CN101422613A - Anti-cancer medicine containing low anticoagulant property heparin and taxol - Google Patents
Anti-cancer medicine containing low anticoagulant property heparin and taxol Download PDFInfo
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- CN101422613A CN101422613A CNA2008101439186A CN200810143918A CN101422613A CN 101422613 A CN101422613 A CN 101422613A CN A2008101439186 A CNA2008101439186 A CN A2008101439186A CN 200810143918 A CN200810143918 A CN 200810143918A CN 101422613 A CN101422613 A CN 101422613A
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- heparin
- paclitaxel
- acetylation
- oxygen
- taxol
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Abstract
The invention discloses an anticancer medicament of heparin-taxol with low hemagglutinating resistance, which relates to a chemical bonding type anticancer medicament. The heparin-taxol medicament is prepared by heparin derivatives and taxol or taxol derivatives by the chemical bonding method, and the anticancer medicament not only has the blood-clot resistance lower than the heparin, but also has the anticancer property stronger than pure taxol medicaments.
Description
Technical field
The present invention relates to a kind of chemical bond mould assembly cancer therapy drug with low anticoagulant performance and strong anti-cancer properties.
Background technology
Paclitaxel is the medicine with unique active anticancer that Americanized scholar of the sixties extracts from Ramulus et folium taxi cuspidatae, treatment breast carcinoma, ovarian cancers etc. are very effective, very are widely used in clinical research in recent years, but, limited its range of application owing to reasons such as its dissolubility extreme differences.Large stretch of Ramulus et folium taxi cuspidatae woods has been cultivated on ground such as the Yunnan of China, Shaanxi, Heilungkiang, have abundant natural resources, research is the nano anti-cancer targeted drug of active component with the paclitaxel, helps the utilization of China's natural resources, for China's deep development paclitaxel provides new approach.Chemical bond mould assembly nano target cancer therapy drug system, mode by chemical bonding is rolled in pharmaceutical pack in the degradable carrier exactly, be prepared into nanometer scale, utilize receptor-mediated system directly medicine to be written into tumor region, improve targeting, can improve the relative concentration of medicine greatly again simultaneously at affected part.Because drug-carried nanometer is less, specific surface area is big, adhesion to receptor tissue is big, anelasticity reaches and the time of contact of organizing after the administration, contact area greatly increases, thereby improves bioavailability of medicament, reduces toxicity, reduce pharmaceutical quantities, systematic research has far reaching significance to the nano anti-cancer targeted drug.Though the application of heparin has certain benefit to the treatment of cancer patient, but because this height of heparin anticoagulant matter can limit its application in clinical, therefore the application that is applied to clinical anticoagulant at heparin need be carried out chemical modification, estimate by anticoagulant character delivery system, the delivery system that preparation is described has safety preferably, can avoid more than situation of bleeding that carrier causes in injection process.
Summary of the invention
The object of the present invention is to provide a kind of is that preparing carriers goes out heparin-paclitaxel cancer therapy drug with the heparin derivatives, this heparin-paclitaxel cancer therapy drug induction system not only improves the dissolubility of taxol drug, compare heparin simultaneously, the anticoagulant performance of this system greatly reduces, and compare single taxol drug, its anti-cancer properties also improves a lot.
The objective of the invention is to realize by following manner.
The present invention adopts the paclitaxel loaded or paclitaxel derivant of heparin derivatives, and described heparin derivatives is an oxygen acetylation heparin, and structure is suc as formula shown in the I,
Formula I
Wherein:
X is H or SO
3 -Group,
Y is H, SO
3 -Or COCH
3Group,
N is 1-17,
Wherein oxygen acetylation carboxyl accounts for whole carboxyl 40-85%.
Paclitaxel derivant is amino-acid modified paclitaxel, and its structure is suc as formula shown in the II:
Formula II
Wherein:
R is CH (CH
3)
2, CH
2CH (CH
3)
2Or CH
2C
6H
5Group.
Described aminoacid is valine, leucine or phenylalanine.
The weight of paclitaxel or paclitaxel derivant is the 15-30% of medicine gross weight.
Heparin derivatives forms ester bond or forms amido link with paclitaxel derivant by chemical bonding mode and paclitaxel.
