CN101181225A - System for transferring nanometer polyalcohol micelle medicament and preparing method as well as application thereof - Google Patents
System for transferring nanometer polyalcohol micelle medicament and preparing method as well as application thereof Download PDFInfo
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Abstract
The invention relates to a nano-polymer micellar drug delivery system for transferring an anti-cancer drug in cells and the preparation method and application thereof. The invention pertains to the fields of biomedical materials and nano-technology. The delivery system includes a nano-polymer micellar carrier and the anti-cancer drug which is enveloped in the nano-polymer micellar carrier, that is, the endogenous biological molecule is modified on the low generation polyamidoamine dendrimer, so as to prepare the nano-polymer micellar drug delivery system. The invention adopts the low generation polyamidoamine dendrimer and can obtain the polymer micellar with the particle size of about 100nm by carrying out simple surface modification to the the low generation polyamidoamine dendrimer. The experiments prove that the micellar has very good drug delivery function in cells for anti-cancer drug. The invention avoids a plurality of synthesis and follow-up purifying works which are needed in the preparation of high generation polyamidoamine dendrimer and replaced with the drug delivery system with simple preparation and small toxicity and side effects in biological bodies. The invention can be used for the treatment of cancers.
Description
[technical field] the present invention relates to bio-medical material and field of nanometer technology, particularly relates to a kind of preparation method that is used for transmitting in the cell transmission system (system for transferring nanometer polyalcohol micelle medicament) of cancer therapy drug.
[background technology] is current, and malignant tumor has become the second largest disease that causes human death.Clinical is main treatment means with excision, combined chemotherapy, immunization therapy and radiotherapy etc., and wherein independent the or use in conjunction of radiation and chemotherapy has significantly improved the therapeutic effect of malignant tumor.
Most radiotherapy and chemotherapy medicine effectively also can destroy normal histiocyte in the killing tumor cell.For targeting that improves medicine and the toxicity that reduces medicine, polymer micelle has caused people's extensive interest as pharmaceutical carrier, the polymer micelle medicine carrying scope is wide, Stability Analysis of Structures, to have in good tissue permeability, the body holdup time long, can make medicine arrive target spot effectively, and particle diameter is less, characteristic with nano material is a kind of very potential pharmaceutical carrier.Comparatively speaking, the micromolecule surfactant forms micellar thermodynamic stability not as polymer micelle, thereby its use is restricted.In recent years, the existing extensive studies of the application of amphipathic nature polyalcohol micelle volume aspect drug delivery.These polymer micelles generally are made up of homopolymer or copolymer.The molecular weight of polymer is bigger, in vivo must be earlier through progressively degradation process energy metabolism, and the catabolite of some polymer can produce new toxic and side effects to human body.
Dendritic (Dendrimer) is current just at a flourish class three-dimensional, the novel synthetic polymer of high-sequential.It structurally has the geometrical symmetry of height, molecular structure, a large amount of surface functional group, molecular memories increase characteristics such as having controllability at cavity and strand accurately.Compare with traditional polymer: the dendritic monodispersity is good, and molecular dimension and surface chemistry can be controlled in building-up process fully.Drug molecule is bonded to behind the cavity of polymer inside or the polymer surfaces and can realizes sustained release to drug molecule by diffusion and Degradation.Therefore, dendritic is a kind of very potential pharmaceutical carrier, and the lot of domestic and international research group is all being carried out the research work of this respect at present.
(polyamidoamine is to study comparatively extensively and sophisticated a kind of dendritic PAMAM) to polyamide-amide type dendritic, and commercial product has been arranged now.The polymer that adopt more than 6 generations when being applied to pharmaceutical carrier, this base polymer end group number is many, the drug loading height more.But high loaded down with trivial details for polymer manufacture, toxicity is relatively large and cost an arm and a leg (6 generation polyamide-amide type dendritic price approximately be 6.6 times of 1 generation).The PAMAM molecular weight of low algebraically is lower, and easily by body metabolism, toxicity is very little.But separately as pharmaceutical carrier the time, exist the shortcoming that molecular weight is low, molecular dimension is little, limited the application of low algebraically PAMAM self as pharmaceutical carrier.
