尽管化疗协同光动治疗在抗肿瘤领域具有良好的临床应用前景，但如何实现化疗药和光敏剂的高效同步递送仍是一个亟待解决的难题。随着纳米递药系统的发展，将化疗药和光敏剂共载于纳米载体有望提高递送效率。然而，传统纳米载体的非共价共载方式存在载药量低、稳定性差和药物提前泄露等问题，且易导致光敏剂发生聚集淬灭效应。本项目拟设计合成光敏剂-化疗药“光化一体”小分子前药，构建自增敏型ROS触发释药的“光化一体”小分子前药自组装纳米递药系统。将焦脱镁叶绿素a和紫杉醇通过ROS敏感的单硫醚键共价连接，合成“光化一体”小分子前药，前药自组装形成纳米粒，实现焦脱镁叶绿素a和紫杉醇的高效共载和同步递送。激光照射下，光敏剂产生ROS进行光动治疗的同时，与肿瘤细胞内原有的ROS协同促进药物释放，纳米结构解体避免光敏剂的聚集淬灭效应，发挥高效的协同抗肿瘤作用。本项目的研究将为化疗药和光敏剂的高效共载和同步递送提供一种新思路。

Although the combination of chemotherapy and photodynamic therapy (PDT) has good potential application in the clinical treatment of cancer, how to realize efficient co-delivery of chemotherapeutic agents (CA) and photosensitizers (PS) for better synergistic effect is still a major challenge. Some drawbacks of the traditional nanocarriers used for non-covalent co-delivery of CA and PS have greatly limited their clinical application, such as low drug-loading efficiency, poor stability, significant drug leakage in systemic circulation postadministration, and limited PDT efficiency due to the quenching effect of PS trapped in nanocarriers. Herein, this project plans to synthesize porphyrin-paclitaxel (PTX) small-molecule prodrugs and prepare self-facilitated reactive oxygen species (ROS)-responsive prodrug-nanosystems assembled by the porphyrin-PTX prodrugs for chemo-photodynamic therapy. Pyrophaeophorbid a (PPa) is covalently conjugated to PTX using a thioether bond as ROS-responsive chemical linkage to obtain a “Two-in-One” prodrug (PPa-S-PTX). PPa-S-PTX can self-assemble into nanoparticles to realize efficient co-delivery of PPa and PTX with high drug-loading efficacy. In tumor cells, additional ROS produced by laser irradiation together with the intrinsic ROS overexpressed in tumor cells will synergistically facilitate drug release from prodrug nanoparticles. The prodrug nanoassemblies will be disintegrated along with drug release from PPa-S-PTX, resulting in improved synergistic combination of chemotherapy and PDT. This project will provide a new strategy for the rational design of prodrug-based drug delivery systems for high-efficiency co-delivery of CA and PS.