金纳米结合物用于肿瘤靶向治疗及其“构效关系”研究

Drug-conjugated gold nanoparticle is a nano drug delivery system (DDS) that employs gold nanoparticle as the core and connects drug molecules on its surface via covalent bonds. In essence, drug-conjugated gold nanoparticle is a class of functionalized prodrug with nanostructures, which is the nano and integrated form for the application of prodrug strategy. In this project, to solve the three important problems of the current gold conjugate DDSs, (1) stability, (2) drug loading, and (3) the effective and selective drug release in tumor cells, a series of doxorubicin-conjugated gold nanoparticles with dual stimulation and step-wise release property will be constructed for the research of targeting cancer therapy, based on our previous studies. Adjusting the position of doxorubicin, the size of gold core, and the molecular weight of polyethylene glycol, it is expected to reveal the "structure-efficacy relationship" between conjugate structure and drug efficacy and biological mechanisms of conjugates inside cells. According to "structure-efficacy relationships" and mechanism studies, it allows to explore the physicochemical or materials science proposals for improving therapy efficacy of nanoconjugates, promote basic research of gold conjugates as a candidate for cancer treatment, and expand design ideas of prodrug in biomedical applications.

金纳米结合物药物递送系统是以金纳米粒子作为内核，通过共价键的方式将药物分子连接于金表面的一种纳米药物递送系统。金纳米结合物在本质上是一类具有纳米结构的功能性前体药物（前药），是前药策略的纳米化和集成化。在本课题组前期研究结果和经验的基础上，本项目针对目前金纳米结合物药物递送系统存在的（1）稳定性、（2）载药量和（3）肿瘤细胞药物释放的有效性和选择性这三大问题，构建一类具有"双重刺激、分步释放"性能的阿霉素-金纳米结合物系统，用于肿瘤靶向治疗研究。调控结合物中阿霉素的位置、金核的尺寸和聚乙二醇的分子量，揭示结合物药效发挥的细胞学机制，评价结合物肿瘤靶向治疗的效果，寻找金纳米结合物的结构与其负载药物疗效之间的"构效关系"。根据"构效关系"，探索进一步提高纳米结合物肿瘤治疗效果的物理化学或材料学方案，推进金纳米结合物作为一种肿瘤治疗候选材料的基础研究，扩展前药的设计思想在生物医学领域的相关应用。