CN101245147B - Composition and synthesizing process for biodegradable amphiphilic polyphosphazenes as dewatering medicament nano-preparations carrier - Google Patents
Composition and synthesizing process for biodegradable amphiphilic polyphosphazenes as dewatering medicament nano-preparations carrier Download PDFInfo
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Abstract
The invention discloses the composition and the synthesis method of a biodegradable amphiphatic polyphosphazene which is taken as a nano carrier for hydrophobic medicament. The chemical structure of polyphosphazene is shown by the figure, wherein: R1 is equal to H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2; R2 is equal to H, CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, CH2CH2CH2SCH3, CH2C6H5, formula (I), formula (II); R is equal to CH3, CH2CH3, CH2CH2CH3; n is equal to 8-800; m is equal to 8-500; x is equal to1.9-0.1, and y is equal to 0.1-1.9. The invention also relates to the synthesis method of the polyphosphazene.
Description
Technical field
The present invention relates to a kind of composition and synthetic method thereof of the biodegradable amphiphilic polyphosphazenes as dewatering medicament nano-preparations carrier.
Background technology
Cancer is one of persistent ailment that threatens at present human health, and cardiovascular and cerebrovascular diseases causes the first cause of disease of mankind nowadays death especially
1,2Based on the chemotherapy of Nanoparticulate formulations is the most effective one of means in the cancer drug treatment, then is to enjoy to pay attention to and the research direction of expectation based on the new therapy of the cardiovascular and cerebrovascular diseases of Nanoparticulate formulations
3,4The polymer micelle administration system is because its good physicochemical performance and cylinder therapeutic effect are the focuses that at present domestic and international cancer therapy drug, cardiovascular and cerebrovascular diseases drug targeting nanometer are transmitted study on the carrier
5,6
The applying nano technology is treated, diagnoses, is detected and control biosystem and is called " nanosecond medical science " by NIH (national sanitary office) recently.Nanosecond medical science is a very huge subject, and it comprises bionic nano grain (for example functionalized nano carbon pipe), " nano-machines " (for example assembly that forms by tradable DNA chain or polyhedron DNA support), as the nanofiber of biomaterial and polymer nanocomposite assembly (for example molecule self-assembly and used in tissue engineering polypeptide, polypeptide amphiphile nanofiber, shape-memory polymer as molecular switch, nano-porous films), little operated implement of nanoscale (silicon microchip of useful for drug delivery, single-crystal-silicon micro mechanical hollow needle and two-dimentional pin array), transmitter and laboratory diagnosis device
7In addition, many noticeable nanoparticle technology are arranged still, adopt these means can the targeted delivery medicine, genetic material (as plasmid DNA, oligonucleotide and siRNA) and diagnostic reagent arrive different cells and extracellular matrix in the body.Undoubtedly, designing and prepare that effective nano-carrier transmits with targeted drug, therapeutical agent and diagnostic reagent is the field, forward position of nanosecond medical science research.This accurate target spot (cell and acceptor) and suitable nano-carrier of selection that comprises that identification is relevant with clinical treatment reaches needed response, and reduces side effect simultaneously to minimum degree.Mononuclear phagocyte, dendritic cell, endotheliocyte and tumour (tumour cell and tumour neovascularity) are main target spots.
