Block copolymer-based formulation of doxorubicin. From cell screen to clinical trials
Block copolymer-based formulation of doxorubicin. From cell screen to clinical trials
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DOI：
10.1016/s0927-7765(99)00064-8
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发表时间：
1999-11-01
影响因子：
5.8
通讯作者：
Kabanov, A
中科院分区：
文献类型：
--
作者：
Alakhov, V;Klinski, E;Kabanov, A
一种新的多柔比星制剂（SP1049C）已经利用两种聚环氧乙烷 - 聚环氧丙烷嵌段共聚物，特别是普朗尼克L61和普朗尼克F127的组合研制出来。对该产品在细胞筛选组上的细胞毒活性分析表明，SP1049C对多药耐药细胞高度有效，这些细胞通常对多柔比星和大多数其他细胞毒药物不敏感。进一步的机制研究揭示，SP1049C比多柔比星具有更高的活性，原因在于：（i）药物摄取增加；（ii）抑制能量依赖型药物外排；（iii）细胞内药物运输的改变。体内肿瘤模型实验证实了SP1049C对耐药肿瘤的高效性，并且表明该产品比多柔比星具有更广泛的疗效。对SP1049C的药代动力学和生物分布分析表明，它在肿瘤组织中的蓄积比多柔比星更有效，而该制剂在正常组织中的分布与多柔比星相似。对SP1049C中使用的共聚物成分以及产品本身的毒性研究表明，载体具有较高的安全边际，而SP1049C的毒性与多柔比星相似，这表明在SP1049C的临床试验中不应预期有额外的不良反应。（C）1999年，爱思唯尔科学出版社。版权所有。
A new doxorubicin formulation (SP1049C) has been developed using a combination of two polyethylene oxide polypropylene oxide block copolymers, in particular Pluronic L61 and Pluronic F127. The analysis of cytotoxic activity of this product on the cell screen panel has shown that SP1049C is highly effective against multidrug resistant cells that are normally not susceptible to doxorubicin and most other cytotoxic drugs. Further mechanistic studies have revealed that SP1049C has higher activity than doxorubicin due to: (i) increase in the drug uptake; (ii) inhibition of the energy-dependent drug efflux; and (iii) changes in intracellular drug trafficking. The experiments on in vivo tumour models have confirmed high efficacy of SP1049C against drug-resistant tumours, as well as suggested that this product has considerably broader efficacy than doxorubicin. The analysis of pharmacokinetics and biodistribution of SP1049C has shown that it accumulates in tumour tissue more effectively than doxorubicin, while distribution of the formulation in normal tissues is similar to that of doxorubicin. The toxicity studies of the copolymer composition used in SP1049C and of the product itself have demonstrated that the carrier has high safety margin, while toxicity of SP1049C is similar to that of doxorubicin suggesting that no additional adverse effects should be expected in clinical trials of SP1049C. (C) 1999 Elsevier Science B.V. All rights reserved.