Krylova Oxana O, Pohl Peter
Forschungsinstitut für Molekulare Pharmakologie, Campus Berlin-Buch, Robert-Roessle Strasse 10, 13125 Berlin, Germany.
Biochemistry. 2004 Mar 30;43(12):3696-703. doi: 10.1021/bi035768l.
Pluronic block copolymers (triblock copolymers of poly(ethylene oxide) and poly(propylene oxide)) exhibit a chemosensitizing effect on multidrug resistant cell lines. Changes in membrane permeability are hypothesized to be responsible because inhibition of drug transport mediated by both the multidrug-resistance-associated protein and the P-glycoprotein drug efflux system has been observed. To test this hypothesis, we now have studied the ion conductivity mediated by Pluronic L61. Besides a detergent-like action, the copolymer was able to form regular channels and to exhibit carrier activity. Long living ion channels were formed by polymer oligomerization. Aggregate equilibrium was shifted toward L61 monomers and dimers, which operated as mobile carriers. Copolymer-induced membrane permeability for potassium ions (1 M KCl) was less than 10(-8) cm s(-1), whereas the permeability for uncharged doxorubicin molecules (1 mM) was equal to 5 x 10(-4) cm s(-1). The results are consistent with reports about an increased doxorubicin accumulation in cells (Venne, Li, S., Mandeville, R., Kabanov, A., and Alakhov, V. Y. (1996) Cancer Res. 56, 3626-3629). However, the increased permeability contrasts with the polymer-mediated decrease of drug efflux from cells. Preferential polymer binding to membrane proteins may mask the unspecific effect of L61 observed on lipid bilayers.
普朗尼克嵌段共聚物（聚环氧乙烷和聚环氧丙烷的三嵌段共聚物）对多药耐药细胞系具有化学增敏作用。据推测，膜通透性的改变是其原因所在，因为已观察到多药耐药相关蛋白和P - 糖蛋白药物外排系统介导的药物转运受到抑制。为验证这一假设，我们现在研究了普朗尼克L61介导的离子电导率。除了具有类似去污剂的作用外，该共聚物还能够形成规则通道并表现出载体活性。通过聚合物低聚作用形成了长效离子通道。聚集体平衡向作为移动载体的L61单体和二聚体方向移动。共聚物诱导的钾离子（1 M KCl）膜通透性小于10^(-8) cm s^(-1)，而对于不带电荷的阿霉素分子（1 mM），其通透性等于5×10^(-4) cm s^(-1)。这些结果与关于细胞中阿霉素积累增加的报道一致（Venne, Li, S., Mandeville, R., Kabanov, A., and Alakhov, V. Y. (1996) Cancer Res. 56, 3626 - 3629）。然而，通透性的增加与聚合物介导的细胞内药物外排减少形成对比。聚合物与膜蛋白的优先结合可能掩盖了在脂质双层上观察到的L61的非特异性作用。
