自增敏型ROS触发释药的卟啉-紫杉醇“光化一体”小分子前药自组装纳米递药系统的研究

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.

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。

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，合成一种新型的“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。本项目取得的具体研究成果总结如下：（1）设计合成了一个氧化敏感的“光化一体”前药（PPa-S-PTX）和一个非敏感的“光化一体”对照前药（PPa-C-PTX），研究发现共价修饰对PPa的紫外和荧光光谱没有显著影响；（2）PPa-S-PTX和PPa-C-PTX均能自组装形成纳米粒，“光化一体”前药自组装纳米粒具有良好的稳定性；（3）ROS敏感的“光化一体”前药自组装纳米粒能有效应对光敏剂PPa的聚集淬灭效应，并在激光照射下能产生大量的单线态氧，在H2O2和激光同时存在的条件下，能够协同促进PTX的快速释放；（4）体外细胞毒实验结果表明ROS敏感的“光化一体”前药自组装纳米粒因存在化疗-光动力学的双协同作用，能够有效促进肿瘤细胞的凋亡；（5）PEG化的“光化一体”前药自组装纳米粒能显著延长紫杉醇和PPa在血液中的循环时间，同时通过化学偶联的方式能够实现PPa和PTX的同步药物递送，并能显著增加药物在肿瘤部位的蓄积；（6）化疗联合光动治疗协同抗肿瘤的“双协同”作用显著提高了抗肿瘤的效果，且未对机体造成显著的非特异性毒性。综上所述，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。