[summary of the invention] the objective of the invention is to solve the low problem that can not use separately as pharmaceutical carrier for dendritic.A kind of system for transferring nanometer polyalcohol micelle medicament and preparation method and application thereof are provided.
The system for transferring nanometer polyalcohol micelle medicament that is used for transmitting in the cell cancer therapy drug provided by the invention, comprise nanometer polymer micelle carrier and the cancer therapy drug that is encapsulated in wherein, wherein said nanometer polymer micelle carrier is by following (a) and (b) dimerous: (a) dendritic macromole, wherein said dendritic macromole is a polyamide-amide type dendritic, (b) be connected biomolecule aglucon on the dendritic macromole, wherein said biomolecule aglucon is cholic acid, cholesterol, tryptophan, phenylalanine.
Described polyamide-amide type dendritic is the polyamide-amide type dendritic in 1-5 generation (preferred 1-3 generation).
The mol ratio of biomolecule aglucon and polyamide-amide type dendritic is 1: 1-8: 1.
A kind of preparation method of above-mentioned system for transferring nanometer polyalcohol micelle medicament, through following steps:
The first, the preparation of polyamide-amide type dendritic:
With the ethylenediamine is nuclear, carries out the Michael additive reaction with acrylic acid methyl ester., gets addition compound product; Make amidated products with ethylenediamine through amidation process more afterwards.Detailed process is:
Acrylic acid methyl ester. is added in the methanol solution of ethylenediamine, reacted 24 hours, obtain behind the purification-0.5 generation polyamide-amide type dendritic; With above-mentioned-0.5 generation product be added in the methanol solution of ethylenediamine, reacted 60 hours.Obtain behind the purification 0 generation polyamide-amide type dendritic.
Repeat above step, can obtain 1-5 for polyamide-amide type dendritic.
Wherein, charge temperature is 0 ℃, and reaction temperature is 20-25 ℃, and the mol ratio of addition compound product and ethylenediamine is 1: 18, and the mol ratio of amidated products and acrylic acid methyl ester. is 1: 2;
The second, the preparation of biomolecule modification polyamide-amide type dendritic:
Add N-hydroxy-succinamide and N in cholic acid solution, the N-dicyclohexylcarbodiimide reacted 24 hours, got the cholic acid Acibenzolar after the purification.The cholic acid activated ester solution is joined in the polyamide-amide type dendritic solution that makes of step, reacted 24 hours, obtain the polyamide-amide type dendritic of cholic acid molecular modification behind the purification;
Perhaps,
Add N-hydroxy-succinamide and N in tryptophan solution, the N-dicyclohexylcarbodiimide reacted 24 hours, got the tryptophan Acibenzolar after the purification.The tryptophan activated ester solution is joined in the polyamide-amide type dendritic solution that makes of step, reacted 24 hours, obtain the polyamide-amide type dendritic of tryptophan molecular modification behind the purification;
Perhaps,
Add N-hydroxy-succinamide and N in phenylalanine solution, the N-dicyclohexylcarbodiimide reacted 24 hours, got the phenylalanine Acibenzolar after the purification.The phenylalanine activated ester solution is joined in the polyamide-amide type dendritic solution that makes of step, reacted 24 hours, obtain the polyamide-amide type dendritic of phenylalanine molecular modification behind the purification;
Perhaps,
The chloro-carbonic acid cholesteryl ester is joined in the polyamide-amide type dendritic solution that makes of step, react 24 hours, obtain the polyamide-amide type dendritic of cholesterol modification behind the purification;
Three, the preparation of system for transferring nanometer polyalcohol micelle medicament:
Cancer therapy drug is joined in the polyamide-amide type dendritic solution that goes on foot the biomolecule modification that makes, obtain system for transferring nanometer polyalcohol micelle medicament.
A kind of above-mentioned system for transferring nanometer polyalcohol micelle medicament transmits cancer therapy drug in cell application:
With the above-described system for transferring nanometer polyalcohol micelle medicament that is encapsulated with cancer therapy drug and cells contacting so that described cancer therapy drug be passed in the described cell.
Described cancer therapy drug is methotrexate, camptothecine.
Described cell is 3T3, HepG2 and Hela.
