CN1332716C - High molecular antineoplastic cisplatin medicine and preparation method thereof - Google Patents
High molecular antineoplastic cisplatin medicine and preparation method thereof Download PDFInfo
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- CN1332716C CN1332716C CNB2005100721557A CN200510072155A CN1332716C CN 1332716 C CN1332716 C CN 1332716C CN B2005100721557 A CNB2005100721557 A CN B2005100721557A CN 200510072155 A CN200510072155 A CN 200510072155A CN 1332716 C CN1332716 C CN 1332716C
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Abstract
The present invention relates to new macromolecular anti-tumor medicine which is prepared from double-arm RPEG2Y as a carrier by coupling with anti-tumor medicine cisplatin, and the present invention also relates to the preliminary study of the medicinal performance of the new macromolecular anti-tumor medicine. At present cisplatin is widely used as anti-tumor medicine for treating cancers, but the cisplatin has the defects of great toxic and side effect, easy and rapid removal in vivo, etc., which limits the further improvement of the treatment index of the cisplatin. Therefore, the reduction of toxic and side effects of the cisplatin and the extension of the metabolic half life of the cisplatin in vivo become problems to be solved first for improving the curative effects of cisplatin, and the cisplatin which is used as a carrier is undoubtedly regarded as an effective approach. In the present invention, double-arm RPEG2Y is used as a carrier, and new macromolecular carrier medicine is obtained by coupling the double-arm RPEG2Y with cisplatin by means of a chemical reaction. Pharmacological experiments preliminarily show that cisplatin medicine with double-arm PEG as a carrier has better curative effects than cisplatin with linear PEG as a carrier.
Description
Technical field
The present invention relates to a kind of medicine, particularly a kind of is the high molecular antineoplastic cisplatin medicine and preparation method thereof of carrier with the both arms Polyethylene Glycol, promptly with both arms RPEG
2Y-(is called for short: the both arms Polyethylene Glycol) be carrier, carry out modification by functionalization reaction pair micromolecule antitumor drug cisplatin.
Background technology
Since B.Rosenberg in 1969 and V.Camp reported first cis-dichloro two ammino platinum (abbreviation cisplatin) have the broad-spectrum active anticancer, application and the research of cisplatin in treatment of cancer has obtained development rapidly, has become the antitumor drug of the general clinical use in various countries at present.Yet, this medicine exist toxic and side effects greatly, in vivo accretion rate soon, easily by shortcomings such as quick removings, thereby limited the exponential further raising of plus cisplatin in treatment.Therefore, reduce the toxic and side effects of cisplatin, prolong its metabolic half life in vivo and become the task of top priority that improves the cisplatin curative effect.Then provide a valid approach its carrierization undoubtedly for this reason.
Polyethylene Glycol (PEG) is a kind of water miscible amphipathic polymer, has excellent biological compatibility, non-immunogenic, characteristics such as nontoxic, and therefore, it is the ideal macromolecular carrier of cisplatin modification.Compare with the line style PEG of same molecular amount, both arms and multi-arm PEG are because it has bigger hydrodynamic volume, and less static viscosity is estimated can produce more efficiently physiological action to medicine.Have not yet to see similar report.
Summary of the invention
The objective of the invention is to obtain a kind of is the high molecular antineoplastic cisplatin medicine and preparation method thereof of carrier with the both arms Polyethylene Glycol.
The present invention is with both arms Polyethylene Glycol (RPEG
2Y-) as carrier, the chelation by its end functional groups diacid carries out modification to micromolecule antitumor drug cisplatin, and chemical general formula is RPEG
2Y-B-C, wherein RPEG
2Y-abbreviates the both arms Polyethylene Glycol as, and B is the structure that has two hydroxy-acid groups of chelating cisplatin, and C is adorned small-molecule drug cisplatin, and its structural formula is as follows:
Or
Wherein R is following linear paraffin, isopropyl or benzyls of 10 carbon; R
1Be CH or phenyl; R
2It is the alkyl of 1～9 carbon atom; A, b, c are 0～9 integer; K is 0～6 integer; S, t make RPEG
2-in RO-(CH
2CH
2O)
s-and RO-(CH
2CH
2O)
tThe Mn of-part is about 2000～80000 integer;
W be O, S,
One of NH can be different groups with W in a part;
Y is
NH, S, O,
One of CH=, N=;
V is
NH, S, O,
One of=HC ,=N.
