College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Mol Pharm. 2012 May 7;9(5):1109-17. doi: 10.1021/mp200356w. Epub 2012 Apr 25.
pH-responsive drug carriers derived from polymers containing weak base groups have been shown to improve the antitumor effect of chemotherapeutics. The common interpretation is that a "proton sponge effect" caused by pH-responsive polymers facilitates endosomal membrane destruction and accelerates cytoplasmic drug release in tumor cells. However, the mechanisms by which pH-responsive weak base polymers disrupt membranes have not been expatiated clearly. Herein, we synthesized a series of pH-responsive amphiphilic polyphosphazenes containing diisopropylamino (DPA) side groups with various contents and investigated the effect of DPA content on the actions of polymers with cell membranes. In a certain pH range, the polymers with elevated DPA content showed enhanced membrane disruptive activity. Electrical interactions between the protonated DPA groups of polymers and the cell lipid bilayer are critical for pH-dependent membrane disruption, which can be competitively prevented by serum proteins. On the other hand, the hydrophobic unprotonated DPA moieties can insert into lipophilic regions of cell membrane. These synergic actions caused the alteration of biomembrane permeability consequently. More interestingly, it was also found that DPA-rich polymers exhibit higher P-glycoprotein (P-gp) inhibition activity as compared with the polymer containing only low levels of DPA by efficiently blocking the internal epitope of P-gp. These findings strongly provide rational support for pH-responsive amphiphilic polyphosphazenes containing DPA side groups to be quite promising drug carriers for intracellular drug delivery applications, especially the treatment of P-gp overexpressing, drug-resistant tumors.
含有弱堿基团的聚合物衍生的 pH 响应型药物载体已被证明可以提高化疗药物的抗肿瘤效果。常见的解释是，pH 响应聚合物引起的“质子海绵效应”促进了细胞内体膜的破坏，并加速了肿瘤细胞中细胞质内药物的释放。然而，pH 响应弱堿聚合物破坏膜的机制尚未得到明确阐述。在此，我们合成了一系列含有不同含量二异丙基氨基（DPA）侧基的 pH 响应两亲性聚膦嗪，并研究了 DPA 含量对聚合物与细胞膜相互作用的影响。在一定的 pH 范围内，DPA 含量较高的聚合物表现出增强的膜破坏活性。聚合物中质子化 DPA 基团与细胞膜脂质双层之间的电相互作用对 pH 依赖性膜破坏至关重要，而血清蛋白可以竞争性地阻止这种相互作用。另一方面，疏水性非质子化的 DPA 部分可以插入细胞膜的亲脂区域。这些协同作用导致生物膜通透性的改变。更有趣的是，还发现与仅含有低水平 DPA 的聚合物相比，富含 DPA 的聚合物通过有效地阻断 P-糖蛋白（P-gp）的内部表位，表现出更高的 P-糖蛋白（P-gp）抑制活性。这些发现为含有 DPA 侧基的 pH 响应两亲性聚膦嗪作为很有前途的细胞内药物递送应用的药物载体提供了强有力的合理支持，特别是在治疗 P-gp 过表达、耐药肿瘤方面。
