光/还原双重响应性多功能时序释放可控型聚合物纳米共载siRNA和化疗药物体系的制备及评价

Polymer based co-delivery system that can simultaneously deliver siRNA and chemotherapeutic drug to the tumor is a promising strategy for effective treatments of cancers with synergistic or combined effects. In this project, we will prepare a series of multifunctional amphiphilic linear-block-hyperbranched star copolymers with a hydrophobic light-responsive linear polymer chain and a hydrophilic disulfide bond containing hyperbranched poly(amido amine)-star- polyethylene glycol polymer chain. The polymer can self-assembly and self-crosslinking into a multifunctional shell-crosslinked core-shell-corona nano-micelles for co-delivery of siRNA and chemotherapeutic drug. The co-delivery system can controlled sequential release of siRNA and chemotherapeutic drug due to the dual-responsive to light and reduction. In cytoplasm, the disulfide crosslinked shell was reduced to small pieces, the siRNA was released and silence the targeted gene, and the drug-resistance cancer cells would re-sensitive to the chemotherapeutic drug. At a predetermined time, best synergistic effects would be achieved with light controlled drug release. Ii is believed that dual-responsive multifunctional delivery system with well stability and long circulation time would be provide useful information for the design of polymer co-delivery system and show great potential application in combination therapy.

利用聚合物共载体系同时输送siRNA和化疗药物实现联合治疗，发挥协同增效作用，可望达到更好的癌症治疗效果。本项目设计合成一类疏水性光响应性的线性聚合物嵌段亲水性的含-S-S-单元的还原响应性超支化聚酰胺-胺-聚乙二醇星形聚合物，利用自组装-自交联法制备具有光和还原双重响应性的多功能壳交联型核-壳-冠聚合物纳米胶束，用于siRNA和化疗药物的共载输送及可控时序释放的研究。一方面先通过还原响应性控制siRNA在细胞质内快速释放，沉默相关抗药性基因的表达，使癌细胞重新对化疗药物敏感；另一方面通过光控制化疗药物在细胞内的释放时机，实现联合治疗的最佳化。该共载体系稳定性好，能长时间体内循环，外围具有可修饰功能团，具备siRNA和化疗药物的可控时序释放性能，其研究具有较大的理论意义和潜在应用价值。

利用聚合物共载体系同时输送siRNA和化疗药物实现联合治疗发挥协同增效作用，可望达到更好的癌症治疗效果。当前通过设计，合成多功能的共载体系非常关键。本项目设计合成了一类具有温度、pH及还原响应性的超支化聚酰胺-胺聚合物，对聚合物的结构性能、细胞毒性、转染效果等进行了研究。研究结果表明，引入pH响应降解单元的还原响应性超支化聚酰胺-胺在pH为5.0下的降解速率是在pH为7.4下降解速率的120倍；由于引入酸降解单元，其毒性相比还原响应性超支化聚酰胺-胺大幅降低，同时仍具有较高的转染效率，是一类潜在的低毒高效基因载体或基因/药物共载体。