Above-mentioned both arms Polyethylene Glycol (RPEG
2Y-) in the carrier structure, R is that methyl is particularly preferred.
The molecular weight of above-mentioned high molecular antineoplastic medicine is 2000-160000.
The preparation method of above-mentioned high molecular antineoplastic medicine is with the functionalized both arms Polyethylene Glycol (RPEG with the conventional method preparation
2Y-X) and contain the chemical compound reaction of malonate structure, hydrolysis obtains containing the compound R PEG of malonic acid structure then
2Y-B, last RPEG
2Y-B and chlorine atom are obtained target product RPEG by the cisplatin reaction that nitrate anion replaces
2Y-B-C.
This chemical reaction has utilized existing reaction condition in the prior art and has got.
Carrier both arms RPEG in the above-mentioned high molecular antineoplastic medicine is to be raw material with linear RPEG, by synthetic RPEG active ester, utilizes multistep reaction to obtain with the amido coupling of the ω of for example lysine and α position in water and oil phase respectively.The synthetic method of both arms branching shape PEG is existing in the art to be described, for example: Yamsuki etc., Agric.Bio.Chem.1988,52,2185-2196; Monfardidi etc., BioconjugateChem.1995,6,62-69.
Above-mentioned high molecular antineoplastic medication preparation is that chemical compound such as the amidomalonic acid diethylester of the carboxylic acid functional on the both arms RPEG with band malonate structure is connected, and hydrolysis obtains the malonic acid structure then, and last and chlorine atom is substituted by the cisplatin coupling of nitrate anion.Both arms Polyethylene Glycol with mono methoxy polyethylene glycol (mPEG) and lysine (lysine) preparation is an example, and the synthetic route of this macromolecule anticancer drug is as follows:
Connect existing in the art description of method of cisplatin about linear PEG, Yuichi etc. for example, Macromol.Biosci.2001,1, No.8,355-363.
The medicine rate that connects of small-molecule drug is between 90%-99% in the above-mentioned high molecular antineoplastic medicine.
Above-mentioned high molecular antineoplastic medicine RPEG
2Y-B-C and preparation method, described RPEG
2-structure be:
Wherein R is following linear paraffin, isopropyl or benzyls of 10 carbon; R
1Be CH or phenyl; A, b, c are 0～9 integer; K is 0～6 integer; S, t, be 10～2000 integer;
W is O, S, NH
One of, can be different groups with W in a part.
For example:
Above-mentioned both arms Polyethylene Glycol RPEG
2R is that methyl is particularly preferred in the structure of Y-.
In above-mentioned the high molecular antineoplastic medicine and preparation method,
Y can for
NH, S, O,
One of CH=, N=;
In above-mentioned the high molecular antineoplastic medicine and preparation method, functionalized both arms Polyethylene Glycol is RPEG
2During CO-X, X wherein can be one of following structure:
-H-OH-NH
2 
Above-mentioned high molecular antineoplastic medicine RPEG
2In Y-B-C and the preparation method, the structure of B can be an one of the following:
R wherein
2It is the alkyl of 1～9 carbon atom;
V is
NH, S, O,
One of=HC ,=N.
For example:
Deng.
In above-mentioned the high molecular antineoplastic medicine and preparation method, the structure of C is two substituted cisplatin of chlorine atom.
