic behind the 1mmol purification is dissolved in the 15mL anhydrous acetonitrile.In addition 10mmol carbonyl dimidazoles (CDI) is dissolved in the 15mL anhydrous acetonitrile, then with the acetonitrile solution of CDI under the nitrogen protection condition, in 2h, slowly be added drop-wise in the mentioned solution.After dropwising, reactant liquor continues to react at ambient temperature 4h.After reaction finished, reactant liquor was concentrated through rotary evaporation, and to remove unreacted CDI, collecting precipitation, vacuum drying namely get Pluronic-CDI with the ether sedimentation of pre-cooling three times.
2. synthesize Pluronic-NH
2
An amount of Pluronic-CDI is dissolved in the 15mL anhydrous acetonitrile.The 10mL ethylenediamine slowly is added drop-wise in 2h in the above-mentioned reactant liquor, and the room temperature magnetic agitation is spent the night.Rotary evaporation is removed excessive ethylenediamine, uses the ether sedimentation of pre-cooling to wash three times, and collecting precipitation, vacuum drying namely get Pluronic-NH
2
3. synthesize Pluronic-MTX
MTX: NHS: DCC=1 in molar ratio: be dissolved in 5mL anhydrous DMSO at 2.2: 2.2, add the 0.1mL triethylamine, nitrogen protection, room temperature magnetic agitation spend the night (A liquid).With 1g Pluronic-NH
2Be dissolved in the anhydrous DMSO of 5mL (B liquid), add the 0.1mL triethylamine again, and upper A liquid slowly is added dropwise to B liquid, magnetic agitation makes its mixing, nitrogen protection, and the room temperature magnetic agitation is spent the night.After the reaction, slowly drip the 20mL deionized water in reactant liquor, the centrifugal 15min of 12000rpm removes unreacted MTX and byproduct of reaction 1,3-Dicyclohexylurea (DCU).Get supernatant with deionized water lucifuge dialysis 2 days, change dialysis medium 3 times every day, then carry out ultrafiltration, lyophilization namely gets Pluronic-MTX.
The MTX-Pluronic copolymer mixed micelle of insoluble drug is carried in preparation:
Embodiment 1
Be P123: F127: F127-MTX=20 with PTX and mass ratio: 9: 1, place the 50mL round-bottomed flask, add the 5mL acetonitrile, it is fully dissolved, at 50 ℃ of lower rotary evaporation 40min, with the organic solvent evaporate to dryness, vacuum drying spends the night under the room temperature, add the 5mL deionized water, constant speed stirs 30min in 70 ℃ of water-baths of 700rpm rotating speed, is cooled to room temperature, with 0.22 μ m acetyl cellulose membrane filtration, namely get the Pluronic mixed micelle solution that MTX modifies, preserve after the lyophilizing.Recording particle diameter is 43.4 ± 3.1nm.
Embodiment 2
Be P105: F127: F127-MTX=100 with Docetaxel and mass ratio: 9: 1, place the 50mL round-bottomed flask, add 5mL methanol, it is fully dissolved, at 50 ℃ of lower rotary evaporation 40min, with the organic solvent evaporate to dryness, vacuum drying spends the night under the room temperature, add the 5mL deionized water, constant speed stirs 30min in 60 ℃ of water-baths of 700rpm rotating speed, is cooled to room temperature, with 0.22 μ m acetyl cellulose membrane filtration, namely get the Pluronic mixed micelle solution that MTX modifies, preserve after the lyophilizing.Recording particle diameter is 73.1 ± 1.1nm.
Embodiment 3
Be P105: F88: P123-MTX=1 with PTX and mass ratio: 100: 4, place the 100mL round-bottomed flask, add the 5mL acetonitrile, it is fully dissolved, at 50 ℃ of lower rotary evaporation 40min, with the organic solvent evaporate to dryness, vacuum drying spends the night under the room temperature, add the 50mL deionized water, constant speed stirs 30min in 40 ℃ of water-baths of 700rpm rotating speed, is cooled to room temperature, with 0.22 μ m acetyl cellulose membrane filtration, namely get the Pluronic mixed micelle solution that MTX modifies, preserve after the lyophilizing.Recording particle diameter is 84.2 ± 5.5nm.
