肿瘤靶向纳米载体-生物降解水凝胶响应性转变体系的构筑、调控及其在肿瘤治疗中的应用研究

Tumor-targeting and long-term treatment are two important points to improve the efficiency of current tumor therapy. However, how to simultaneously perform these two properties on one device is still a issue. The aim of this study is to provide a solution by fabricating a stimuli-responsive nanocarriers-hydrogel switchable theranostic platform for sustained and selective cancer treatment, using mesoporous silica nanoparticles, responsive host-gust molecules functionalized hyaluronic acid (HA) and upconverting nanoparticles. Owing to the specific affinity between the hyaluronic acid on MSNs and the antigen over-expressed on tumor cells, the nanocarrier can selectively attach to tumor cells. The nanocarrier then exploits stumili-responsive interactions between host and gust molecules to in situ self-assemble into a hydrogel under near-infrared radiation or acetic environment (pH value < 7). Upon gelation, the drug loaded MSNs carriers were enclosed in the HA network of hydrogel. Whilst further degradation of the HA in the hydrogelwill result in release of MSNs from the hydrogel, which can then be endocytosed by tumor cells and deliver their drug to the cell. The upconverting nanoparticle is not only in charge of triggering the nanoparticles-hydrogel transformation, but made the circulation and treatment process visible. In summary, our study will integrate the property of tumor targeting, labeling and sustained treatment on one device, showing a new concept for tumor therapy.

特异性靶向富集和局部长期给药是提高肿瘤化疗效果的两个重要因素，但如何同时实现肿瘤治疗的靶向性和长效性依然有待解决。本项目拟制备上转换荧光粒子/介孔二氧化硅纳米核壳结构，并在其中引入肿瘤靶向分子和各种响应性主客体相互作用，构建能够在不同刺激因素下发生粒子-凝胶转变的新型抗肿瘤平台，解决肿瘤治疗中靶向性和长效性无法共存的问题。通过靶向分子与纳米载体的结合，该体系在治疗初期将以粒子状态循环于有机体内并逐步靶向富集到肿瘤组织周围。响应性主客体分子的引入使得纳米载体在红外辐照下或特定肿瘤生理环境中（pH < 7）能够发生快速的凝胶化反应，从而在肿瘤组织周围形成能够长期释放抗肿瘤药物载体的生物降解凝胶。上转换荧光纳米粒子的负载为红外光触发粒子-凝胶转换，以及体系在机体内输送行为和治疗效果的无创监控提供了条件。本项目将实现载体靶向富集、肿瘤实时标记和长效智能药物控释的“三位一体”，开辟肿瘤治疗的新途径。

通过新型药物载体的设计及其结构和功能的调控，实现肿瘤化疗的靶向性和长效性，从而提高肿瘤治疗效果，降低癌症复发几率，具有很重要的临床意义和应用价值。然而如何同时实现针对不可见肿瘤的精准化疗，同时延长药物作用的有效时间依然有待解决。本项目制备了一系列介孔二氧化硅纳米载体，并在其中引入肿瘤靶向分子和各种响应性主客体相互作用，构建能够在不同刺激因素下发生粒子-凝胶转变的新型抗肿瘤平台，解决肿瘤治疗中靶向性和长效性无法共存的问题。通过靶向分子与纳米载体的结合，该体系在治疗初期以粒子状态循环于有机体内并逐步靶向富集到肿瘤组织周围。响应性主客体分子的引入使得纳米载体在红外光辐照下以及特定肿瘤生理环境中（pH < 7）能够发生快速的凝胶化反应，从而在肿瘤组织周围形成纳米载体构成的生物降解凝胶。随着该凝胶在肿瘤生理环境下的缓慢降解，装载抗肿瘤药物的纳米载体能够被缓慢释放到肿瘤组织周围并进入肿瘤细胞，实现长达数周的精准治疗。研究显示我们的载体-凝胶转化体系可以持续杀灭肿瘤细胞并有效避免传统纳米载体短期给药所导致的肿瘤复发，为响应性结构转变材料在癌症治疗领域的应用提供理论基础和关键技术。此外，结合荧光探针的修饰，纳米载体在机体内的输送、凝胶化、长效释放以及治疗效果均可以被无创监控，从而开辟了集载体靶向富集、肿瘤实时标记和长效智能药物控释的“三位一体”肿瘤治疗新途径。