After administration nano-drug administration system can improve parenteral administration such as polymkeric substance-medicine key compound, liposome or other nano-carriers based on polymkeric substance, the pharmacological characteristics of medicine or result of treatment
5Along with the successful exploitation of many liposome anticancer preparations and polymkeric substance-medicine key compound administration nano-drug administration system, and use clinically, the problem of many early stage obstruction administration nano-drug administration system exploitations solves
5In addition, the special performance of expanding administration nano-drug administration system is used to transmit medicine of new generation and the biologically active substance that obtains based on proteomics and genetics research, also is the focus of studying both at home and abroad at present
8Aspect the treating cardiovascular disease medicine, someone has prepared poly-(lactide-co-glycolide) that load has a t-PA (PLGA) nanoparticle, and at its surface applied chitosan (Chitosan), in vitro study shows that such nanoparticle can quicken thrombolysis, and the level of raising being controlled Treatment embolic cardiovascular and cerebrovascular diseases is significant
9
Polymer micelle is that targeted drug transmits the nano-carrier that the field is looked at by the researchist parent most in recent years
10As super-molecule assembling body, copolymer micelle is formed through spontaneous assembling in the aqueous solution by amphipathic copolymer, and it has typical nucleocapsid structure, wherein has the nuclear of the shell parcel carrying medicament of good biocompatibility.Polymer micelle is proposed in 1984 by people such as Ringsdorf the earliest first as the conception of drug carrier system, and they have also carried out preliminary study simultaneously
11Shortly after that two groups of Kataoka and Kabanov have independently carried out the further investigation of relevant polymer micelle administration nano-drug administration system respectively
12,13The former has designed and synthesized polyoxyethylene glycol-block-poly-(L-aspartic acid) (PEG-b-PAsp), and wherein the PAsp paragraph key has closed Zorubicin, has prepared the polymer micelle of particle diameter 50nm size with this, and its physical and chemical performance has been carried out detailed sign.On this basis, be embedded in by simple physics and introduce free Zorubicin in the hydrophobic core of polymer micelle, obtained the polymer micelle administration nano-drug administration system of high drug loading amount thus.Because the distinctive pathological characters in solid tumor position, be that enhanced sees through and retention effect (EPR effect), such nano-carrier energy passive target is in tumor locus, thereby improve lesions position active drug concentration, reduce the drug level of its hetero-organization and organ, thereby when improving curative effect, greatly reduce the toxic side effect of medicine to normal internal organs
14What deserves to be mentioned is, on good experimentation on animals result's basis, respectively load taxol (NK105) and Zorubicin (NK911) arranged such polymer micelle preparation at present Japan carry out clinical study
15On the other hand, Kabanov group is based on ternary block polymer polyoxyethylene-block-polyoxypropylene-block-polyoxyethylene (PEO-b-PPO-PEO) studies show that (Pluronics), the Pluronic micella not only can be used as the carrier of dewatering medicament, and can transmit tranquilizer through hemato encephalic barrier (BBB)
16The research of this group also proves, the medicine that Pluronics unit molecule chain can suppress P-glycoprotein (P-GP) mediation leaks, and therefore can improve useful for drug delivery by BBB and overcome multidrug-resisting (MDR) problem.In addition, such preparation that carries out clinical trial at present still has load that the polyoxyethylene glycol-block-poly(lactic acid) micellar system of taxol and the polyethylene glycol-aspartic acid micellar system that load has cis-platinum class medicine are arranged
17
In the last few years, the range of application of polymer micelle as pharmaceutical carrier expanded in the work of study group such as Kataoka and Kabanov greatly, make this system not be only applicable to the transmission of dewatering medicament, and can become complexing action, hydrogen bond action or the electrostatic interaction of section and active substance to transmit some medicines that contain metallic element (such as containing platinic compound), polypeptide protein and macromole biologically active substances such as RNA, DNA by karyomorphism
18,19Compare with long circulating liposome preparation, polymer micelle has controlled drug release, stronger tissue permeability, and can effectively reduce toxicity, such as brothers' syndromes and allergy.Generally speaking, the advantage that has of polymer micelle administration nano-drug administration system is: (1) is applicable to (such as hydrophobic substance, metallic compound and charged macromole for example polypeptide, albumen and the poly-nucleotide) wide in variety of the therapeutant of this carrier; (2) do not adopt chemical modification, be easy to the physical load medicine; (3) the micella preparation method is simple; (4) drug loading amount height; (5) controlled drug release
15Simultaneously, drug loading amount and drug release kinetics can effectively be regulated and control by the structure of polymkeric substance; Depend on the chemical property of medicine to be passed, the characteristic of micella transfer system can become section to optimize by regulation and control micellar karyomorphism; The pharmacokinetics of polymer micelle is not subjected to the performance impact of the medicine of institute's load, and mainly by micella size and surface property control
15Recently synthetic chemistry and cell surface specific receptors and target spot progress of research make it possible to design and preparation intelligent polymer micella, these systems can also externally discharge medicine under the hormesis by the special lesions position of target, realize the medicine controllable release of regularly fixing a point, this also is this field trend of research both at home and abroad
12At present, a plurality of countries such as the U.S., Britain, Japan and Korea S have set up nanosecond medical science in succession and intersect the center and carry out the development of polymer micelle in the application of biomedical sectors such as biochemical analysis, major disease diagnosis, treatment specially.