Advantage of the present invention and beneficial effect:
The present invention adopts low for polyamide-amide type dendritic, by it is carried out simple finishing, can obtain the polymer micelle about particle diameter 100nm.Experimental results show that this micelle has good cell delivery effect to cancer therapy drug.The present invention has avoided preparing height for the required a large amount of synthetic and subsequent purification work of polyamide-amide type dendritic, and this drug delivery system prepares simply, and toxic and side effects in vivo is little.Can be used for treatment for cancer.
The present invention has following advantage compared with the prior art:
1. drug prepared carrier of the present invention can improve the cell transmission capacity to cancer therapy drug;
2. the prepared polymer micelle of the present invention does not have organic solvent;
3. drug prepared carrier toxicity of the present invention is little, and catabolite is nontoxic;
4. drug prepared preparing carriers of the present invention is simple, with low cost, is easy to apply.
[description of drawings]
The micellar transmission electron microscope picture that the polyamide-amide type dendritic that Fig. 1 modifies for cholic acid of the present invention forms;
The micellar cytotoxicity experiment result of polyamide-amide type dendritic that Fig. 2 modifies for cholic acid of the present invention, used cell is the 3T3 cell;
At intracellular transmission effect, used cell is the HepG2 cell to the polyamide-amide type dendritic micelle that Fig. 3 modifies for cholic acid of the present invention to methotrexate;
At intracellular transmission effect, used cell is the Hela cell to the polyamide-amide type dendritic micelle that Fig. 4 modifies for cholic acid of the present invention to camptothecine.
[specific embodiment]
Embodiment 1.
The first, the ethylenediamine of 108ml acrylic acid methyl ester. and 9.8ml reacted in methanol 24 hours.Distilling under reduced pressure removes desolvates and remaining raw material, obtain-0.5 generation polyamide-amide type dendritic.Afterwards again in methanol with big excessive reacting ethylenediamine, distilling under reduced pressure removes desolvates and remaining raw material, obtain 0 generation polyamide-amide type dendritic.Repeat above operation, can obtain 1 generation polyamide-amide type dendritic.
The second, 1g N-hydroxy-succinamide, 1.5g DCC, 3g cholic acid are joined in the solution of being made up of 100ml oxolane and 15ml acetonitrile room temperature reaction 24 hours.Reactant mixture is removed by filter two cyclohexyl ureas, use saturated sodium bicarbonate solution, saturated nacl aqueous solution, water washing successively, purify with silica gel column chromatography behind the vacuum drying, get Acibenzolar.
The 0.30g Acibenzolar is joined in the DMF solution that contains 0.43g 1 generation polyamide-amide type dendritic.Room temperature reaction 24 hours.Reactant liquor is poured in the 30ml distilled water, obtained white emulsion,, separate out solid to the sodium hydroxide solution that wherein adds 4%.Solid is washed till neutrality with distilled water, the washing of reuse oxolane.With 30ml dissolve with methanol solid, added anhydrous magnesium sulfate drying 24 hours, be spin-dried for solution, obtain the polyamide-amide type dendritic that the 0.11g cholic acid is modified.
Embodiment 2.
With embodiment 1 synthetic 1 generation polyamide-amide type dendritic and Acibenzolar.
The 0.45g Acibenzolar is joined in the absolute methanol solution that contains 0.33g 1 generation polyamide-amide type dendritic.Reaction is 24 hours under the room temperature.Then reactant liquor is spin-dried for, again water, alkali liquor, oxolane washing.Get the polyamide-amide type dendritic white solid 0.47g that cholic acid is modified.
Embodiment 3.
With embodiment 1 synthetic 1 generation polyamide-amide type dendritic and Acibenzolar.
The 0.37g Acibenzolar is joined in the absolute methanol solution that contains 0.53g 1 generation polyamide-amide type dendritic.Reaction is 48 hours under the room temperature.Then reactant liquor is put into the bag filter purification of dialysing.Distillation obtains the polyamide-amide type dendritic that the 0.73g cholic acid is modified after removing and desolvating.
Embodiment 4.
With embodiment 1 synthetic 1 generation polyamide-amide type dendritic and Acibenzolar.
