Department of Nanoengineering and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
ACS Nano. 2010 Jan 26;4(1):251-8. doi: 10.1021/nn9014032.
We report the synthesis of novel acid-responsive therapeutic nanoparticles (NPs) with sub-100 nm size consisting of polymer--cisplatin conjugates. The uniqueness of these drug delivery polymeric NPs lies in the covalent conjugation of each cisplatin drug to the hydrophobic segment of two biocompatible diblock copolymer chains through a hydrazone bond, resulting in highly differential drug release profile at different environmental acidity. We demonstrate that the synthesized polymer--cisplatin conjugates can readily precipitate to form sub-100 nm NPs in aqueous solution due to their very low critical micelle concentration (CMC). The resulting NPs show well-controlled cisplatin loading yield, excellent acid-responsive drug release kinetics, and enhanced in vitro cytotoxicity against ovarian cancer cells as compared to free cisplatin. As an environmentally sensitive drug delivery vehicle, these NPs can potentially minimize the drug loss during NP circulation in the blood, where the pH value is neutral, and trigger rapid intracellular drug release after the NPs are endocytosed by the target cells. This characteristic drug release profile holds the promise to suppress cancer cell chemoresistance by rapidly releasing a high dose of chemotherapy drugs inside the tumor cells, thereby improving the therapeutic efficacy of the drug payload.
我们报告了一种新型酸响应治疗纳米粒子（NPs）的合成，这些 NPs 的尺寸小于 100nm，由聚合物-顺铂缀合物组成。这些药物传递聚合物 NPs 的独特之处在于，每个顺铂药物通过腙键共价连接到两条两亲性嵌段共聚物链的疏水区段，从而在不同的环境酸度下产生高度差异化的药物释放曲线。我们证明，由于其极低的临界胶束浓度（CMC），合成的聚合物-顺铂缀合物可以在水溶液中轻易沉淀形成小于 100nm 的 NPs。与游离顺铂相比，所得 NPs 具有良好的顺铂载药产率、优异的酸响应药物释放动力学和增强的体外卵巢癌细胞毒性。作为一种环境敏感的药物传递载体，这些 NPs 可以在 NPs 在血液中循环时最小化药物损失，因为血液中的 pH 值为中性，并且在 NPs 被靶细胞内吞后迅速释放大量化疗药物。这种特征性的药物释放曲线有望通过在肿瘤细胞内迅速释放高剂量的化疗药物来抑制癌细胞的化疗耐药性，从而提高药物有效载荷的治疗效果。