As seen by above-mentioned, design and preparation multifunctional polymer micellar system are for realizing that the controlled targeted delivery of medicine is a very significant job.And the prerequisite that the synthetic amphiphilic polymer that can prepare the smart polymeric micellar system of design is such new formulation of exploitation.
With respect to biodegradable polymers such as polyester and poly-acid anhydrides, polyphosphonitrile is later with the exploitation of polymkeric substance as novel biomaterial
20By the Allcock group exploitation of the U.S., correlative study afterwards shows the equal in vivo and in vitro degradable of this base polymer to the hydrophobic polymer that amino acid ester replaces, so it begins to be subjected to numerous national researchists' concern as biomaterial the earliest.The U.S., China, Italy, Korea S and Japan etc. all have research group to carry out the development and research of association area at present.On the other hand, existing research group has developed the drug delivery system based on amphiphilic polyphosphazenes.Wherein the American Studies personnel to have synthesized with the polyoxyethylene glycol be the amphiphilic polyphosphazenes of hydrophilic chain, and prepared polymer micelle with this
21But for this micellar system, Shang Weiyou is seen in report as the correlated results of drug carrier system.Simultaneously, it is the amphiphilic polymer of side group that the Korea S investigator has synthesized with polyoxyethylene glycol and amino acid ester, and with such polymer manufacture temperature-sensitive hydrogel as drug carrier system
22,23It is hydrophilic chain that the Chinese research personnel have then synthesized with poly-(N-N-isopropylacrylamide) and polyoxyethylene glycol, and glycine ethyl ester, parathesin, tryptophane ethyl ester, n-hexylamine, n-amino dodecane and n-stearylamine are the amphiphilic polyphosphazenes of hydrophobic side group
24-26And be carrier with this series polymer, prepared the drug-carrying polymer micelle system, carried out relevant Evaluation in Vivo and in Vitro.
The composition and the synthetic method thereof that the purpose of this invention is to provide a kind of biodegradable amphiphilic polyphosphazenes as dewatering medicament nano-preparations carrier.
In order to achieve the above object, the present invention takes following measure:
Chemical structure as the biodegradable amphiphilic polyphosphazenes of dewatering medicament nano-preparations carrier is:
Wherein:
R1＝H，CH
3，CH
2CH
3，CH
2CH
2CH
3，CH(CH
3)
2
R2＝H，CH
3，CH(CH
3)
2，CH(CH
3)CH
2CH
3，CH
2CH(CH
3)
2，CH
2CH
2CH
2SCH
3，CH
2C
6H
5，
R＝CH
3，CH
2CH
3，CH
2CH
2CH
3
n＝8-800
m＝8-500
x＝1.9-0.1
y＝0.1-1.9
The synthetic method of above-claimed cpd is: under the nitrogen protection, the solution that will contain 0.01-0.09mol end amino poly-(N-vinyl-2-Pyrrolidone) or terminal hydroxy group poly-(2-alkyl-2-azoles quinoline) and 40ml organic solvent joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50ml organic solvent, reacts under 8-90 ℃ of magnetic agitation after adding the 0.01-0.09mol triethylamine simultaneously; Add the solution that contains 0.1-0.5mol amino acid ester and 50ml organic solvent after 48 hours in this reaction system, add the 0.1-0.5mol triethylamine simultaneously, then 8-90 ℃ is continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Advantage of the present invention is:
1), resulting material has excellent biological compatibility, and is biodegradable;
2) the material building-up process is simple, the regulation and control within a large range by the substituent that adds different performance in building-up process simply of the degradation property of polymkeric substance;
3) introduced poly-(N-vinyl-2-Pyrrolidone) in the amphipathic copolymer, therefore given biocompatibility and blood compatibility in the good body of final polymkeric substance with the interior good biocompatibility of body and blood compatibility;
4) introducing of poly-(2-alkyl-2-azoles quinoline) has given final polymkeric substance certain temperature-responsive, and response temperature size and scope can be regulated and control by the wherein kind of alkyl and the content of this hydrophilic polymer, so can develop the polymer nano micelle drug delivery system with temperature-responsive with this base polymer;
5), can prepare form, size and all regulatable nanoparticle that distributes by this series amphiphilic polyphosphazenes self-assembly in the aqueous solution.
