自适应两亲性树形分子作为siRNA载体的研究

The promise that small interfering RNA molecules (siRNAs) can efficiently and specifically inactivate disease-related genes brings new hope for treating various diseases including aggressive cancer. However, successful implementation of siRNA therapeutics requires safe and effective vectors, and developing nanocarriers with controlled and synergetic multifunction remains particular challenging. In this project, we would like to construct dendrimer-based delivery systems which can enhance in vivo circulation time, accumulate specifically at tumor lesions, yet with efficient cell uptake and drug release. Specifically, biodegradable and tumor-environment responsive amphiphilic dendrimers bearing labile ester functions and thioacetal moiety sensitive to reactive oxygen species will be designed and synthesized. Their adaptive ability to form stable nanoparticles with siRNA and protect siRNA from degradation will be evaluated. The obtained nanoparticles will be decorated with tumor targeting peptide as nanocarriers for siRNA delivery in a proof-of-concept study. This project realize the controlled and synergetic multifunction via small adaptive self-assembly of low generation multifunctional amphiphilic dendrimers which open a new view for the design of drug delivery system. This approach significantly facilitate the synthesis of effective dendrimeric drug delivery system, will exploit important view to develop biocompatible and intelligent multifunctional delivery platform, and promote the development of siRNA-based gene therapy.

小干扰RNA（siRNA）在治疗肿瘤等重大疾病上颇有应用前景。但体内高效安全递送是提高其成药性的前提。尽管多功能载体尽管在克服siRNA体内转运屏障具有优势，但其功能协同和可控集成仍不理想。本项目利用树形分子独特结构，采用低代树形分子可控合成具有自适应、生物降解、自组装、靶向、细胞膜穿透和胞内环境响应等功能的两亲性树形分子，通过自适应调整其结构最稳定包载siRNA，实现药物富集肿瘤，高效递送至靶细胞内，响应胞内生化环境，自适应释药，产生基因沉默和抗肿瘤效果，同时可自身降解增加安全性。本项目将深入研究树形分子自适应载药和自适应释药机制、多功能协同作用及递药系统对肿瘤治疗的效果。本项目利用简便合成的低代树形分子自适应组装载药实现功能可控集成的理念为多功能药物载体设计提供新思路，对克服高效树形分子合成瓶颈、发挥其作为药物载体材料的独特优势、促进基因治疗的发展具有重要研究意义和潜在临床应用价值。

小干扰RNA（siRNA）在药物开发中具有广阔的应用前景，尤其是肿瘤等重大疾病领域。但是，siRNA本身的性质制约了其进一步的临床应用，构建安全高效siRNA递送体系是提高siRNA成药性的重要前提。本项目利用树形分子独特结构和功能集成和协同放大的特性，通过点击化学可控合成具有自适应性自组装、生物降解性、靶向性、细胞膜穿透和胞内刺激响应性等功能的一系列自适应两亲性树形分子。该系列两亲性树形分子通过疏水相互作用自组装形成均一稳定的组装体，其进一步通过静电相互作用自适应包载siRNA，促进药物在肿瘤部位的富集，高效地送至靶细胞，响应胞内病理刺激，按需释药，产生显著的基因沉效果和抗肿瘤活性。同时，两亲性树形分子在胞内刺激下可自身降解，增加递送体系的安全性。此外，本项目还探索了两亲性树形分子的自组装和多功能协同作用与其自适应载药和释药机制之间的关系。这种基于自适应两亲性树形分子构建的siRNA递送体系为多功能基因药物载体设计提供了新思路，克服了传统树形分子的制备难的共性问题，以发挥其作为药物载体材料的独特优势，对促进了基因治疗的发展具有重要研究意义和潜在临床应用价值。本项目的研究成果共发表论文7篇，其中SCI收录3篇，1篇IF＞10，1篇IF>5，包括J. Am. Chem. Soc.（IF 14.357），J. Control. Release（IF 7.901）和Mater. Sci. Eng. C（IF 4.959）。申请发明专利2项。参加国际会议3次，区域性会议1次，口头报告4次。培养博士生4名，硕士生6名。