Yolk/Shell结构纳米笼型动态主动靶向给药系统的构建及其热化疗协同抗肿瘤研究

The combination of photothermal therapy (PTT) and chemotherapeutic agents is an encouraging approach,which can result in synergistic effects that are greater than the two treatments alone. Traditional Thermo-chemotherapy could not,however,have ideal effects in vivo. The causes are ascribed to the chemotherapeutics and the thermotherapeutic agent could not simultaneously arrive at the tumor tissure and play a synergistic inhibitory effect. Nanorattle,a new type of Mesoporous Silica nanoparticles(MSNs),have great potential as carries for drug delivery. In these project,we design an original rattle-type systerm with supported lipid bilayers(SLB)for drug delivery.The enhanced fluidity of MSNs-SLB enables the systerm modified with a minimal number of targeting aptamer which is charactersed as high-uptake by cancer cells rather than high-affinity to selectively bind to and become internalized by cancer cells. If sub-nanomolar affinity is undesirable(results in reduced tumour penetration, for example), the affinity of aptamer-targeted carrier can be precisely modulated by incorporating various amounts of fluid and non-fluid lipids into the SLB. The nanorattle,or yolk-shell nanoparticles are consited of a movable core of monodispersed gold nanorod for PTT and an outer shell based on periodic mesoporous organosilica. A hollow structure between the yolk and the shell in nanorattle have huge voids to accommodate Doxorubicin,a model therapeutics agent,as anti-tumor preparations. This intelligent drug-delivery system has a wide application prospect with the advantages of simultaneous achieving Thermo-Chemotherapy, simultaneous achieving photo-trigger drug release & endosome escape,and simultaneous achieving kill two type of prostate cancer(androgen-dependent prostate cancer,ADPC & androgen-independent prostate cancer, AIPC)cells. These reseach,in our opinion,will provides a new platform and a new idea in design of active-targeting drug delivery system.

光热治疗-化疗联合治疗技术未能在体内发挥理想效果，主要受限于化疗药物和光热转换体难以同时到达肿瘤组织，定位协同的发挥功效。Nanorattle是一类新型纳米笼结构的介孔硅纳米粒，具有开发成给药载体的巨大潜力。本项目设计了一种新颖的脂质双层包覆的nanorattle型载药系统：分布在系统表面低拷贝数（减少调理素效应）但高入胞率（而非过分强调高亲和力）的适配体靶头借助脂质双层的流动性达到动态主动靶向的功能，并通过微调这种流动性（以改变脂质双层成分配比的方式）和靶头密度实现对靶细胞可控、适度的亲和力；而内部由Yolk层（光热转换体金纳米棒）、中空层（装载模型药物阿霉素）和壳层（介孔硅）构成的nanorattle提供了对脂质双层良好的支撑稳定和靶头助流作用。该系统有望同步实现化疗和光热治疗（PTT）、同位完成光控定时定位定量释药和内涵体逃逸、同时杀伤两类前列腺癌（雄性激素依赖型和雄性激素非依赖型）细胞。本研究为主动靶向药物递释系统的设计提供了一种新思路、新平台。

本项目旨在构建yolk/shell结构纳米粒（nanorattle）并初步探索其在抗肿瘤主动靶向给药领域的应用价值。按照计划书拟定的研究方案，项目组已经完成了金纳米棒（GNRs），介孔硅包覆的金纳米棒纳米粒（GNRs@mSiO2）等前期重要纳米结构的合成和表征工作，并多次探索和初步合成了以金纳米棒为内核（yolk层）及介孔硅为外壳（shell层）的nanorattle型纳米粒，但是，所合成的这种纳米粒的一致性尚未得到有效控制。目前，项目组正在继续开展这方面的科研攻关工作。