The present invention is with the paclitaxel loaded cancer therapy drug of heparin derivatives and study its anticoagulant performance.Heparin derivatives gets by the esterification preparation of heparin sodium; The paclitaxel cancer therapy drug can be paclitaxel or paclitaxel derivant, and paclitaxel derivant gets by aminoacid and paclitaxel prepared in reaction, and wherein suitable preferred aminoacid is valine, leucine or phenylalanine.Heparin-paclitaxel cancer therapy drug is by heparin derivatives and paclitaxel or paclitaxel derivant forms ester bond by the chemical bonding mode or the amido link preparation gets, medicine of the present invention is used for to the anticoagulant performance of normal person's blood with to the evaluation of MCF-7 breast cancer cell rejection, the result shows, cancer therapy drug of the present invention has the anticoagulant characteristic lower than heparin, and compare single taxol drug, its anti-cancer properties improves a lot.
The specific embodiment
The embodiment of following preparation process and effect is intended to illustrate the present invention rather than limitation of the invention further.
(1) preparation of oxygen acetylation heparin
(250mg 0.1mmol-OH), is dissolved in the 20mL deionized water weighing heparin sodium, and low temperature is down by 732 (H
+) cation exchange resin, and constant to pH value with deionized water drip washing, drench fluid and transfer to pH value to 6.0 with tri-n-butylamine, with the liquid concentration lyophilization get three fourth ammonium heparin derivatives (500mg, 0.1mmol-OH).At N
2Protection is dissolved in it among 10ml DMF down; adding DMAP under stirring (36mg, 0.3mmol), acetic anhydride (1330mg; 13mmol); add again triethylamine (1300mg, 13mmol), behind the ice bath reaction 30h; reaction is transferred to room temperature reaction 24h; reaction is finished, and adds 200mL ice ethanol in the reactant liquor, and magnetic agitation 1h fully precipitates it.Behind the solution centrifugal, abandon the supernatant, precipitation is used a small amount of dissolved in distilled water, passes through 732 (H under the liquid sub
+) cation exchange resin, deionized water drip washing is constant to pH value, drenches to cross Sephadex G-25 sephadex column after fluid concentrates, and deionized water rinsing drenches fluid concentrated frozen drying and obtains oxygen acetylation heparin white solid (140mg), yield 56%.
(2) preparation of paclitaxel and paclitaxel derivant medicine
(1) the former medicine of unmodified paclitaxel abbreviates Drugl as.
(2) the fluorenylmethyloxycarbonyl propylhomoserin (27mg, 0.08mmol) with paclitaxel (60mg, add in 20mL anhydrous methylene chloride 0.072mmol) DMAP (38.7mg, 0.32mmol), 0 ℃ of stirring reaction 30min.In reactant liquor, add EDC (30.4mg again, 0.16mmol) behind 0 ℃ of reaction 30min, be warming up to room temperature reaction 8h, reaction is finished, use 0.1N HCl (20mL) and water (20mL) to wash respectively, with telling organic facies, the water dichloromethane extraction, merge organic facies anhydrous magnesium sulfate drying after-filtration, steaming removes organic facies and gets concentrated solution.In concentrated solution, add and contain 10% tetrahydropyridine 20mL dichloromethane room temperature reaction 2h.Reaction is finished, and concentration of reaction solution, concentrate be with 50mL normal hexane precipitation 2 times, removes supernatant after centrifugal, crude product with column chromatography (chloroform: methanol, 25:1) separate valine modification taxol drug (being called for short Drug2).
(3) adopt said method can prepare leucine modification taxol drug (being called for short Drug3).
(4) adopt said method can prepare phenylalanine modification taxol drug (being called for short Drug4).
(3) preparation of chemical bond mould assembly heparin-taxol drug
0.14g oxygen acetylation heparin is dissolved among the DMF of 20mL, stirs the HClO that adds 0.06g paclitaxel or paclitaxel derivant and catalytic amount down
4, N
2Protection is room temperature reaction 24h down, and reaction is finished and steamed excessive DMF, and product is dissolved in bag filter (MWCO3500) dialysis 2 days of packing into of 5mL deionized water, dialysis solution concentrated freeze-dried white solid product, and measure drug loading by ultraviolet spectroscopy.
(4) the anticoagulant performance is estimated
Adopt pipe: get normal person's venous blood 2.7ml with the disposal vacuum blood taking tube, anticoagulant is the sodium citrate 0.3ml of 0.109M in the blood taking tube.
Normal humanplasma's preparation: above-mentioned blood sampling is shaken up gently, carry out the centrifugal 10min of rotating speed 3000rpm then, collect upper strata liquid (blood plasma, yellow).