Embodiment
Below in conjunction with embodiment the present invention is elaborated.
Embodiment 1
Under the nitrogen protection, the 50ml THF solution that will contain the 0.05mol number-average molecular weight and be 1200 end amino poly-(N-vinyl-2-Pyrrolidone) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50mlTHF, reacts under 60 ℃ of magnetic agitation after adding the 0.05mol triethylamine simultaneously; Add the 50ml THF solution that contains the 0.1mol glycine ethyl ester after 48 hours in this reaction system, add the 0.1mol triethylamine simultaneously, then 60 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 2
Under the nitrogen protection, the 50ml THF solution that will contain the 0.06mol number-average molecular weight and be 1000 end amino poly-(N-vinyl-2-Pyrrolidone) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50mlTHF, reacts under 60 ℃ of magnetic agitation after adding the 0.06mol triethylamine simultaneously; Add the 50ml THF solution that contains the 0.12mol alanine ethyl ester after 48 hours in this reaction system, add the 0.12mol triethylamine simultaneously, then 60 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 3
Under the nitrogen protection, the 50ml THF solution that will contain the 0.055mol number-average molecular weight and be 1100 end amino poly-(N-vinyl-2-Pyrrolidone) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50mlTHF, reacts under 60 ℃ of magnetic agitation after adding the 0.055mol triethylamine simultaneously; Add the 50ml THF solution that contains the 0.2mol phenylalanine ethyl ester after 48 hours in this reaction system, add the 0.2mol triethylamine simultaneously, then 60 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 4
Under the nitrogen protection, the 50ml THF solution that will contain the 0.05mol number-average molecular weight and be 1000 end amino poly-(N-vinyl-2-Pyrrolidone) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50mlTHF, reacts under 60 ℃ of magnetic agitation after adding the 0.05mol triethylamine simultaneously; Add the 50ml THF solution that contains the 0.2mol leucinethylester after 48 hours in this reaction system, add the 0.2mol triethylamine simultaneously, then 60 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 5
Under the nitrogen protection, the 50ml THF solution that will contain the 0.05mol number-average molecular weight and be 800 end amino poly-(N-vinyl-2-Pyrrolidone) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50mlTHF, reacts under 60 ℃ of magnetic agitation after adding the 0.05mol triethylamine simultaneously; Add the 50ml THF solution that contains 0.2mol Xie Ansuan ethyl ester after 48 hours in this reaction system, add the 0.2mol triethylamine simultaneously, then 60 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 6
Under the nitrogen protection, the 50ml THF solution that will contain the 0.05mol number-average molecular weight and be 1800 end amino poly-(N-vinyl-2-Pyrrolidone) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50mlTHF, reacts under 60 ℃ of magnetic agitation after adding the 0.05mol triethylamine simultaneously; Add the 50ml THF solution that contains 0.2mol Histidine ethyl ester after 48 hours in this reaction system, add the 0.2mol triethylamine simultaneously, then 60 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 7
Under the nitrogen protection, the 50ml THF solution that will contain the 0.05mol number-average molecular weight and be 1600 end amino poly-(N-vinyl-2-Pyrrolidone) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50mlTHF, reacts under 65 ℃ of magnetic agitation after adding the 0.05mol triethylamine simultaneously; Add the 50ml THF solution that contains 0.3mol tryptophane ethyl ester after 48 hours in this reaction system, add the 0.3mol triethylamine simultaneously, then 65 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 8
