聚磷酸酯纳米载体共负载化疗药物及光热试剂协同增强抗肿瘤效果的研究

Simultaneous delivery of chemotheraputic drug and photothermal agent (photothermal-chemotherapy) using polymeric nanoparticles has emerged as a promising strategy to improve the anticancer efficacy. However, the current photothermal-chemotherapy via polymeric co-delivery system did not demonstrate the synergistic effect. Recent studies demonstrated that the release rate of the encapsulated chemotheraputic drug by near-infrared light (NIR) irradiation is closely related to its synergistic tumor suppression effect. The preliminary work of the project showed that the heat generated by the absorption of NIR via encapsualted photothermal agent can trigged chemotheraputic drug rapid release from hydrophobic polyphosphoester-based nanoparticles. In this project, we aim at developing hydrophobic polyphosphoester with different side chain and its copolymers, and preparing the polymeric nanoparticles by these polymers to encapsulate chemotheraputic drug and photothermal agent. The chemotheraputic drug and photothermal agent can be simultaneously delivered to the same tumor cells for synergistic tumor suppression effect. We will investigate the relationship between the structure of polymeric delivery systems and synergistic tumor suppression effect. This project will provide provide valuable reference for design and application chemotheraputic drug and photothermal agent encapsulated polymeric delivery system.

利用高分子纳米载体同步输送化疗药物和光热试剂，实现化疗和光热疗联用有望提高抗肿瘤疗效。然而，现有高分子纳米载体系统同步输送化疗药物和光热试剂，仅获得两种疗法对肿瘤杀伤的叠加效果，未能实现抑制肿瘤的协同增效。研究发现，在光热转换时，化疗药物从载体的释放速率与其抗肿瘤协同效应密切相关。本项目的前期工作表明，具有较低粘流温度的疏水性聚磷酸酯作为化疗药物及光热试剂输送载体，在光热转换时，有助于药物从其快速释放。本项目拟在合成具有不同化学结构和组成的疏水性聚磷酸酯及其共聚物的基础上，制备高分子纳米颗粒，作为化疗药物和光热试剂的共输送载体，以同步输送化疗药物和光热试剂到肿瘤组织，实现化疗和光热疗法协同增效，并深入研究载体结构与抗肿瘤效应的构效关系，以及协同增效的机制。本项目研究将为同步输送化疗药物和光热试剂的高分子纳米载体的设计和应用提供有价值的参考。

本项目旨在构建合成具有不同化学结构和组成的疏水性聚磷酸酯纳米载体，同步输送化疗药物和光热试剂，利用聚磷酸酯室温下处于粘流态的特点，实现光热效应触发的药物超敏释放，实现化疗和光热疗法协同增效。主要成果包括：（1）成功合成多种具有不同侧链基团的疏水性聚磷酸酯材料，制备了基于疏水性聚磷酸酯的高分子纳米颗粒；（2）基于疏水性聚磷酸酯材料，共包载光热试剂和化疗药物，揭示了微量光热效应触发化疗药物的超敏释放效应，并阐明了其机制和体内外疗效；（3）聚磷酸酯纳米载体负载具有光热效应的共轭聚合物，提高光稳定性，用于触发药物超敏释放；（4）发展ROS敏感的聚磷酸酯材料，结合光敏剂在光照条件下产生的光动力效应，实现类似于光热超发药物释放的效应。本项研究的成果Nano Lett.、Adv. Funct. Mater.、Chem. Mater.、Biomaterials等SCI刊物上发表研究论文19篇，2篇论文入围ESI高被引论文，1篇论文曾入围ESI热点论文，培养硕士研究生7人。