基于细胞内原位诱导组装的新型癌症靶向治疗材料研究

The project explored to develop a new strategy for cancer targeting therapy via intracellular induced assembly of nanoparticle. The biocompatible multifunctional gold nanoparticle (aptamer@asON@Au) will be developed via surface tethered by antisense oligonucleotide(asON) and aptamer. The principle of surface engineering of nanoparticle via mixed-charge will be explored to promote the stability of aptamer@asON@Au and its circulation time in vivo. The intracellular assembly of aptamer@asON@Au triggered by the mRNA within cancer will be investigated to build up a new concept of mRNA regulated self-assembly. The intracellular mRNA regulated self-assembly of gold nanoparticle will offers a unique means for scientists to integrate nanoparticle aggregation with inherent oligonucleotide assemble inside cells for developing new targeting therapeutics for cancer. The “spatiotemporally concerted” effect of gene silencing and the cell apoptosis, due to the aggregation of Au nanoparticle and its NIR photothermal effect, may provide new effective anticancer therapy in vivo.

本项目以细胞层次的癌症靶向治疗为背景，突破传统的受激解组装释放途径，探索制备基于细胞内原位诱导组装的癌细胞靶向治疗新材料。项目依托具有自主创新特点的混合电荷金纳米微粒平台，将核酸适配体（aptamer）技术、反义寡核苷酸（asON）技术和小尺寸金纳米微粒技术结合，制备具有高生物安全性和长效循环能力的aptamer及asON联合修饰小尺寸金纳米微粒（aptamer@ asON@Au）；通过aptamer和癌细胞表面受体的特异性选择作用实现靶向内吞；并深入研究癌细胞内特异性mRNA诱导asON@Au的组装行为，揭示癌细胞内原位诱导asON@Au组装对癌细胞凋亡行为及近红外热杀灭效应的基本规律，为基于癌细胞内受激组装实现癌细胞靶向治疗的创新途径建立理论依据和切实可行的技术途径。

本项目以细胞层次的癌症靶向治疗为背景，突破传统的受激解组装释放途径，我们成功制备了反义寡核苷酸修饰金纳米微粒asON@Au，实现了通过癌细胞内特异性survivin mRNA诱导asON@Au的胞内原位组装，提高了纳米粒子在细胞内的滞留性能。研究了癌细胞内原位诱导的asON@Au组装对癌细胞凋亡行为及近红外热杀灭效应的基本规律，为基于癌细胞内受激组装实现癌细胞靶向治疗的创新途径建立理论依据和切实可行的技术途径。达到了预期目标。.在以上工作的基础上，依据肿瘤细胞内谷胱甘肽和pH值的特性，拓展构建了谷胱甘肽和pH值介导的癌细胞内原位诱导组装材料。制备了基于环糊精主客体组装的光动力学纳米功能载体，为构建具有癌症光动力学治疗的材料提供了切实可行的方法。研究肿瘤细胞内源信号受激释放的基本规律，实现了在组织、细胞甚至亚细胞层次上的靶向传递，获得了多种新型癌症靶向治疗材料。..