Under the nitrogen protection, the 50ml THF solution that will contain the 0.06mol number-average molecular weight and be 1200 terminal hydroxy group poly-(2-methyl-2-azoles quinoline) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50ml THF, reacts under 70 ℃ of magnetic agitation after adding the 0.06mol triethylamine simultaneously; Add the 50ml THF solution that contains the 0.2mol glycine ethyl ester after 48 hours in this reaction system, add the 0.2mol triethylamine simultaneously, then 70 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 9
Under the nitrogen protection, the 50ml THF solution that will contain the 0.04mol number-average molecular weight and be 1800 terminal hydroxy group poly-(2-ethyl-2-azoles quinoline) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50ml THF, reacts under 60 ℃ of magnetic agitation after adding the 0.04mol triethylamine simultaneously; Add the 50ml THF solution that contains the 0.3mol alanine ethyl ester after 48 hours in this reaction system, add the 0.3mol triethylamine simultaneously, then 60 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 10
Under the nitrogen protection, the 50ml THF solution that will contain the 0.04mol number-average molecular weight and be 800 terminal hydroxy group poly-(2-propyl group-2-azoles quinoline) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50ml THF, reacts under 65 ℃ of magnetic agitation after adding the 0.04mol triethylamine simultaneously; Add the 50ml THF solution that contains the 0.4mol phenylalanine ethyl ester after 48 hours in this reaction system, add the 0.4mol triethylamine simultaneously, then 65 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 11
Under the nitrogen protection, the 50ml THF solution that will contain the 0.06mol number-average molecular weight and be 800 terminal hydroxy group poly-(2-methyl-2-azoles quinoline) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50ml THF, reacts under 65 ℃ of magnetic agitation after adding the 0.06mol triethylamine simultaneously; Add the 50ml THF solution that contains the 0.3mol leucinethylester after 48 hours in this reaction system, add the 0.3mol triethylamine simultaneously, then 65 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 12
Under the nitrogen protection, the 50ml THF solution that will contain the 0.03mol number-average molecular weight and be 900 terminal hydroxy group poly-(2-propyl-2-azoles quinoline) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50ml THF, reacts under 60 ℃ of magnetic agitation after adding the 0.03mol triethylamine simultaneously; Add the 50ml THF solution that contains 0.3mol Xie Ansuan ethyl ester after 48 hours in this reaction system, add the 0.3mol triethylamine simultaneously, then 75 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 13
Under the nitrogen protection, the 50ml THF solution that will contain the 0.03mol number-average molecular weight and be 1200 terminal hydroxy group poly-(2-ethyl-2-azoles quinoline) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50ml THF, reacts under 50 ℃ of magnetic agitation after adding the 0.03mol triethylamine simultaneously; Add the 50ml THF solution that contains 0.3mol Histidine ethyl ester after 48 hours in this reaction system, add the 0.3mol triethylamine simultaneously, then 75 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 14
Under the nitrogen protection, the 50ml THF solution that will contain the 0.04mol number-average molecular weight and be 1100 terminal hydroxy group poly-(2-ethyl-2-azoles quinoline) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50ml THF, reacts under 40 ℃ of magnetic agitation after adding the 0.04mol triethylamine simultaneously; Add the 50ml THF solution that contains 0.4mol tryptophane ethyl ester after 48 hours in this reaction system, add the 0.4mol triethylamine simultaneously, then 85 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 15