The 0.45g Acibenzolar is joined in the absolute methanol solution that contains 0.33g 1 generation polyamide-amide type dendritic.Reaction is 48 hours under the room temperature.Then reactant liquor is put into the bag filter purification of dialysing.Distillation obtains the polyamide-amide type dendritic that the 0.68g cholic acid is modified after removing and desolvating.
Embodiment 5.
With embodiment 1 synthetic 3 generation polyamide-amide type dendritic and Acibenzolar.
The 0.22g Acibenzolar is joined in the absolute methanol solution that contains 0.38g 3 generation polyamide-amide type dendritic.Room temperature reaction dialyse after 48 hours purification, drying obtain the polyamide-amide type dendritic that white solid 0.56g cholic acid is modified.
Embodiment 6.
With embodiment 1 synthetic 1 generation polyamide-amide type dendritic.
0.07g N-hydroxy-succinamide and 0.13g DCC are joined in the DMF solution that contains the 0.10g phenylalanine stirring at room 6 hours.Above-mentioned solution is joined in the DMF solution that contains 0.43g 1 generation polyamide-amide type dendritic.Reaction is 72 hours under the room temperature.Add ether, centrifugal, precipitate dialysis purification obtains the polyamide-amide type dendritic that phenylalanine is modified after the drying.
Embodiment 7.
With embodiment 1 synthetic 1 generation polyamide-amide type dendritic.
0.07g N-hydroxy-succinamide and 0.13g DCC are joined in the DMF solution that contains the 0.123g tryptophan stirring at room 6 hours.Above-mentioned solution is joined in the DMF solution that contains 0.43g 1 generation polyamide-amide type dendritic.Reaction is 72 hours under the room temperature.Add ether, centrifugal, precipitate dialysis purification obtains the polyamide-amide type dendritic that tryptophan is modified after the drying.
Embodiment 8.
With embodiment 1 synthetic 1 generation polyamide-amide type dendritic.
0.27g chloro-carbonic acid cholesteryl ester is joined in the DMF solution that contains 0.1ml triethylamine and 0.43g 1 generation polyamide-amide type dendritic.Reaction is 24 hours under the room temperature.Add ether, centrifugal, precipitate dialysis purification obtains the polyamide-amide type dendritic that cholesterol is modified after the drying.
Embodiment 9.
Polyamide-amide type dendritic with embodiment 3 synthetic cholic acid modifications.Compound concentration is that (the room temperature vibration obtains polymer micelle for 15mM, pH=7.4) solution for the Tris-HCl of the polyamide-amide type dendritic modified of the cholic acid of 0.5mg/ml.
Embodiment 10.
Polyamide-amide type dendritic with embodiment 4 synthetic cholic acid modifications.Compound concentration is that (65 ℃ of water-baths vibration 3h obtain polymer micelle for 15mM, pH=7.4) solution for the Tris-HCl of the polyamide-amide type dendritic modified of the cholic acid of 0.5mg/ml.Micellar particle diameter is about 100nm.The results are shown in accompanying drawing 1.
Embodiment 11.
Dispose the polyamide-amide type dendritic micellar solution of the cholic acid modification of variable concentrations with embodiment 10.Filtration sterilization.25mg Thiazolyl blue (MTT) is dissolved among the 5ml PBS, and MTT solution is made in filtration sterilization.
With 3T3 cell kind in 96 orifice plates, every hole 100 μ l, about 104 cells are cultivated 24h, the polyamide-amide type dendritic micellar solution 100 μ l that the cholic acid of the variable concentrations that is disposed above adding is then modified, cultivation 24h is continued in every group of three holes.
Every hole adds 10 μ l MTT solution, continues to cultivate 4h, and the liquid in the last sucking-off hole is washed several times with PBS, adds the DMSO of 150 μ l, lucifuge concussion 10min.Microplate reader detects, and records the in vitro toxicity of polymer micelle: do not have toxicity at 100 μ g/ml and when following, the results are shown in accompanying drawing 2.
Embodiment 12.
Polyamide-amide type dendritic with embodiment 4 synthetic cholic acid modifications.With DMEM culture medium obtain solution, wherein the polyamide-amide type dendritic concentration of cholic acid modification is 100 μ g/ml, and the concentration of methotrexate is 50 μ g/ml.
