Cytocompatibility and P-glycoprotein Inhibition of Block Copolymers: Structure-Activity Relationship
Cytocompatibility and P-glycoprotein Inhibition of Block Copolymers: Structure-Activity Relationship
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DOI：
10.1021/mp4002848
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发表时间：
2013-08-01
影响因子：
4.9
通讯作者：
Mosquera, V.
中科院分区：
文献类型：
--
作者：
Cambon, A.;Brea, J.;Mosquera, V.
两亲性聚合物胶束极大地提高了疏水性药物的溶解和缓释，为水介质中的货物分子提供了保护环境，有利于降低给药剂量，减少不良副作用，增加血液循环次数和被动靶向特定细胞。除其他变量外，这些能力取决于聚合物链的结构和组成。当聚合单聚体/胶束与细胞紧密接触时，组成，特别是嵌段长度，在细胞反应的改变中发挥着重要作用，例如药物内化过程或转导途径。在这里，我们详细研究了共聚物结构和组成对几种细胞系的细胞活力和细胞反应的作用。为此，我们分析了 30 多种结构相关的共聚物，这些共聚物具有二嵌段和三嵌段结构，包含不同的疏水性嵌段和聚环氧乙烷作为共同的亲水单元，通过测试它们对负责癌细胞多药耐药性的 P-gp 泵流出机制的影响，分析了其细胞相容性和作为“活性”细胞反应调节剂的潜力。细胞活力的经验阈值可以在共聚物 EO/PO 有效值高于约 1 时建立。对于具有三嵌段结构的共聚物，为1.5，而对于二嵌段结构，没有观察到经验规则。此外，一些测试的共聚物（例如，显着增加 P-gp ATP 酶活性的 BO12EO227BO12 和 EO57PO46EO57 以及降低 P-gp ATP 酶活性的 C16EO455C16）被观察到可作为 P-gp 外排泵的有效抑制剂，促进多柔比星（DOXO）在多药耐药体内的积累。 (MDR) NCI-ADR-RES 细胞。
Amphiphilic polymeric micelles greatly improve the solubilization and sustained release of hydrophobic drugs and provide a protective environment for the cargo molecules in aqueous media, which favors lower drug administration doses, reduces adverse side effects, and increases blood circulation times and passive targeting to specific cells. These capabilities depend, among other variables, on the structure and composition of the polymer chains. Composition and, in particular, block length have been shown to play an important role in the modification of cellular responses such as drug internalization processes or transduction pathways when polymeric unimer/micelles are in close contact with cells. Here we present a detailed study about the role copolymer structure and composition play on cell viability and cellular response of several cell lines. To do that, more than 30 structurally related copolymers with diblock and triblock architectures containing different hydrophobic blocks and poly(ethylene oxide) as the common hydrophilic unit have been analyzed regarding cytocompatibility and potential as "active" cell response modifiers by testing their influence on the P-gp pump efflux mechanism responsible of multidrug resistance in cancerous cells. An empirical threshold for cell viability could be established at a copolymer EO/POeffective value above ca. 1.5 for copolymers with triblock structure, whereas no empirical rule could be observed for diblocks. Moreover, some of the tested copolymers (e.g., BO12EO227BO12 and EO57PO46EO57 that notably increased and C16EO455C16 that decreased the P-gp ATPase activity) were observed to act as efficient inhibitors of the P-gp efflux pump promoting an enhanced doxorubicin (DOXO) accumulation inside multidrug resistant (MDR) NCI-ADR-RES cells.