Above-mentioned high molecular antineoplastic medicine is a carrier with both arms RPEG, by chemical reaction, with micromolecule antitumor drug cisplatin and carrier coupling.With the linear RPEG of same molecular amount relatively, both arms RPEG has bigger hydrodynamic volume, like this with regard to the more effective medicine inactivation or by the speed of enzyme hydrolysis in vivo that reduced.Chelation by malonic acid is connected the stable hexatomic ring that generates with cisplatin simultaneously, makes the release of medicine slower, has increased the medicine half-life in vivo.
Above-mentioned have a general formula R PEG
2The both arms mPEG cisplatin conjugates (DImPEG-Pt) of CO-B-C shows that through the vitro cytotoxicity experiment this medicine has kept the anti-tumor activity of certain degree; Simultaneously, compare, have general formula R PEG with the linear mPEG cisplatin even summation thing of same molecular amount
2The high molecular antineoplastic medicine of CO-B-C has higher cell in vitro cytotoxic activity, and this has illustrated that also both arms mPEG is more suitable in the modification to small-molecule drug than linear mPEG, can reduce the degree of medicine inactivation to a greater extent.
Description of drawings
Fig. 1 is the dose-effect curve figure of the poly ethyldiol modified cisplatin of both arms (DImPEG-Pt) series
Fig. 2 is the dose-effect curve figure of the poly ethyldiol modified cisplatin of single armed (mPEG-Pt) series
The specific embodiment
Embodiment one
RPEG
2The synthetic method of CO-B-C (is example with mono methoxy polyethylene glycol (mPEG) molecular weight 2000) is 1. with 10g mPEG (Mn=2000; 5mmol) be dissolved in about 150mL toluene; normal pressure steams and removes most toluene under nitrogen protection, to remove micro-moisture contained among the mPEG.After being chilled to room temperature,, heating little boiling to mPEG and dissolve fully to wherein adding the anhydrous THF of about 200mL.The sodium naphthalene solution that drips 0.2mol/L subsequently in mPEG solution is celadon until solution.(6.03g 50mmol) adds in the reaction solution stirring reaction 4h under the room temperature with 50mL THF dilution back to get the 5.24mL ethyl chloroacetate.With the absolute ether precipitation, the gained crude product is added in the 300mL 0.1mol/L NaOH solution reactant liquor after concentrating, and 50 ℃ are stirred 12h.Regulate pH=3 with 1mol/L HCl then, use CH
2Cl
2Extract three times, combining extraction liquid concentrates the back and precipitates with absolute ether.Through twice dissolving-filtration-post precipitation, vacuum drying gets mPEG-CH again
2COOH 9.5g, productive rate 92%.Through nuclear magnetic resonance measuring, mPEG-CH in the product
2The COOH molar content is 95%.(
1HNMR(CDCl
3)mPEG-C
H 2COOH，δ＝4.15)
2. with above-mentioned 9.5g mPEG-CH
2(Mn=2058 4.6mmol) is dissolved in about 150mL toluene to COOH, and normal pressure steams and removes most toluene under nitrogen protection, to remove wherein contained micro-moisture.After being chilled to room temperature, to wherein adding about 120mL anhydrous methylene chloride dissolving mPEG-CH
2COOH.In solution, add N-hydroxy-succinamide (NHS) 1.06g (9.2mmol) subsequently respectively, dicyclohexylcarbodiimide (DCC) 2.86g (13.8mmol), stirring reaction 12h under ice-water bath.Reactant liquor is through concentrating the back with the absolute ether precipitation, and the gained crude product is dissolved in about 40mL dry toluene under heating, and filtration precipitates with absolute ether after removing insoluble matter wherein.Through twice dissolving-filtration-post precipitation, vacuum drying gets mPEG-CH again
2COOSu (mPEG-succinimdyl carbonate) 9.0g, productive rate 90%.Measure through ultraviolet spectroscopy, the molar content of succinimdyl carbonate is 94% in the product.