With HepG2 cell kind in 96 orifice plates, every hole 100 μ l, about 10
4Individual cell is cultivated 24h, adds above-mentioned solution 100 μ l then, and 24h is continued to cultivate in every group of three holes.
Every hole adds 10 μ l MTT solution, cultivates 4h, with the DMSO of PBS washing back adding 150 μ l, and lucifuge concussion 10min.Microplate reader detects, and records the cell transmission effect of polymer micelle to methotrexate: can make the drug effect of methotrexate improve about 24.7%.The results are shown in accompanying drawing 3.
Embodiment 13.
Polyamide-amide type dendritic with embodiment 4 synthetic cholic acid modifications.With DMEM culture medium obtain solution, wherein the polyamide-amide type dendritic concentration of cholic acid modification is 100 μ g/ml, and the concentration of camptothecine is 8 μ g/ml.
With Hela cell kind in 96 orifice plates, every hole 100 μ l, about 10
4Individual cell is cultivated 24h, adds above-mentioned solution 100 μ l then, and 24h is continued to cultivate in every group of three holes.
Every hole adds 10 μ l MTT solution, cultivates 4h, with the DMSO of PBS washing back adding 150 μ l, and lucifuge concussion 10min.Microplate reader detects, and records the cell transmission effect of polymer micelle to camptothecine: make the drug effect of camptothecine improve 36.3%.The results are shown in accompanying drawing 4.
Claims (9)
1. one kind is used for the interior system for transferring nanometer polyalcohol micelle medicament that transmits cancer therapy drug of cell, it is characterized in that comprising nanometer polymer micelle carrier and the cancer therapy drug that is encapsulated in wherein, wherein said nanometer polymer micelle carrier is by following (a) and (b) dimerous: (a) dendritic macromole, wherein said dendritic macromole is a polyamide-amide type dendritic, (b) be connected biomolecule aglucon on the dendritic macromole, wherein said biomolecule aglucon is cholic acid, cholesterol, tryptophan or phenylalanine.
2. system for transferring nanometer polyalcohol micelle medicament according to claim 1 is characterized in that the mol ratio of biomolecule aglucon and polyamide-amide type dendritic is 1: 1-8: 1.
3. system for transferring nanometer polyalcohol micelle medicament according to claim 1 is characterized in that polyamide-amide type dendritic is that 1-5 is for product.
4. system for transferring nanometer polyalcohol micelle medicament according to claim 3 is characterized in that polyamide-amide type dendritic is preferably 1-3 for product.
5. the preparation method of the described system for transferring nanometer polyalcohol micelle medicament of claim 1 is characterized in that this method is through following steps:
The first, the preparation of polyamide-amide type dendritic:
With the ethylenediamine is nuclear, carries out the Michael additive reaction with acrylic acid methyl ester., gets addition compound product; Afterwards again with ethylenediamine through amidation process, amidated products, detailed process is:
Acrylic acid methyl ester. is added in the methanol solution of ethylenediamine, reacted 24 hours, obtain behind the purification-0.5 generation polyamide-amide type dendritic; With above-mentioned-0.5 generation product be added in the methanol solution of ethylenediamine, reacted 60 hours, obtain behind the purification 0 generation polyamide-amide type dendritic;
Repeat above step, can obtain 1-5 for polyamide-amide type dendritic wherein, charge temperature is 0 ℃, and reaction temperature is 20-25 ℃, and the mol ratio of addition compound product and ethylenediamine is 1: 18, and the mol ratio of amidated products and acrylic acid methyl ester. is 1: 2;
The second, the preparation of the polyamide-amide type dendritic of biomolecule modification:
Add N-hydroxy-succinamide and N in cholic acid solution, the N-dicyclohexylcarbodiimide reacted 24 hours, got the cholic acid Acibenzolar after the purification; The cholic acid activated ester solution is joined in the polyamide-amide type dendritic solution that makes of step, reacted 24 hours, obtain the polyamide-amide type dendritic of cholic acid molecular modification behind the purification;
Perhaps,
Add N-hydroxy-succinamide and N in tryptophan solution, the N-dicyclohexylcarbodiimide reacted 24 hours, got the tryptophan Acibenzolar after the purification; The tryptophan activated ester solution is joined in the polyamide-amide type dendritic solution that makes of step, reacted 24 hours, obtain the polyamide-amide type dendritic of tryptophan molecular modification behind the purification;
Perhaps,
Add N-hydroxy-succinamide and N in phenylalanine solution, the N-dicyclohexylcarbodiimide reacted 24 hours, got the phenylalanine Acibenzolar after the purification; The phenylalanine activated ester solution is joined in the polyamide-amide type dendritic solution that makes of step, reacted 24 hours, obtain the polyamide-amide type dendritic of phenylalanine molecular modification behind the purification;
Perhaps,
The chloro-carbonic acid cholesteryl ester is joined in the polyamide-amide type dendritic solution that makes of step, react 24 hours, obtain the polyamide-amide type dendritic of cholesterol modification behind the purification;
Three, the preparation of system for transferring nanometer polyalcohol micelle medicament:
Cancer therapy drug is joined in the polyamide-amide type dendritic solution that goes on foot the biomolecule modification that makes, obtain system for transferring nanometer polyalcohol micelle medicament.
