有机/无机杂化纳米药物输运系统的设计、制备及其在药物共输运中的应用探索

This project will design and synthesize a new type of molecularly organic/inorganic hybrid hollow periodic mesoporous organosilica nanoparticles (HPMOs) to overcome the drawbacks of tranditional inorganic mesoporous silica nanoparticles (MSNs), such as low degradation rates and their biocompatibility. Furthermore, the hollow nanostructure and mesopores will be tailored to co-load two types of anticancer drugs with different functions. Such co-loading and co-delivery of anticancer drugs can reverse the multi-drug resistance of cancer cells,restrict the metastasis of cancer cells and reduce the side-effects of anticancer drugs. This project innovatively employs the SiO2-based etching chemistry to design and prepare HPMOs with tailored dispersity, particle sizes, pore sizes, compositions, shell-thickness, etc..The biodegradation and biological effects will be systematically investigated. The anticancer effects of co-loaded HPMOs will be evaluated from in vitro to in vivo (breast cancer models of multidrug-resistant MCF-7/ADR and metastatic 4T1), and the detailed mechanism will be studied. The launching of this project will play the significant role for the development of nano-synthetic chemistry and achievement of chemotherapy with high efficiency, which will further give the strong impetus to the clinical applications of inorganic nanobiomaterials.

本项目通过设计与制备一种在分子层次高度有机/无机杂化的新型介孔有机硅空心纳米粒子（HPMOs），克服传统无机质介孔SiO2纳米粒子（MSNs）降解性和生物相容性较差的难题。进一步通过HPMOs空心纳米结构和介孔孔道的调控实现两种具有不同功效的抗癌药物分子的共负载，实现逆转肿瘤细胞耐药性、抑制肿瘤细胞转移和降低抗癌药物毒副作用的多重目的。本项用创新采用SiO2刻蚀化学调控HPMOs的分散性和粒径、孔径、组成、壁厚、空腔大小等关键结构参数；系统地评价该有机/无机杂化纳米粒子的生物降解性与细胞生物学效应；通过体外与体内动物乳腺癌模型（MCF-7/ADR耐药模型和4T1转移模型）研究HPMOs共负载抗癌药物的药效，并考察其作用机制。本项目的开展将对纳米合成化学的发展和实现肿瘤的高效化疗具有重要的意义，有望推动无机纳米生物材料的临床应用。

分子层次有机/无机杂化的介孔有机硅纳米颗粒结合了有机载体和无机载体的优点，是一类具有重要临床转化前景的药物输运载体材料。本项目创新地基于氧化硅刻蚀化学的基础原理，实现了单分散介孔有机硅空心纳米颗粒的可控制备，并对其化学组成、粒径、孔径等关键结构参数进行了调控。此外，系统的考察并调控了介孔有机硅空心纳米颗粒的生物降解性，并从体外和体内系统地评价了介孔有机硅空心纳米颗粒的体内生物安全性。基于介孔有机硅空心纳米颗粒，实现了针对肿瘤的高效化疗。在此基础上，基于介孔有机硅共输运抗癌药物和治疗基因，成功实现了逆转乳腺癌肿瘤细胞耐药性和抑制肿瘤细胞转移，并采用免疫组化和Western-blot等方法系统地研究了利用介孔有机硅空心纳米颗粒提高化疗药效的分子机制。基于介孔有机硅空心纳米颗粒的良好降解性和高生物安全性，以及高的药物输运特性，因此其具有良好的临床转化前景。后续研究就系统地从长期生物安全性开展研究，进一步推动其临床试验的开展。