Embodiment 4
Be P123: F68-MTX=10 with PTX and mass ratio: 1, place the 50mL round-bottomed flask, add the 5mL acetonitrile, it is fully dissolved, at 50 ℃ of lower rotary evaporation 40min, with the organic solvent evaporate to dryness, vacuum drying spends the night under the room temperature, add the 5mL deionized water, constant speed stirs 30min in 70 ℃ of water-baths of 700rpm rotating speed, is cooled to room temperature, with 0.22 μ m acetyl cellulose membrane filtration, namely get the Pluronic mixed micelle solution that MTX modifies, preserve after the lyophilizing.Recording particle diameter is 26.6 ± 2.7nm.
Embodiment 5
Be L64: F127: F127-MTX=15 with PTX and mass ratio: 9: 2, place the 50mL round-bottomed flask, add the 5mL acetonitrile, it is fully dissolved, at 50 ℃ of lower rotary evaporation 40min, with the organic solvent evaporate to dryness, vacuum drying spends the night under the room temperature, add the 5mL deionized water, constant speed stirs 30min in 70 ℃ of water-baths of 700rpm rotating speed, is cooled to room temperature, with 0.22 μ m acetyl cellulose membrane filtration, namely get the Pluronic mixed micelle solution that MTX modifies, preserve after the lyophilizing.Recording particle diameter is 120.1 ± 9.2nm.
Embodiment 6
Be L62: F68: P105-MTX=11 with PTX and mass ratio: 8: 2, place the 50mL round-bottomed flask, add the 5mL acetonitrile, it is fully dissolved, at 50 ℃ of lower rotary evaporation 40min, with the organic solvent evaporate to dryness, vacuum drying spends the night under the room temperature, add the 5mL deionized water, constant speed stirs 30min in 70 ℃ of water-baths of 700rpm rotating speed, is cooled to room temperature, with 0.22 μ m acetyl cellulose membrane filtration, namely get the Pluronic mixed micelle solution that MTX modifies, preserve after the lyophilizing.Recording particle diameter is 32.7 ± 8.3nm.
Embodiment 7
Be P105: P105-MTX=2 with PTX and mass ratio: 1, place the 50mL round-bottomed flask, add the 5mL acetonitrile, it is fully dissolved, at 50 ℃ of lower rotary evaporation 40min, with the organic solvent evaporate to dryness, vacuum drying spends the night under the room temperature, add the 5mL deionized water, constant speed stirs 30min in 70 ℃ of water-baths of 700rpm rotating speed, is cooled to room temperature, with 0.22 μ m acetyl cellulose membrane filtration, namely get the Pluronic mixed micelle solution that MTX modifies, preserve after the lyophilizing.Recording particle diameter is 39.2 ± 4.6nm.
Embodiment 8
Be L44: P84: P104-MTX=15 with DOX and mass ratio: 1: 100, place the 50mL round-bottomed flask, add the 5mL chloroform, it is fully dissolved, at 50 ℃ of lower rotary evaporation 40min, with the organic solvent evaporate to dryness, vacuum drying spends the night under the room temperature, add the 5mL deionized water, constant speed stirs 30min in 70 ℃ of water-baths of 700rpm rotating speed, is cooled to room temperature, with 0.22 μ m acetyl cellulose membrane filtration, namely get the Pluronic mixed micelle solution that MTX modifies, preserve after the lyophilizing.Recording particle diameter is 55.8 ± 3.8nm.
Embodiment 9
Be L92: F87: P105-MTX=10 with PTX and mass ratio: 8: 2, place the 50mL round-bottomed flask, add the 5mL oxolane, it is fully dissolved, at 50 ℃ of lower rotary evaporation 40min, with the organic solvent evaporate to dryness, vacuum drying spends the night under the room temperature, the sodium hydrate aqueous solution that adds 5mL pH=13, constant speed stirs 30min in 70 ℃ of water-baths of 700rpm rotating speed, is cooled to room temperature, with 0.22 μ m acetyl cellulose membrane filtration, namely get the Pluronic mixed micelle solution that MTX modifies, preserve after the lyophilizing.Recording particle diameter is 85.9 ± 7.7nm.
