基于药物分子引发聚合的聚磷酸酯大分子前药的可控合成及其用于癌症治疗

Various polymeric prodrugs or polymer-drug conjugates have been synthesized and evaluated at the preclinical stage for cancer therapy. They are, however, still troubled by the requirement of complex procedures for synthesis and purification. This issue can be partially addressed by the use of drug initiated polymerization, which allows for facile one-pot synthesis of polymer-drug conjugates. In this proposal, we propose to develop a novel synthetic strategy of versatile polyphosphoesters-based polymeric prodrugs. Hydroxyl- or amine-containing drugs (e.g., paclitaxel and doxorubicin) will be used to initiate controlled ring-opening polymerization cyclic phosphate monomers. Cyclic phosphate monomers with different ring sizes (5-, 6-, 7-, and 8-membered rings), various functional side groups (e.g., hydroxyl, amine, alkyl, and carboxylic groups) will be synthesized and used as monomers. Metal alkoxide and organocyatlyst will be used as polymerization catalysts. Compared with existing polymeric prodrugs based on polylactide and PHMA, the thus-obtained polyphosphoester-based prodrugs have well-controlled composition, molecular weight, and topological structures. In addition, this strategy allows for the synthesis of amphiphilic prodrugs, which could self-assemble into nanostructures. The in vitro and in vivo capabilities of these conjugates as nanomedicine for cancer therapy will be systematically evaluated. The strategy may provide a novel route to the generation of novel polymeric prodrugs and the formation of corresponding nanoparticles.

高分子键合药是纳米载体药物的重要组成部分，具有良好应用前景，部分已经进入不同临床试验阶段，但其广泛应用受到传统高分子键合药复杂合成路线的制约。基于药物分子引发聚合的大分子前药的新的设计思想有助于解决这一问题，但如何调控这类大分子前药的化学组分、结构和功能对提高药物输送能力和肿瘤治疗效果十分关键。本项目拟基于可降解聚磷酸酯在生物医学材料应用领域的独特性能和结构特点，以小分子化疗药物作为不同结构环状磷酸酯单体开环聚合的引发剂，合成不同结构两亲性聚磷酸酯嵌段聚合物，发展组分、结构和功能可调控，对肿瘤微环境有酶促响应的药物分子引发聚合的聚磷酸酯大分子前药。项目将重点研究药物分子引发聚合的可控合成新方法，建立高效纯化方法和精确的表征手段，研究其物理化学性能及可控性，并在细胞和动物水平揭示其和生物效应的关系，证明药物分子引发聚合的聚磷酸酯大分子前药的优势和重要意义，为纳米药物载体的构建提供新思路。

本项目旨在发展多样的纳米载体进行不同策略的肿瘤治疗，建立了多种针对肿瘤本身和微环境干预的策略，实现了肿瘤生长的高效抑制。主要成果包括：（1）利用二维材料在红外二区吸收的特性实现肿瘤光热治疗；（2）利用超小金颗粒和全氟化碳组成的纳米液滴实现肿瘤原位的放疗增敏；（3）仿生的中性粒细胞纳米颗粒破坏髓系来源的抑制细胞增强免疫治疗（4）共价键的荧光金属环芯聚合物作为造影剂用于细胞成像；（5）建立过氧化氢响应的硫代磷酸酯单体可控聚合的方法。（6）利用葡萄糖氧化酶和过氧化氢还原酶的纳米级联体系实现肿瘤的饥饿治疗；（7）利用双乳化法递送siLDHA调节肿瘤弱酸微环境增敏免疫治疗。基于这些纳米载体策略，我们实现了不同疗法杀伤肿瘤细胞，并改善肿瘤微环境，为肿瘤治疗提供新的有效途径。相关研究成果在Nano Letters、ACS Nano、PNAS、Macromolecules.等SCI刊物上发表研究论文18篇，培养博士生7人、硕士研究生1人。完成了预期目标。