Development of functional polymeirc micelles responding to intracellular microenvironments for cancer chemotherapy

聚合物胶束是嵌段共聚物的自组装体，是一种很有前途的药物纳米载体系统。事实上，已经在临床试验中研究了几种制剂。聚合物胶束的特征在于几十nm的尺寸和独特的核-壳结构，其中载药核被生物相容性聚（乙二醇）（PEG）链包围。聚合物胶束的这些特性允许它们在血流中的寿命和在它们的全身施用后的有效肿瘤积累。在本项目中，我们制备了pH敏感的聚合物胶束，其中阿霉素（ADR）通过酸不稳定的腙键连接到嵌段共聚物的成核链段的侧链上。该系统在细胞内低pH条件下显示出明显的药物释放，而在生理pH条件下不显示药物释放。我们应用这种pH敏感的聚合物胶束治疗胰腺癌，这是已知的是由于血管和厚纤维化是难治的。结果表明，pH敏感的聚合物胶束对小鼠皮下胰腺癌显示出显著的抗肿瘤功效。同时，用叶酸分子修饰pH敏感性胶束，构建具有肿瘤靶向能力的聚合物胶束。已知大量癌细胞过表达叶酸结合蛋白（FBP）。与非靶向胶束相比，叶酸缀合的胶束更有效地被FBP过表达的癌细胞吸收，在低得多的ADR浓度下实现了显着的抗肿瘤效果。这些结果表明，叶酸偶联胶束的使用可能会降低有效剂量超过游离ADR，提高临床化疗的安全性。因此，本研究中开发的功能性pH敏感聚合物胶束有望提高治疗难治性恶性肿瘤的安全性和有效性。

Polymeric micelles, the self-assemblies of block copolymers, are a promising nanocarrier system for drug delivery. Indeed, several formulations have been studied in clinical trials. Polymeric micelles are characterized by a size of several tens nm and unique core-shell structure, where the drug-loaded core is surrounded by biocompatible poly(ethylene glycol) (PEG) chains. These characteristics of polymeric micelles allow their longevity in the bloodstream and effective tumor accumulation after their systemic administration. In this project, we have prepared pH-sensitive polymeric micelles, in which adriamycin (ADR) is attached to the side chain of the core-forming segment of the block copolymers via an acid-labile hydrazone bond. The system showed appreciable drug release under intracellular low pH conditions, while exhibiting no drug release under physiological pH conditions. We applied such pH-sensitive polymeric micelles for the treatment of pancreatic cancers, which are known to be intractable due to hypovascularity and thick fibrosis. As a result, pH-sensitive polymeric micelles showed significant antitumor efficacy against subcutaneous pancreatic cancers in mice. Meanwhile, the pH-sensitive micelles were modified with a folate molecule to construct the polymeric micelles with the tumor-targetability. A large number of cancer cells are known to overexpress folate-binding proteins (FBP). The folate-conjugated micelles were more efficiently taken up by the FBP-overexpressing cancer cells, achieving remarkable antitumor effect at much lower ADR concentrations than the non-targeted micelles. These results indicate that the use of the folate-conjugated micelles may lower the effective doses over free ADR, improving the safety of the clinical chemotherapy. Thus, functional pH-sensitive polymeric micelles developed in this study are expected to improve the safety and efficacy of the treatments against intractable malignant tumors.