The mensuration of activated partial thromboplastin time (APTT): heparin mark product are made into the solution of 0.15u/ml, 0.3u/ml, 0.45u/ml, 0.6u/ml, 0.75u/ml with distilled water.Treat that test sample is made into the solution of 3 μ g/ml with distilled water.In 0.1ml blood plasma, add heparin mark product solution or treat test sample solution 25 microlitres, behind the mixing, add 0.1mlAPTT reagent.Mixed liquor places 37 ℃ of incubators, after 2 minutes, adds the CaCl of 37 ℃ of preheatings
2Solution 0.1ml.PRECIL C2000 type Blood coagulation instrument writes down setting time automatically.Estimate the anticoagulant performance of delivery system by measuring activated partial thromboplastin time (APTT), promptly tire.
(5) anti-cancer properties evaluation
After frozen MCF-7 breast cancer cell recovery, add complete culture solution (RPMI 1640+10% calf serum+0.1% antibiotic), put into 37 ℃, 5%CO
2Cultivate in the incubator.Cell culture is used 0.25% trypsinization to exponential phase of growth, adds the 10mL complete culture solution and adjusts cell concentration, gets 96 porocyte culture plates, and every hole adds cell suspension 100 μ L, and flat board places 37 ℃, 5% CO
2Cultivate 24h in the incubator.
The reference substance paclitaxel is mixed with 0.01,0.1,1,10,100 a μ g/mL5 concentration; Get medicine HD1 to be measured, HD2 and prepare 5 concentration that are equivalent to paclitaxel concentration with complete culture solution respectively.With the culture fluid sucking-off in the 96 porocyte plates, after cleaning with PBS simultaneously, in orifice plate, add the complete culture solution that 100 μ L contain medicine, place and put into 37 ℃, 5% CO
2After cultivating 48h in the incubator, use mtt assay and measure, measure every hole in the OD of 570nm value, calculate cell inhibitory rate with microplate reader:
Cell inhibitory rate (%)=(normal cell hole OD value-dosing cell hole OD value)/normal cell hole OD value * 100%
Sample concentration logarithm value and cell inhibitory rate linear regression calculate the half-inhibition concentration IC50 value of medicine to be measured to the MCF-7 cell.
The anticoagulant performance of concrete delivery system and anti-cancer properties are estimated as follows:
Embodiment 1
Oxygen acetylation heparin n=5, wherein oxygen acetylation carboxyl accounts for whole carboxyls 53%, and medicine is Drugl, and drug loading is 25.4%, the anticoagulant performance, promptly tiring is 25U/mg.The anticoagulant performance of as a comparison, independent oxygen acetylation heparin is 127U/mg; Half-inhibition concentration IC50 value to the MCF-7 cell is 0.65 μ g/mL, and as a comparison, single taxol drug is 4.2 μ g/mL to the half-inhibition concentration IC50 value of MCF-7 cell.
Embodiment 2
Oxygen acetylation heparin n=5, wherein oxygen acetylation carboxyl accounts for whole carboxyls 53%, and medicine is Drug2, and drug loading is 16.3%, the anticoagulant performance, promptly tiring is 17U/mg.The anticoagulant performance of as a comparison, independent oxygen acetylation heparin is 127U/mg; Half-inhibition concentration IC50 value to the MCF-7 cell is 0.42 μ g/mL, and as a comparison, single taxol drug is 4.2 μ g/mL to the half-inhibition concentration IC50 value of MCF-7 cell.
Embodiment 3
Oxygen acetylation heparin n=5, wherein oxygen acetylation carboxyl accounts for whole carboxyls 53%, and medicine is Drug3, and drug loading is 18.4%, the anticoagulant performance, promptly tiring is 28U/mg.The anticoagulant performance of as a comparison, independent oxygen acetylation heparin is 127U/mg; Half-inhibition concentration IC50 value to the MCF-7 cell is 0.046 μ g/mL, and as a comparison, single taxol drug is 4.2 μ g/mL to the half-inhibition concentration IC50 value of MCF-7 cell.
Embodiment 4
Oxygen acetylation heparin n=5, wherein oxygen acetylation carboxyl accounts for whole carboxyls 53%, and medicine is Drug4, and drug loading is 16.1%, the anticoagulant performance, promptly tiring is 12U/mg.The anticoagulant performance of as a comparison, independent oxygen acetylation heparin is 127U/mg; Half-inhibition concentration IC50 value to the MCF-7 cell is 0.037 μ g/mL, and as a comparison, single taxol drug is 4.2 μ g/mL to the half-inhibition concentration IC50 value of MCF-7 cell.
