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

聚合物胶束，嵌段共聚物的自组装，是一种很有前途的纳米药物载体系统。事实上，一些配方已经在临床试验中进行了研究。聚合物胶束具有几十纳米大小和独特的核-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使得它们能够在血液中长期存在，并在全身给药后有效地积累肿瘤。在这个项目中，我们制备了ph敏感的聚合物胶束，其中阿霉素（ADR）通过一个酸不稳定的腙键附着在嵌段共聚物的成核段的侧链上。该体系在细胞内低pH条件下有明显的药物释放，而在生理pH条件下无药物释放。我们将这种ph敏感聚合物胶束应用于胰腺癌的治疗，胰腺癌由于血管不足和厚纤维化而难以治疗。结果表明，ph敏感聚合物胶束对小鼠皮下胰腺癌具有明显的抗肿瘤作用。同时，用叶酸分子修饰ph敏感胶束，构建具有肿瘤靶向性的聚合物胶束。已知大量癌细胞过度表达叶酸结合蛋白（FBP）。叶酸偶联胶束被过表达fbp的癌细胞更有效地吸收，在较低的ADR浓度下比非靶向胶束具有显著的抗肿瘤作用。这些结果表明，使用叶酸缀合胶束可以降低有效剂量，从而提高临床化疗的安全性。因此，本研究开发的功能性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.