3. taking by weighing lysine (Lysine) 1.46g (10mmol) is dissolved in the boric acid, borax buffer solution of 80mL pH=8.With the mPEG-CH that makes in the 2nd step
2COOSu4.3g (2mmol) progressively adds in 1h in batches, during to keep the pH value of solution by the NaOH solution that drips 0.2mol/L be 8 (monitoring with pH meter).After room temperature continued stirring reaction 12h, the pH value with solution under ice-water bath transferred to 2-3 with hydrochloric acid, uses the dichloromethane extraction product.Extract repeatedly three times, extract is merged, concentrate, in absolute ether, precipitate.Behind dissolving-filtration again-precipitation secondary, vacuum drying obtains product mPEG-CH
2CO-Lysine is used for next step reaction.
4. will go up step reaction products therefrom mPEG-CH
2CO-Lysine is dissolved in about 80mL anhydrous methylene chloride, drips triethylamine regulator solution pH value to 8-9 (drips of solution to moistening accurate pH test paper is recorded).In 3 hours, progressively add the mPEG-CH that makes in the 2nd step in batches
2COOSu 4.7g (2.2mmol), and constantly drip triethylamine, keeping the pH value of solution is 8-9.Reactant liquor is warming up to 40 ℃ then, refluxes and stir after 48 hours, filter, concentrate, in absolute ether, precipitate.Products therefrom dissolves-filters-precipitate secondary after, vacuum drying, product 8.0g.Measure through GPC, wherein both arms mPEG
2The content of-CHCO-Lysine is about 80%.
Above-mentioned product is made into 10% aqueous solution, selects the ultrafilter membrane in suitable aperture, under 1.5 atmospheric pressure, ultra-filtration and separation, the both arms mPEG that can purify, final product mPEG
2-CHCO-Lysine5.0g.
The 4th the step in make with 5.0g mPEG
2(Mn=4226 1.2mmol) is dissolved in about 100mL toluene solution to-CHCO-Lysine, and normal pressure steams and removes most toluene under nitrogen protection, to remove wherein contained micro-moisture.After being chilled to room temperature, to wherein adding about 120mL anhydrous methylene chloride dissolving mPEG
2-CHCO-Lysine.In solution, add N-hydroxy-succinamide (NHS) 0.28g (2.4mmol) subsequently respectively, dicyclohexylcarbodiimide (DCC) 0.75g (3.6mmol), stirring reaction 12h under ice-water bath.With the absolute ether precipitation, the gained crude product is dissolved in about 40mL dry toluene to reactant liquor under heating, filter, and removes insoluble matter wherein after concentrating.Through twice dissolving-filtration-post precipitation, vacuum drying gets mPEG again
2-CHCO-Lysine-OSu 4.5g, productive rate 90%.Measure through ultraviolet spectroscopy, the molar content of succinimdyl carbonate is 98% in the product.
6. take by weighing 0.7g amidomalonic acid diethylester (DEAM) (3.3mmol), be dissolved in the 50mL anhydrous methylene chloride, add triethylamine 1mL, ice-water bath stirred 2 hours down.The mPEG that 4.5g the 5th was made in the step
2-CHCO-Lysine-OSu (1.1mmol) is dissolved in about 80mL anhydrous methylene chloride, drips triethylamine regulator solution pH value to 8-9 (drips of solution to moistening accurate pH test paper is recorded).Under the ice-water bath amidomalonic acid diethylester solution that reacts is previously joined mPEG