Be L101: F108: L101-MTX=10 with PTX and mass ratio: 7: 3, place the 50mL round-bottomed flask, add the 5mL acetonitrile, it is fully dissolved, at 50 ℃ of lower rotary evaporation 40min, with the organic solvent evaporate to dryness, vacuum drying spends the night under the room temperature, the aqueous hydrochloric acid solution that adds 5mL pH=1.0, constant speed stirs 30min in 70 ℃ of water-baths of 700rpm rotating speed, is cooled to room temperature, with 0.22 μ m acetyl cellulose membrane filtration, namely get the Pluronic mixed micelle solution that MTX modifies, preserve after the lyophilizing.Recording particle diameter is 95.8 ± 11.6nm.
Embodiment 11
Be L92: P103: P104-MTX=20 with PTX and mass ratio: 8: 3, place the 50mL round-bottomed flask, add 5mL ethanol, it is fully dissolved, at 50 ℃ of lower rotary evaporation 40min, with the organic solvent evaporate to dryness, vacuum drying spends the night under the room temperature, the phosphate solution that adds 1mL pH=6.5, constant speed stirs 30min in 70 ℃ of water-baths of 700rpm rotating speed, is cooled to room temperature, with 0.22 μ m acetyl cellulose membrane filtration, namely get the Pluronic mixed micelle solution that MTX modifies, preserve after the lyophilizing.Recording particle diameter is 66.3 ± 5.7nm.
The apoptosis of embodiment 12 cells were tested by flow cytometry KBv cells
Measure according to a conventional method the apoptosis of KBv cell, wherein add the negative contrast of blank RPMI RPMI-1640, the positive contrast of Taxol, PF-PTX is the mixed micelle of PluronicP123/F127, MPF-PTX is the PluronicP123/F127 mixed micelle that MTX modifies; The result as shown in Figure 3, negative control group nucleus rule rounding shows that apoptosis does not occur; Karyomorphism after the Taxol group is processed is compared substantially with negative control group and is not changed, and only individual cells is slight accordion; PF-PTX group parts of fine karyon is corrugated or is the crease sample, namely is in apoptotic early stage; And the cell after the MPF-PTX processing, the nuclear chromatin height cohesion of part, marginalisation, and have some nucleus to be cracked into fragment, produce apoptotic body, namely existing part cell is in apoptotic late period.
The folacin receptor blocking experiment of embodiment 13MPF-PTX
For the folacin receptor blocking experiment that sensitive strain KB cell and the persister KBv cell of folacin receptor expressed in abundance carries out MPF-PTX, the result as shown in Figure 4, the equal significance of the picked-up of MPF-PTX is higher than free PTX, and more obvious for the effect of persister cell; Under the free folic acid existence condition of 1mM, the ingestion of medicines of MPF-PTX all significantly reduces (P＜0.01), show that there is the competitive binding effect in MPF-PTX to folacin receptor, MTX-Pluronic copolymer mixed micelle has the targeting of reversion MDR effect and folacin receptor.
Anti-KBv tumor test in the body of embodiment 14MPF-PTX
Carry out according to a conventional method the interior anti-KBv tumor test of body of MPF-PTX, observe the interior anti-KBv tumor effect of body of (a) MPF-PTX; (b) subcutaneous lotus KBv tumor nude mice body weight temporal evolution; (c) tumor photo of each group the 22nd day the time; The tumor weight that takes out when (d) putting to death; The result compares with the Taxol group as shown in Figure 5, and PF-PTX group and MPF-PTX organize the 22nd day gross tumor volume all significantly less than Taxol group (P＜0.05), show that two kinds of mixed micelle preparations all have therapeutic effect to the Subcutaneous tumor of KBv mdr cell inoculation; After putting to death mice on the 22nd day, gross tumor volume and the tumor weight of Taxol group, PF-PTX group and MPF-PTX group are respectively (1590.9 ± 276.7mm
31.64 ± 0.26g), (1195.9 ± 166.7mm
31.17 ± 0.10g) and (751.7 ± 122.2mm
30.71 ± 0.17g) all have between any two a significant difference (P＜0.01); The tumour inhibiting rate of MPF-PTX group and PF-PTX group is respectively 3 times and 2 times of Taxol group, shows that the antitumous effect of the Pluronic micelle group that MTX modifies is better than modifying Pluronic micelle group without MTX, and treatment multidrug resistance of tumor effect is more obvious; The body weight change curve shows, the body weight of MPF-PTX group confirms that without significant change the toxicity of MPF-PTX group is little.
