肿瘤的多药耐药是导致肿瘤患者死亡的主要原因之一，肿瘤耐药机制复杂，迄今克服肿瘤耐药尚无突破性进展。本项目拟设计合成对肿瘤细胞内涵体/溶酶体酸性环境和细胞浆内还原性环境同时具有刺激响应性的新型两亲性聚(β-氨基酯)共聚物，构建针对肿瘤凋亡抑制基因Survivin和抑制肿瘤坏死状凋亡的溶酶体保护基因MT2的siRNA或shRNA表达载体，制备能同时包载化疗药物阿霉素（DOX）和两种基因药物、并将其分步骤地释放至细胞内特定位点的DOX/RNA/PBA-PBD共输送纳米载药系统（DRN），从分子、细胞、组织和整体动物水平上研究DRN作为化疗药物输送载体，提高多药耐药肿瘤内药物蓄积和作为RNA输送载体干扰基因表达的效果及降低耐药的机制；该项目旨在以肿瘤多药耐药的不同机制为靶点，利用所构建的新型pH-还原双响应性纳米载药系统，将化疗与基因治疗相结合，协同增效，为改善多药耐药肿瘤治治疗效果提供新思路。

In this project, we will design and synthesize a new amphiphilic poly (β-amino esters) co-polymer with responsiveness to both the endo/lysosomal acidic and cytoplasm reductive environments, construct the multifunctional nanoparticles co-delivering doxorubicin and si/shRNA targeting the apoptosis inhibition gene, Survivin and the necroptosis inhibition gene, MT2 (DRN), which can release the cargoes into specific intracellular site step by step, and investigate the efficacies of DRN to increase the drug accumulation in multidrug resistant tumors as the chemotherapeutic agents vector and to silence the expression of the targeted genes as the RNA carrier. The purpose of this project is focusing on the challenges in clinical cancer chemotherapy, aiming at multiple mechanisms of tumor multidrug resistance, using the constructed pH-reduction dual-responsive nano-sized drug delivery system and improving the therapeutic effect for multidrug resistant tumor by combining chemotherapy with gene therapy to obtain the synergy between them.