2In-CHCO-Lysine-OSu the solution.0 ℃ reaction is after 12 hours down, and filtration, concentrated precipitates in absolute ether.Products therefrom dissolves-filters-precipitate secondary after, vacuum drying, product 4.3g.Through nuclear magnetic resonance measuring, mPEG wherein
2The content of-CHCO-Lysine-DEAM is about 80%.(
1H NMR(CDCl
3)COOCH
2C
H 3，δ＝1.30)
Under the ice-water bath with the 4.3g mPEG that makes in the 6th step
2-lysine-DEAM (0.98mmol) is dissolved in the NaOH methanol solution (methanol 92mL, 1mol/L NaOH 13.5mL), stirs 2h.Regulate pH=6 with 1mol/L HCl, 40 ℃ of rotary evaporation solvents add the dichloromethane dissolving then, add anhydrous magnesium sulfate drying.Filter, filtrate is concentrated, in absolute ether, precipitate.Again behind twice of the dissolution precipitation, vacuum drying, product (mPEG
2-CHCO-Lysine-DA) 4.0g, productive rate 95%.Through nuclear magnetic resonance measuring, mPEG wherein
2-CHCO-Lysine-DA content is 75%.(peak at 1.30 places disappears in the nuclear-magnetism)
8. cisplatin 1.35g (4.5mmol) is dissolved in about 200mL deionized water, is heated to 60 ℃ and makes it to dissolve fully.Add silver nitrate 1.52g (9mmol) again, behind 60 ℃ of lucifuge stirring reaction 6h, filter the silver nitride precipitation of generation.In filtrate, add 4.0gmPEG
2-CHCO-Lysine-DA (0.92mmol), continue at 60 ℃ of lucifuge stirring reaction 24h after, use the dichloromethane extraction product.Extract repeatedly three times, extract is merged, concentrate, in absolute ether, precipitate.Behind dissolving-filtration again-precipitation secondary, vacuum drying gets product mPEG
2-CHCO-Lysine-Pt productive rate 82%.Through aas determination, the molar content of cisplatin is 87.1% in the product.
Embodiment two
The preparation of RPEGCO-B-C-Pt (is example with mPEG molecular weight 4000)
(Mn=4000 2.5mmol), prepares the mPEG-CH that end group is a carboxyl with embodiment one identical method to take by weighing 10g mPEG
2COOH connects the amidomalonic acid diethylester, hydrolysis, synthetic at last mPEG-CH
2CO-Lysine-Pt.Productive rate is 81%, and the molar content of cisplatin is 85.2% in the end product.
Embodiment three
RPEG
2The synthetic method of CO-B-C (is example with mono methoxy polyethylene glycol (mPEG) molecular weight 80000) with 16g mPEG (Mn=80000,0.2mmol), with the identical method of embodiment one, mPEG-CH
2CO-Lysine-Pt 4.5g, gross production rate 28%.The molar content of cisplatin is 80.4% in the end product.
According to the step of above embodiment, the present invention has synthesized the polymer drug of three kinds of molecular weight, is used for the vitro cytotoxicity experiment.Having synthesized the carrier molecule amount and be three kinds of both arms mPEG of 4000,6000 and 9400 (is called for short: DImPEG) cisplatin conjugates: DImPEG-4000-Pt, DImPEG-6000-Pt, DImPEG-9400-Pt and three kinds of linear mPEG cisplatin conjugates: mPEG-4000-Pt, mPEG-6000-Pt, mPEG-9400-Pt.More than in the various medicines molar content of cisplatin be listed in the table below 1:
The molar content of platinum in the table .1 macromolecular drug
| Medicine | DImPEG- 4000-Pt | DImPEG- 6000-Pt | DImPEG- 9400-Pt | mPEG- 4000-Pt | mPEG- 6000-Pt | mPEG- 9400-Pt |
| Platinum content (%) | 87.1 | 89.6 | 87.5 | 85.2 | 88.5 | 84.3 |
The vitro cytotoxicity experimentation of said medicine and the results are shown in embodiment four.
The acute toxicity testing process of said medicine and the results are shown in embodiment five.