Embodiment 5
Oxygen acetylation heparin n=10, wherein oxygen acetylation carboxyl accounts for whole carboxyls 72%, and medicine is Drug1, and drug loading is 22.8%, the anticoagulant performance, promptly tiring is 29U/mg.The anticoagulant performance of as a comparison, independent oxygen acetylation heparin is 127U/mg; Half-inhibition concentration IC50 value to the MCF-7 cell is 0.57 μ g/mL, and as a comparison, single taxol drug is 4.2 μ g/mL to the half-inhibition concentration IC50 value of MCF-7 cell.
Embodiment 6
Oxygen acetylation heparin n=10, wherein oxygen acetylation carboxyl accounts for whole carboxyls 72%, and medicine is Drug2, and drug loading is 19.2%, the anticoagulant performance, promptly tiring is 20U/mg.The anticoagulant performance of as a comparison, independent oxygen acetylation heparin is 127U/mg; Half-inhibition concentration IC50 value to the MCF-7 cell is 0.35 μ g/mL, and as a comparison, single taxol drug is 4.2 μ g/mL to the half-inhibition concentration IC50 value of MCF-7 cell.
Embodiment 7
Oxygen acetylation heparin n=10, wherein oxygen acetylation carboxyl accounts for whole carboxyls 72%, and medicine is Drug3, and drug loading is 17.9%, the anticoagulant performance, promptly tiring is 24U/mg.The anticoagulant performance of as a comparison, independent oxygen acetylation heparin is 127U/mg; Half-inhibition concentration IC50 value to the MCF-7 cell is 0.078 μ g/mL, and as a comparison, single taxol drug is 4.2 μ g/mL to the half-inhibition concentration IC50 value of MCF-7 cell.
Embodiment 8
Oxygen acetylation heparin n=10, wherein oxygen acetylation carboxyl accounts for whole carboxyls 72%, and medicine is Drug4, and drug loading is 17.2%, the anticoagulant performance, promptly tiring is 15U/mg.The anticoagulant performance of as a comparison, independent oxygen acetylation heparin is 127U/mg; Half-inhibition concentration IC50 value to the MCF-7 cell is 0.081 μ g/mL, and as a comparison, single taxol drug is 4.2 μ g/mL to the half-inhibition concentration IC50 value of MCF-7 cell.
Embodiment 9
Oxygen acetylation heparin n=15, wherein oxygen acetylation carboxyl accounts for whole carboxyls 81%, and medicine is Drug1, and drug loading is 19.2%, the anticoagulant performance, promptly tiring is 27U/mg.The anticoagulant performance of as a comparison, independent oxygen acetylation heparin is 127U/mg; Half-inhibition concentration IC50 value to the MCF-7 cell is 0.62 μ g/mL, and as a comparison, single taxol drug is 4.2 μ g/mL to the half-inhibition concentration IC50 value of MCF-7 cell.
Embodiment 10
Oxygen acetylation heparin n=15, wherein oxygen acetylation carboxyl accounts for whole carboxyls 81%, and medicine is Drug2, and drug loading is 20.3%, the anticoagulant performance, promptly tiring is 25U/mg.The anticoagulant performance of as a comparison, independent oxygen acetylation heparin is 127U/mg; Half-inhibition concentration IC50 value to the MCF-7 cell is 0.25 μ g/mL, and as a comparison, single taxol drug is 4.2 μ g/mL to the half-inhibition concentration IC50 value of MCF-7 cell.
Embodiment 11
Oxygen acetylation heparin n=15, wherein oxygen acetylation carboxyl accounts for whole carboxyls 81%, and medicine is Drug3, and drug loading is 18.8%, the anticoagulant performance, promptly tiring is 29U/mg.The anticoagulant performance of as a comparison, independent oxygen acetylation heparin is 127U/mg; Half-inhibition concentration IC50 value to the MCF-7 cell is 0.046 μ g/mL, and as a comparison, single taxol drug is 4.2 μ g/mL to the half-inhibition concentration IC50 value of MCF-7 cell.
Embodiment 12
Oxygen acetylation heparin n=15, wherein oxygen acetylation carboxyl accounts for whole carboxyls 81%, and medicine is Drug4, and drug loading is 21.6%, the anticoagulant performance, promptly tiring is 17U/mg.The anticoagulant performance of as a comparison, independent oxygen acetylation heparin is 127U/mg; Half-inhibition concentration IC50 value to the MCF-7 cell is 0.052 μ g/mL, and as a comparison, single taxol drug is 4.2 μ g/mL to the half-inhibition concentration IC50 value of MCF-7 cell.
