具有“药物自控开关”的智能介孔纳米硅球“以毒攻毒”治疗肿瘤

In this research, a smart methenamine-loaded drug-self-gated mesoporous nanoplatform based on pH-sensitive dynamic covalent bond will be developed for cancer therapy. The benzaldehyde-functionalized MSNs will be loaded with DOX and methenamine at pH 6.0. Then, the solution is alkalized to enable the formation of benzoic–imine bonds between DOX and benzaldehyde groups on the pore outlets, finally obtaining the DOX-self-gated nanoparticles. The PEGylated and targeting nanoparticles were carried out through adding the NH2-PEG and targeting molecules (antibody, peptide, etc) during the preparation of DOX-self-gated MSNs. A drug-self-gated strategy for mesoporous nanocarrier could achieve on-demand drug (methenamine and DOX) release at tumor tissue/cells and "fighting fire with fire" to kill cancer cells. The synergistic antitumor mechanism of methenamine and DOX will be studied thoroughly. The cellular internalization mechanism and intracellular trafficking of the nanoparticles within individual cells will be further investigated. The role of autophagy in endocytosis and exocytosis will be also clarified.

本研究拟制备一种载乌洛托品的pH敏感的具有“阿霉素自控开关”的智能介孔纳米硅球载药系统。乌洛托品和阿霉素共载入苯甲醛功能化的介孔纳米硅球，在pH7.4的生理条件下，阿霉素与苯甲醛反应形成苯甲酰亚胺共价键，可自动“堵孔”，形成智能“门控开关”。同时，也可将PEG-NH2和/或带有端氨基的靶向分子如多肽、抗体等连接在苯甲醛功能化的MSNs表面，制备成具有长循环和靶向性能的多功能MSNs载药系统。在弱酸条件下，苯甲酰亚胺共价键自动断裂，阿霉素分子、表面的靶向分子和/或PEG自动释放。MSNs的阿霉素“门控”打开后，乌洛托品暴露在酸性条件下，生成甲醛，与阿霉素协同作用于DNA，从而诱导肿瘤细胞凋亡，“以毒攻毒”杀伤肿瘤细胞。此外，还将研究MSNs抗肿瘤作用机制、对细胞自噬的影响及其分子机制，MSNs的细胞摄取和胞内转运机制，揭示细胞自噬在细胞内吞和外排过程中所发挥的作用。

本项目制备了一种载乌洛托品的pH敏感的具有“阿霉素自控开关”的智能介孔纳米硅球载药系统。乌洛托品和阿霉素共载入苯甲醛功能化的介孔纳米硅球，在pH7.4的生理条件下，阿霉素与苯甲醛反应形成苯甲酰亚胺共价键，可自动“堵孔”，形成智能“门控开关”。同时，将PEG-NH2和/或带有端氨基的靶向分子如多肽、抗体等连接在苯甲醛功能化的MSNs表面，制备成具有长循环和靶向性能的多功能MSNs载药系统。在弱酸条件下，苯甲酰亚胺共价键自动断裂，阿霉素分子、表面的靶向分子和/或PEG自动释放。MSNs的阿霉素“门控”打开后，乌洛托品暴露在酸性条件下，生成甲醛，与阿霉素协同作用于DNA，从而诱导肿瘤细胞凋亡，“以毒攻毒”杀伤肿瘤细胞。此外，还研究MSNs抗肿瘤作用机制、对细胞自噬的影响及其分子机制，MSNs的细胞摄取和胞内转运机制，揭示细胞自噬在细胞内吞和外排过程中所发挥的作用。本项目已在Advanced Materials、Angewandte Chemie International Edition、ACS Nano、Advanced Functional Materials、Advanced Science和Journal of Controlled Release等期刊发表论文20篇，申请2项中国发明专利并获得天津市科技进步二等奖和华夏医学科技奖三等奖。