Fundamental relationships between the composition of Pluronic block copolymers and their hypersensitization effect in MDR cancer cells
Fundamental relationships between the composition of Pluronic block copolymers and their hypersensitization effect in MDR cancer cells
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DOI：
10.1023/a:1018942823676
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发表时间：
1999-09-01
影响因子：
3.7
通讯作者：
Kabanov, A
中科院分区：
文献类型：
--
作者：
Batrakova, E;Lee, S;Kabanov, A
目的。先前的研究表明Pluronic嵌段共聚物使多重耐药（MDR）癌细胞超敏，显著增加蒽环类药物和其他抗癌细胞毒素在这些细胞中的细胞毒作用。本研究评估了这些聚合物对(i)多药耐多药癌细胞中多柔比星（Dox）细胞毒性和（ii） p -糖蛋白探针罗丹明123 （R123）细胞积累的剂量依赖性效应。在药物敏感（KB、MCF-7、Aux-B1）和耐多药（KBv、MCF7/ADR、CH(r)C5）细胞单层上进行了Dox细胞毒性和R123积累研究。这两项测试都揭示了Pluronic共聚物在低于临界胶束浓度（CMC）时的强烈影响，并表明这些影响是由于共聚物单链（“unimers”）造成的。使用具有不同长度的疏水性环氧丙烷（PO）和亲水性环氧乙烷（EO）片段的嵌段共聚物，这些研究表明Pluronic单体在MDR细胞中的效力随着其分子疏水性的提高而增加。Pluronic共聚物在R123积累和Dox细胞毒性研究中的组成优化表明，具有中等长度PO链和相对较短EO段的Pluronic共聚物对MDR细胞的净疗效最高。Pluronic嵌段共聚物的结构与其在MDR细胞中的生物反应修饰作用之间的关系有助于确定对MDR肿瘤具有最大功效的配方。
Purpose. Previous studies have demonstrated that Pluronic block copolymers hypersensitize multiple drug resistant (MDR) cancer cells, drastically increasing the cytotoxic effects of anthracyclines and other anticancer cytotoxics in these cells. This work evaluates the dose dependent effects of these polymers on (i) doxorubicin (Dox) cytotoxicity and (ii) cellular accumulation of P-glycoprotein probe, rhodamine 123 (R123) in MDR cancer cells.Methods. Dox cytotoxicity and R123 accumulation studies are performed on monolayers of drug-sensitive (KB, MCF-7, Aux-B1) and MDR (KBv, MCF7/ADR, CH(r)C5) cells.Results. Both tests reveal strong effects of Pluronic copolymers observed at concentrations below the critical micelle concentration (CMC) and suggest that these effects are due to the copolymer single chains ("unimers"). Using block copolymers with various lengths of hydrophobic propylene oxide (PO) and hydrophilic ethylene oxide (EO) segments these studies suggest that the potency of Pluronic unimers in MDR cells increases with elevation of the hydrophobicity of their molecule. Optimization of Pluronic composition in R123 accumulation and Dox cytotoxicity studies reveals that Pluronic copolymers with intermediate lengths of PO chains and relatively short EO segments have the highest net efficacy in MDR cells.Conclusions. The relationship between the structure of Pluronic block copolymers and their biological response modifying effects in MDR cells is useful for determining formulations with maximal efficacy with respect to MDR tumors.