Relationship between the structure of amphiphilic copolymers and their ability to disturb lipid bilayers
Relationship between the structure of amphiphilic copolymers and their ability to disturb lipid bilayers
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DOI：
10.1021/bi048373q
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发表时间：
2005-03-15
期刊：
影响因子：
2.9
通讯作者：
Melik-Nubarov, N
中科院分区：
文献类型：
--
作者：
Demina, T;Grozdova, I;Melik-Nubarov, N
非离子两亲物，特别是环氧乙烷和环氧丙烷的嵌段共聚物（Pluronics）引起对化疗药物表现出多重耐药性的肿瘤细胞的显著化学增敏。该效应是由于抑制了负责药物外排的P-糖蛋白（P-gp）。认为P-gp的抑制可能是由于其脂质环境的改变。事实上，证明了P-gp活性对膜微粘度的高度依赖性[Regev等人（1999）Eur. J.Biochem.259，18-24]，这表明Pluronics影响P-gp活性的能力是由它们对膜结构的作用介导的。我们最近发现，Pluronics在脂质双层上的吸附引起脂质堆积的相当大的干扰[Krylova等人（2003）Chemistry 9. 39303936]。本文研究了19种两亲性共聚物，包括新合成的超支化聚甘油、Pluronic和Brij表面活性剂，它们对脂质体中抗肿瘤药物阿霉素（DOX）的触发和渗透的促进作用。结果表明，共聚物的整体疏水性和微观结构决定了其膜扰动能力。含有聚环氧丙烷的共聚物比含有脂肪族链的聚表面活性剂引起更高的触发器和DOX渗透加速。含有超支化聚甘油“冠”的共聚物的效果更明显，与线性聚（环氧乙烷）链的共聚物相比，表明一个庞大的亲水性嵌段诱导脂质双层中的额外干扰。发现共聚物翻转酶活性与共聚物本体疏水性和其疏水嵌段的货车德瓦尔斯体积的线性组合之间存在良好的相关性.本文提出的共聚物结构与其干扰脂膜能力之间的关系可能有助于设计能够影响活细胞中膜转运蛋白活性的新型两亲性共聚物.
Nonionic amphiphiles and particularly block copolymers of ethylene oxide and propylene oxide (Pluronics) cause pronounced chemosensitization of tumor cells that exhibit multiple resistance to antineoplastic drugs. This effect is due to inhibition of P-glycoprotein (P-gp) responsible for drug efflux. It was sti-ested that the inhibition of P-gp might be due to changes in its lipid surrounding. Indeed, high dependence of P-gp activity on the membrane microviscosity was demonstrated [Regev et al. (1999) Eur. J. Biochem. 259, 18-24], suggesting that the ability of Pluronics to affect the P-gp activity is mediated by their effect on the membrane structure. We have found recently that adsorption of Pluronics on lipid bilayers induced considerable disturbance of the lipid packing [Krylova et al. (2003) Chemistry 9. 39303936]. In the present paper, we studied 19 amphiphilic copolymers, including newly synthesized hyperbranched polyglycerols, Pluronic and Brij surfactants, for their ability to accelerate flip-flop and permeation of antitumor drug doxorubicin (DOX) in liposomes. It was found that not only bulk hydrophobicity but also the chemical microstructure of the copolymer determines its membrane disturbing ability. Copolymers containing polypropylene oxide caused higher acceleration of flip-flop and DOX permeation than polysurfactants containing aliphatic chains. The effects of copolymers containing hyperbranched polyglycerol "corona" were more pronounced, as compared to the copolymers with linear poly(ethylene oxide) chains, indicating that a bulky hydrophilic block induces additional disturbances in the lipid bilayer. A good correlation between the copolymer flippase activity and a linear combination of copolymer bulk hydrophobicity and the van der Waals volume of its hydrophobic block was found. The relationship between the structure of a copolymer and its ability to disturb lipid membranes presented in this paper may be useful for the design of novel amphiphilic copolymers capable of affecting the activity of membrane transporters in living cells.