Under the nitrogen protection, the 50ml THF solution that will contain the 0.05mol number-average molecular weight and be 1100 terminal hydroxy group poly-(2-ethyl-2-azoles quinoline) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50ml THF, reacts under 45 ℃ of magnetic agitation after adding the 0.05mol triethylamine simultaneously; Add the 50ml THF solution that contains 0.3mol methionine(Met) ethyl ester after 48 hours in this reaction system, add the 0.3mol triethylamine simultaneously, then 80 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 16
Under the nitrogen protection, the 50ml THF solution that will contain the 0.06mol number-average molecular weight and be 800 terminal hydroxy group poly-(2-methyl-2-azoles quinoline) joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50ml THF, reacts under 65 ℃ of magnetic agitation after adding the 0.06mol triethylamine simultaneously; Add the 50ml THF solution that contains 0.35mol Isoleucine ethyl ester after 48 hours in this reaction system, add the 0.35mol triethylamine simultaneously, then 65 ℃ are continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
Embodiment 17
5mg Zorubicin and 100mg substituting group are that the amphiphilic polyphosphazenes (wherein hydrophobic and hydrophilic substituent mol ratio is 4: 1) of tryptophane ethyl ester and poly-(N-vinyl-2-Pyrrolidone) is dissolved in the 10ml dimethyl sulfoxide (DMSO), and to be placed on molecular weight cut-off be in 8000 the dialysis tubing, in water, dialysed 24 hours afterwards, the dialyzate freeze-drying obtains being loaded with the polymer nanoparticle of Zorubicin, wherein entrapment efficiency 70%, drug-carrying nanometer particle median size 320nm.
Embodiment 18
2mg taxol and 100mg substituting group are that the amphiphilic polyphosphazenes (wherein hydrophobic and hydrophilic substituent mol ratio is 5: 1) of leucinethylester and poly-(2-ethyl-2-azoles quinoline) is dissolved in the 10ml dimethyl sulfoxide (DMSO), and to be placed on molecular weight cut-off be in 8000 the dialysis tubing, in water, dialysed 24 hours afterwards, the dialyzate freeze-drying obtains being loaded with the polymer nanoparticle of taxol, wherein entrapment efficiency 80%, drug-carrying nanometer particle median size 200nm.
Embodiment 19
5mg camptothecine and 100mg substituting group are that the amphiphilic polyphosphazenes (wherein hydrophobic and hydrophilic substituent mol ratio is 3: 1) of phenylalanine ethyl ester and poly-(N-vinyl-2-Pyrrolidone) is dissolved in the 10ml dimethyl sulfoxide (DMSO), and to be placed on molecular weight cut-off be in 8000 the dialysis tubing, in water, dialysed 24 hours afterwards, the dialyzate freeze-drying obtains being loaded with the polymer nanoparticle of camptothecine, wherein entrapment efficiency 75%, drug-carrying nanometer particle median size 150nm.
Embodiment 20
5mg vincristine(VCR) and 100mg substituting group are that the amphiphilic polyphosphazenes (wherein hydrophobic and hydrophilic substituent mol ratio is 3: 1) of Histidine ethyl ester and poly-(2-ethyl-2-azoles quinoline) is dissolved in the 10ml dimethyl sulfoxide (DMSO), and to be placed on molecular weight cut-off be in 8000 the dialysis tubing, in water, dialysed 24 hours afterwards, the dialyzate freeze-drying obtains being loaded with the polymer nanoparticle of vincristine(VCR), wherein entrapment efficiency 65%, drug-carrying nanometer particle median size 230nm.
Embodiment 21
5mg vinorelbine and 100mg substituting group are that the amphiphilic polyphosphazenes (wherein hydrophobic and hydrophilic substituent mol ratio is 3.5: 1) of Isoleucine ethyl ester and poly-(2-methyl-2-azoles quinoline) is dissolved in the 10ml dimethyl sulfoxide (DMSO), and to be placed on molecular weight cut-off be in 8000 the dialysis tubing, in water, dialysed 24 hours afterwards, the dialyzate freeze-drying obtains being loaded with the polymer nanoparticle of vinorelbine, wherein entrapment efficiency 68%, drug-carrying nanometer particle median size 110nm.