Embodiment four
Use the DMEM culture fluid that contains 10% hyclone at 37 ℃ the strain of C6 human breast cancer cell, 5%CO
2Cultivate under the condition, go down to posterity.Eugonic C6 cell behind 0.25% trypsinization, is made into the cell suspension that final concentration is 70000 cell/mL, this suspension is pressed the 100uL/ hole evenly add in the flat culture plate in 96 holes.Every porocyte number is 7000.At 37 ℃, 5%CO
2, hatch 24h under the condition of humidity 100%.Above-mentioned each macromolecular drug is dissolved in the DMEM culture fluid, uses the 0.22um filtering with microporous membrane.The gained drug solution is a benchmark with the content of cisplatin in the macromolecular drug, is diluted to variable concentrations, is converted to the micromolecule cisplatin and is respectively 0.02ug/mL, 0.2ug/mL, 2ug/mL, 20ug/mL, 200ug/mL, 2mg/mL.In the flat culture plate in above-mentioned 96 holes, add the medicine 100uL/ hole of variable concentrations, cultivated 2 days, change liquid, cultivated one day.Every hole adds 20uL 0.5% tetrazole (MTT) solution, and after 4 hours, the sucking-off supernatant adds 150uL dimethyl sulfoxide (DMSO), vibration 10min.Detect the light absorption value (OD value) at each 570nm place, hole with microplate reader, the record result, calculate cell survival rate by following formula:
Cell survival rate=experimental group OD value/matched group OD value * 100%
From accompanying drawing, can obtain the half-inhibition concentration (IC of each medicine to cancerous cell
50), the connect medicine rate different according to macromolecular drug is benchmark with the content of cisplatin, the IC of each medicine
50Value is listed in table .2.
The IC of table .2 DImPEG-Pt and mPEG-Pt medicine series
50Value
| Medicine | IC 50，10 -5mol/L |
| DImPEG-4000-Pt | 6.265 |
| DImPEG-6000-Pt | 27.159 |
| DImPEG-9400-Pt | 13.396 |
| mPEG-4000-Pt | 61.184 |
| mPEG-6000-Pt | 30.725 |
| mPEG-9400-Pt | 61.817 |
As can be seen from the table, in the homologous series medicine, the molecular weight of carrier PEG does not produce regular influence to the vitro cytotoxicity of medicine, but the IC of DImPEG-Pt medicine series
50Value but all is lower than the mPEG-Pt medicine series of same molecular amount.This DImPEG-Pt medicine that same molecular amount has been described has embodied better anti tumor activity in vitro than mPEG-Pt medicine.
Fig. 1 is the dose-effect curve figure of the poly ethyldiol modified cisplatin of both arms (DImPEG-Pt) series,
Fig. 2 is the dose-effect curve figure of the poly ethyldiol modified cisplatin of single armed (mPEG-Pt) series,
The present invention has obtained the dose-effect curve of above-mentioned several medicines with the dosage mapping of cell survival fraction to medicine.The present invention's same period has also recorded the dose-effect curve of control sample cisplatin.As can be seen from the figure, the DImPEG-Pt of different molecular weight and mPEG-Pt have better antitumor activity external to the C6 cell.
Embodiment five
In order to check the acute toxicity of cisplatin after PEG modifies to change, measured the LD of above-mentioned polymer drug
50
The TA1 white mice is divided into 5 groups at random, and 20 every group, male and female half and half are used cisplatin respectively, have connect the cisplatin administration of line style and two arm PEG, with ip * 1 therapeutic scheme, establishes five metering groups, observes immediate reaction after the administration.The death distribution of record mice in two weeks.With 24 hours was dead peak.The dead animal postmortem is not found macroscopic, tangible substantial pathological changes.The surviving animals ordinary circumstance is good after two weeks.Experimental result is calculated with the Bliss method, and is as shown in table 3.
The LD of table .3 DImPEG-Pt and mPEG-Pt medicine series
50Value
| Medicine | LD 50，mg/kg |
| CDDP | 25.8 |
| DImPEG-4000-Pt | 901.5 |
| DImPEG-6000-Pt | 988.1 |
| DImPEG-9400-Pt | 1013.7 |
| mPEG-4000-Pt | 895.6 |
| mPEG-6000-Pt | 976.0 |
| mPEG-9400-Pt | 1095.3 |
As can be seen from the table, after cisplatin was modified by PEG, its acute toxicity obviously reduced.