6. preparation method according to claim 5 is characterized in that: in the amidation process in above-mentioned whole generation half methanol solution for the dendritic reactant is added drop-wise in the methanol solution of ethylenediamine.
7. the described system for transferring nanometer polyalcohol micelle medicament of claim 1 transmits cancer therapy drug in cell application is characterized in that: with the described system for transferring nanometer polyalcohol micelle medicament that is encapsulated with cancer therapy drug of claim 1 and cells contacting so that described cancer therapy drug be passed in the described cell.
8. application according to claim 7 is characterized in that described cancer therapy drug is methotrexate, camptothecine.
9. according to claim 7 or 8 described application, it is characterized in that described cell is 3T3, HepG2 and Hela.
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Cited By (7)
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| CN102429870A (en) * | 2011-12-21 | 2012-05-02 | 中国药科大学 | Novel tumor-targeting arboraceous polymer nano carrier of camptothecin drug |
| CN102973513A (en) * | 2012-12-27 | 2013-03-20 | 南开大学 | Intelligent nano-medicament delivery system and preparation method and application thereof |
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| CN101039620A (en) * | 2004-08-25 | 2007-09-19 | 密执安州立大学董事会 | Dendrimer based compositions and methods of using the same |
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| CN102429870A (en) * | 2011-12-21 | 2012-05-02 | 中国药科大学 | Novel tumor-targeting arboraceous polymer nano carrier of camptothecin drug |
| CN103509193A (en) * | 2012-06-30 | 2014-01-15 | 中国石油化工股份有限公司 | Preparation method of polyamide-amine dendritic compound |
| CN103509193B (en) * | 2012-06-30 | 2017-11-24 | 中国石油化工股份有限公司 | A kind of preparation method of daiamid dendrimer |
| CN102973513A (en) * | 2012-12-27 | 2013-03-20 | 南开大学 | Intelligent nano-medicament delivery system and preparation method and application thereof |
| CN103242517A (en) * | 2013-05-17 | 2013-08-14 | 中国药科大学 | Preparation of multifunctional linear-dendritic segmented copolymer and application in pharmaceutics thereof |
| CN109206614A (en) * | 2017-07-05 | 2019-01-15 | 大连医科大学 | A kind of reagent and its preparation method and application of the detection containing sugar chain biomolecule |
| CN109206614B (en) * | 2017-07-05 | 2020-10-16 | 大连医科大学 | Reagent for detecting sugar chain-containing biomolecule and preparation method and application thereof |
| CN107510849A (en) * | 2017-08-16 | 2017-12-26 | 暨南大学 | A kind of glutathione response type dual drug carrier and its preparation method and application |
| CN107510849B (en) * | 2017-08-16 | 2020-02-07 | 暨南大学 | Glutathione response type dual drug carrier and preparation method and application thereof |
| CN109456490A (en) * | 2018-10-23 | 2019-03-12 | 青岛大学 | A kind of preparation method and product of dendritic macromole hydrogel |
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