Claims (7)
1. carry the methotrexate of insoluble drug-pluronic copolymer mixed micelle, it is characterized in that, be connected by chemistry with methotrexate MTX by pluronic Pluronic, after the hydroxyl of Pluronic one or both ends activates into amino, after obtaining the MTX-Pluronic copolymer with the carboxyl reaction of MTX, mix with pluronic Pluronic class material, make methotrexate MTX-pluronic Pluronic copolymer mixed micelle system, the hydrophobic core of described mixed micelle, bag carries insoluble drug.
2. by the methotrexate of claimed in claim 1 year insoluble drug medicine-pluronic copolymer mixed micelle, it is characterized in that, described pluronic Pluronic class material is selected from: L35, L43, L44, L61, L62, L64, F68, L81, P84, P85, F87, F88, L92, F98, L101, P103, P104, P105, F108, L121, P123 or F127.
3. by the methotrexate of claimed in claim 2 year insoluble drug medicine-pluronic copolymer mixed micelle, it is characterized in that, described pluronic Pluronic class material is selected from F68, L101, P104, P105, P123 or F127.
4. by the methotrexate of claimed in claim 3 year insoluble drug medicine-pluronic copolymer mixed micelle, it is characterized in that, described mixed micelle is F68, L101, P104, P105, the mixed micelles of any one or two kinds and the preparation of MTX-Pluronic copolymer among P123 or the F127, described both quality is 0.01 than scope: 1-1: 100.
5. by the methotrexate of claimed in claim 1 year insoluble drug medicine-pluronic copolymer mixed micelle, it is characterized in that, in the described MTX-Pluronic copolymer preparation, adopt acetone, normal hexane and ether purification Pluronic, take anhydrous acetonitrile and anhydrous dimethyl sulphoxide as solvent, ethylenediamine; Carbonyl dimidazoles (CDI), N-hydroxyl-butanimide (NHS), N, N '-dicyclohexylcarbodiimide (DCC) is reaction reagent, lucifuge, room temperature, nitrogen protection, response time 4-12hr; Remove impurity with dialysis and ultrafiltration.
6. the preparation method of the methotrexate of carrying the insoluble drug medicine of claim 1-pluronic copolymer mixed micelle, it is characterized in that, adopt thin film aquation method, it comprises step: with the MTX-Pluronic copolymer, pluronic Pluronic class material and insoluble drug are dissolved in methanol in proportion, acetonitrile, triethylamine, oxolane, in ethanol or the chloroform organic solvent, after evaporated under reduced pressure is removed organic solvent, the water or the aqueous solution that add the pH scope 0.1-14 of 1-50ml, aquation is made MTX-Pluronic copolymer mixed micelle system for hydration temperature 40-70 ℃.
7. by the methotrexate of claimed in claim 1 year insoluble drug medicine-pluronic copolymer mixed micelle, it is characterized in that, described insoluble drug comprises hydrophobic drug paclitaxel, Docetaxel or can be transformed into after treatment medicine amycin or the doxorubicin hydrochloride of hydrophobic form.
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| CN104208707A (en) * | 2014-09-02 | 2014-12-17 | 中国人民解放军第二军医大学 | Preparation method of folic acid modified Pluronic P85 copolymer and application of folic acid modified Pluronic P85 copolymer in 5-fluorouracil nano drug |
| CN109200288A (en) * | 2018-09-14 | 2019-01-15 | 哈尔滨医科大学 | Application of the MSH3 protein inhibitor in the drug that preparation reverses MTX cells of resistant tumors drug resistance |
| CN109289051A (en) * | 2018-09-14 | 2019-02-01 | 哈尔滨医科大学 | Application of the MSH2 inhibitor in the drug that preparation reverses MTX cells of resistant tumors drug resistance |
| CN109289051B (en) * | 2018-09-14 | 2021-01-08 | 哈尔滨医科大学 | Application of MSH2 inhibitor in preparation of medicine for reversing drug resistance of MTX-resistant tumor cells |
| CN109200288B (en) * | 2018-09-14 | 2021-05-18 | 哈尔滨医科大学 | Application of MSH3 protein inhibitor in preparation of medicine for reversing drug resistance of MTX-resistant tumor cells |
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