Demina Tatiana, Grozdova Irina, Krylova Oxana, Zhirnov Artem, Istratov Vladislav, Frey Holger, Kautz Holger, Melik-Nubarov Nikolay
Chemistry Department, Lomonosov Moscow State University, Vorobiovy Gory, 119899 Moscow, Russia.
Biochemistry. 2005 Mar 15;44(10):4042-54. doi: 10.1021/bi048373q.
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 suggested 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, 3930-3936]. 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.
非离子两亲物，尤其是环氧乙烷和环氧丙烷的嵌段共聚物（普朗尼克），可使对抗肿瘤药物表现出多重耐药性的肿瘤细胞产生显著的化学增敏作用。这种效应是由于抑制了负责药物外排的P-糖蛋白（P-gp）。有人认为，对P-gp的抑制可能是由于其脂质环境的变化。事实上，已证明P-gp活性对膜微粘度高度依赖[雷格夫等人（1999年），《欧洲生物化学杂志》259卷，18 - 24页]，这表明普朗尼克影响P-gp活性的能力是由它们对膜结构的影响介导的。我们最近发现，普朗尼克在脂质双层上的吸附会引起脂质堆积的显著扰动[克里洛娃等人（2003年），《化学》9卷，3930 - 3936页]。在本文中，我们研究了19种两亲共聚物，包括新合成的超支化聚甘油、普朗尼克和布里杰表面活性剂，考察它们加速脂质体中抗肿瘤药物阿霉素（DOX）翻转和渗透的能力。结果发现，不仅共聚物的整体疏水性，而且其化学微观结构也决定了其膜扰动能力。含环氧丙烷的共聚物比含脂肪链的多表面活性剂能更有效地加速翻转和DOX渗透。与具有线性聚环氧乙烷链的共聚物相比，含超支化聚甘油“冠”的共聚物的影响更为显著，这表明一个庞大的亲水嵌段会在脂质双层中引起额外的扰动。发现共聚物翻转酶活性与共聚物整体疏水性及其疏水嵌段的范德华体积的线性组合之间存在良好的相关性。本文所呈现的共聚物结构与其扰动脂质膜能力之间的关系，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共聚物。