Claims (5)
1, a kind of have low blood-clot resistance heparin-paclitaxel cancer therapy drug, it is characterized in that, adopts the paclitaxel loaded or paclitaxel derivant of heparin derivatives, and described heparin derivatives is an oxygen acetylation heparin, and structure is suc as formula shown in the I,
Formula I
Wherein:
X is H or SO
3 -Group,
Y is H, SO
3 -Or COCH
3Group,
N is 1-17,
Wherein oxygen acetylation carboxyl accounts for whole carboxyl 40-85%.
2, according to claims 1 described a kind of low blood-clot resistance heparin-paclitaxel cancer therapy drug that has, it is characterized in that paclitaxel derivant is amino-acid modified paclitaxel, its structure is suc as formula shown in the II:
Formula II
Wherein:
R is CH (CH
3)
2, CH
2CH (CH
3)
2Or CH
2C
6H
5Group.
3, according to claims 2 described a kind of low blood-clot resistance cancer therapy drugs that have, it is characterized in that described aminoacid is valine, leucine or phenylalanine.
4, according to each described a kind of low blood-clot resistance cancer therapy drug that has of claims 1-3, it is characterized in that the weight of paclitaxel or paclitaxel derivant is the 15-30% of medicine gross weight.
According to each described a kind of low blood-clot resistance cancer therapy drug that has of claims 1-3, it is characterized in that 5, heparin derivatives forms ester bond or forms amido link with paclitaxel derivant by chemical bonding mode and paclitaxel.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101439186A CN101422613A (en) | 2008-12-12 | 2008-12-12 | Anti-cancer medicine containing low anticoagulant property heparin and taxol |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101439186A CN101422613A (en) | 2008-12-12 | 2008-12-12 | Anti-cancer medicine containing low anticoagulant property heparin and taxol |
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|---|---|
| CN101422613A true CN101422613A (en) | 2009-05-06 |
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ID=40613644
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|---|---|---|---|
| CNA2008101439186A Pending CN101422613A (en) | 2008-12-12 | 2008-12-12 | Anti-cancer medicine containing low anticoagulant property heparin and taxol |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012088391A1 (en) * | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Non-ring hydroxy substituted taxanes and methods for synthesizing the same |
| CN103705534A (en) * | 2013-12-30 | 2014-04-09 | 中国药科大学 | Preparation of natural active substance constructed polymer composite medicine and application thereof in inhibiting angiogenesis |
| US9504755B2 (en) | 2008-08-11 | 2016-11-29 | Nektar Therapeutics | Multi-arm polymeric alkanoate conjugates |
| US10098865B2 (en) | 2010-12-22 | 2018-10-16 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of taxane-based compounds |
| CN109731106A (en) * | 2019-03-12 | 2019-05-10 | 南方医科大学 | A kind of preparation method for treating glioma compound |
| US10894087B2 (en) | 2010-12-22 | 2021-01-19 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of cabazitaxel-based compounds |
-
2008
- 2008-12-12 CN CNA2008101439186A patent/CN101422613A/en active Pending
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9504755B2 (en) | 2008-08-11 | 2016-11-29 | Nektar Therapeutics | Multi-arm polymeric alkanoate conjugates |
| US10039737B2 (en) | 2008-08-11 | 2018-08-07 | Nektar Therapeutics | Multi-arm polymeric alkanoate conjugates |
| US11672776B2 (en) | 2008-08-11 | 2023-06-13 | Nektar Therapeutics | Multi-arm polymeric alkanoate conjugates |
| WO2012088391A1 (en) * | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Non-ring hydroxy substituted taxanes and methods for synthesizing the same |
| US9199954B2 (en) | 2010-12-22 | 2015-12-01 | Nektar Therapeutics | Non-ring hydroxy substituted taxanes and methods for synthesizing the same |
| US10098865B2 (en) | 2010-12-22 | 2018-10-16 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of taxane-based compounds |
| US10894087B2 (en) | 2010-12-22 | 2021-01-19 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of cabazitaxel-based compounds |
| US11813241B2 (en) | 2010-12-22 | 2023-11-14 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of taxane-based compounds |
| CN103705534A (en) * | 2013-12-30 | 2014-04-09 | 中国药科大学 | Preparation of natural active substance constructed polymer composite medicine and application thereof in inhibiting angiogenesis |
| CN109731106A (en) * | 2019-03-12 | 2019-05-10 | 南方医科大学 | A kind of preparation method for treating glioma compound |
| CN109731106B (en) * | 2019-03-12 | 2021-04-27 | 南方医科大学 | Preparation method of compound for treating brain glioma |
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Open date: 20090506 |