MB/Dox-AuNP@SiO2-mAb靶向继发联动控释系统的构建及诊疗相关性表征

Current real-time visible monitoring of drug release in tumor site is still in the blind area, which split the therapy and diagnosis. Our previous study found that the aggregation and dispersed Au nanoparticles have significant differences on CT values, which positively correlated to the drug release rate in tumor. According to the result obtained, the MB/Dox-AuNP@SiO2-mAb system was built up by dual drug loading, designing stimuli responsive drug release layer and targeting decoration. After the system enter the cells via endocytosis, the high concentration level GSH trigger the PEG layer dissociation, the drug and AuNP start to release in the endo/lysosomes, which could be used for building up the mathematics model based on the AuNP aggregation and MB release, realizing the visible and digital monitoring drug release in tumor. The light irradiation was performed at the CT value which correlated to the MB release peak, enhanced the permeability of endo/lysosome membrane, and triggered the second drug release in cytoplasm. The drug concentration simultaneously arrived and keep at the therapeutic level, avoiding P-gp pump active, overcome MDR and maximize the anti tumor efficacy. We then search proper tumor models, investigated the correlations among the drug release in tumor, CT values and therapeutic efficacy. The goal of this project is to provide a new strategy for invasive drug visible monitoring theranostics.

现有的诊疗纳米药物在动态监测瘤内释药方面仍属盲区，诊疗处于割裂状态。项目前期发现，分散态和团聚态的纳米金（AuNP）具有显著CT值差异，且CT值与瘤内释药呈正相关。本课题通过双重载药，智能控释堵孔层及靶向修饰，构建具有继发联动控释功能的靶向MB/Dox-AuNP@SiO2-mAb体系。体系特异性内化入胞后，先经高浓度谷胱甘肽（GSH）触发堵孔层脱去，MB、Dox及AuNP在内体进入释放模式，依据瘤体CT值与瘤内释药率的相关性，构建MB释放率与CT值的数学模型，实现瘤内释药的数字化图像监测；通过CT值提示内体释药达峰，适值给予光刺激，增强内体膜通透性，触发第二次胞浆释药，使胞浆DOX浓度达到并稳定在治疗窗水平，避免启动P-gp耐药泵，克服多药耐药性，实现疗效最大化。考察不同肿瘤模型，交叉验证“瘤体CT值-瘤内释药率-疗效”三者之间的拟合关系，为瘤内药物继发联动控释的可视诊疗一体化提供新策略。

本课题的预期研究目标分为两部分，（1）构建靶向入胞、瘤内可视化智能 释药且安全高效的“诊疗一体化”MB/Dox-AuNP@SiO2-mAb 体系，建立 CT值变化与瘤内释药的对应关系，实现“瘤内释药”可视化。（2）基于材料继发联动控释原理，通过 CT值判断胞内MB 释放达峰时间，适值启动光刺激，迅速增高胞浆Dox浓度，克服MDR实现疗效最大化。构建一定范围内“瘤体CT 值”-“瘤内释药”-“协同作用疗效”同步统一的数学模型，为个体化用药提供初步理论依据。在课题实施过程中，通过5部分研究内容，已完全实现研究目标，并进行了课题延伸拓展研究。包括：1）基于自解离二氧化硅诊疗一体化纳米递药系统的构建及其诊疗相关性表征研究；2）基于自解离二氧化硅“大小复合”式纳米递送系统的序贯光动力治疗及联合化疗研究；3）基于自解离二氧化硅“鸡尾酒”式纳米递送系统的序贯化疗与序贯光动力治疗研究；4）以MB为光敏剂的自解离二氧化硅递送系统逆转多药耐药性作用及机制的研究；5）开发精准定量溶酶体pH值及其变化的自解离系统。研究结果已发表SCI论文13篇，申请发明专利2项。本项目的研究，为肿瘤诊疗相关性表征提供了新策略、新方法及新技术。