Claims (5)
1. a high molecular antineoplastic medicine is characterized in that, chemical general formula is RPEG
2Y-B-C:
Wherein: RPEG
2-structural formula as follows:
Wherein, R is following linear paraffin, isopropyl or benzyls of 10 carbon; R
1Be CH or phenyl; A, b, c are 0～9 integer; K is 0～6 integer; S, t make RPEG
2-in RO-(CH
2CH
2O)
s-and RO-(CH
2CH
2O)
tThe Mn of-part is about 2000～80000 integer;
W be O, S,
One of NH,, can be different groups with W in a part;
Wherein, the structure of B is an one of the following:
R
2It is the alkyl of 1～9 carbon atom;
The structure of described C is two substituted cisplatin of chlorine atom, and structural formula is as follows:
2. high molecular antineoplastic medicine as claimed in claim 1 is characterized in that R is a methyl.
3, as the arbitrary described high molecular antineoplastic medicine of claim 1 to 2, it is characterized in that, prepare: functionalized both arms Polyethylene Glycol RPEG according to following steps
2Y-X and the chemical compound reaction that contains the malonate structure, hydrolysis obtains containing the compound R PEG of malonic acid structure then
2Y-B, last RPEG
2Y-B and chlorine atom are obtained target product RPEG by the cisplatin reaction that nitrate anion replaces
2Y-B-C, wherein, X is one of following structure:
4. as the preparation method of the arbitrary described high molecular antineoplastic medicine of claim 1 to 3, it is characterized in that, may further comprise the steps: functionalized both arms Polyethylene Glycol RPEG
2Y-X and the chemical compound reaction that contains the malonate structure, hydrolysis obtains containing the compound R PEG of malonic acid structure then
2Y-B, last RPEG
2Y-B and chlorine atom are obtained target product RPEG by the cisplatin reaction that nitrate anion replaces
2Y-B-C, wherein, X is one of following structure:
Wherein, described RPEG
2-structural formula as follows:
Wherein R is following linear paraffin, isopropyl or benzyls of 10 carbon; R
1Be CH or phenyl; A, b, c are 0～9 integer; K is 0～6 integer; S, t make RPEG
2-in RO-(CH
2CH
2O)
s-and RO-(CH
2CH
2O)
tThe Mn of-part is about 2000～80000 integer;
W be O, S, NH,
One of, can be different groups with W in a part;
The structure of described B is an one of the following:
R wherein
2It is the alkyl of 1～9 carbon atom;
The structure of C is two substituted cisplatin of chlorine atom, and structural formula is as follows:
5. the preparation method of high molecular antineoplastic medicine as claimed in claim 4 is characterized in that, R is a methyl.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6235313B1 (en) * | 1992-04-24 | 2001-05-22 | Brown University Research Foundation | Bioadhesive microspheres and their use as drug delivery and imaging systems |
| CN1476330A (en) * | 2000-09-26 | 2004-02-18 | ��ʽ�����ȶ˿�ѧ������������ | Polymeric micelle containing cisplatin enclosed therein and use thereof |
| CN1558777A (en) * | 2001-10-29 | 2004-12-29 | �Ϻ���ͨ��ѧ | An antineoplastic dendritic polymer drug delivery system |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6235313B1 (en) * | 1992-04-24 | 2001-05-22 | Brown University Research Foundation | Bioadhesive microspheres and their use as drug delivery and imaging systems |
| CN1476330A (en) * | 2000-09-26 | 2004-02-18 | ��ʽ�����ȶ˿�ѧ������������ | Polymeric micelle containing cisplatin enclosed therein and use thereof |
| CN1558777A (en) * | 2001-10-29 | 2004-12-29 | �Ϻ���ͨ��ѧ | An antineoplastic dendritic polymer drug delivery system |
Non-Patent Citations (1)
| Title |
|---|
| 聚（L－天冬氨酸）衍生物－顺铂结合物的制备及体外细胞毒性研究 吕正荣等，高等学校化学学报，第19卷第5期 1998 * |
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