Claims (4)
1. biodegradable amphiphilic polyphosphazenes as dewatering medicament nano-preparations carrier is characterized in that:
Its chemical structure is
Wherein:
R1＝H，CH
3，CH
2CH
3，CH
2CH
2CH
3，CH(CH
3)
2
R2＝H，CH
3，CH(CH
3)
2，CH(CH
3)CH
2CH
3，CH
2CH(CH
3)
2，CH
2CH
2CH
2SCH
3，CH
2C
6H
5，?
R＝CH
3，CH
2CH
3，CH
2CH
2CH
3
n＝8-800
m＝8-500
x＝1.9-0.1
y＝0.1-1.9。
2. synthetic method as the biodegradable amphiphilic polyphosphazenes of dewatering medicament nano-preparations carrier, it is characterized in that: under the nitrogen protection, the solution that will contain 0.01-0.09mol end amino poly-(N-vinyl-2-Pyrrolidone) or terminal hydroxy group poly-(2-alkyl-2-azoles quinoline) and 40ml organic solvent joins in the solution of the polyphosphonitrile that contains 0.1mol P-Cl and 50ml organic solvent, reacts under 8-90 ℃ of magnetic agitation after adding the 0.01-0.09mol triethylamine simultaneously; Add the solution that contains 0.1-0.5mol amino acid ester and 50ml organic solvent after 48 hours in this reaction system, add the 0.1-0.5mol triethylamine simultaneously, then 8-90 ℃ is continued reaction; Stopped reaction after 72 hours filters, and filtrate concentrates the back and obtains purpose polymers with ether sedimentation and vacuum-drying.
3. the synthetic method of a kind of biodegradable amphiphilic polyphosphazenes as dewatering medicament nano-preparations carrier according to claim 2, it is characterized in that: said organic solvent is a toluene, tetrahydrofuran (THF), chloroform or their mixture.
4. the synthetic method of a kind of biodegradable amphiphilic polyphosphazenes as dewatering medicament nano-preparations carrier according to claim 2, it is characterized in that: said amino acid ester is methyl esters, ethyl ester, propyl ester or the isopropyl ester of glycine, L-Ala, leucine, Isoleucine, Xie Ansuan, methionine(Met), phenylalanine, Histidine and tryptophane.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4948720A (en) * | 1987-08-20 | 1990-08-14 | Eastman Kodak Company | Photographic element containing polyphosphazene antistatic composition |
| US5041524A (en) * | 1988-11-16 | 1991-08-20 | Consiglio Nazionale Delle Ricerche | Polyphosphazene derivatives containing carbonyl groups suitable for photoreticulation processes |
| CN1663985A (en) * | 2005-02-03 | 2005-09-07 | 浙江大学 | Biodegradable fluorescent polyphosphonitrile and process for synthesis therof |
| CN101134817A (en) * | 2007-08-31 | 2008-03-05 | 浙江大学 | Amphipathy polyphosphazene and preparation and use thereof |
-
2008
- 2008-03-12 CN CN2008100694591A patent/CN101245147B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4948720A (en) * | 1987-08-20 | 1990-08-14 | Eastman Kodak Company | Photographic element containing polyphosphazene antistatic composition |
| US5041524A (en) * | 1988-11-16 | 1991-08-20 | Consiglio Nazionale Delle Ricerche | Polyphosphazene derivatives containing carbonyl groups suitable for photoreticulation processes |
| CN1663985A (en) * | 2005-02-03 | 2005-09-07 | 浙江大学 | Biodegradable fluorescent polyphosphonitrile and process for synthesis therof |
| CN101134817A (en) * | 2007-08-31 | 2008-03-05 | 浙江大学 | Amphipathy polyphosphazene and preparation and use thereof |
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