肿瘤细胞对药物的耐药性以及药物较大的毒副作用是肿瘤化疗过程中面临的关键问题。本项目拟构建基质金属蛋白酶2（MMP-2）触发的肿瘤细胞/亚细胞器双重靶向的两亲性多肽类药物传递体系用以克服肿瘤细胞耐药性。本项目拟提出“三位一体”的治疗策略杀灭耐药性肿瘤细胞，即通过MMP-2响应性药物传递增加药物在耐药性肿瘤细胞中的内吞；化学治疗与光动力学治疗的联合治疗；降低细胞内的关键活性物质如三磷酸腺苷（ATP）含量，从而降低药物的主动外排。通过体外MMP-2酶响应性的肿瘤细胞靶向、细胞亚细胞器完整性、药物的内吞与外排、毒性测试以及动物体内的抗肿瘤实验系统评估该药物传递体系对肿瘤耐药性的抑制。深入探讨光照条件、细胞内ATP等物质的含量、耐药性细胞存活率之间的关系，深层次地揭示亚细胞器的破坏在抑制肿瘤细胞耐药性中的机制,为新型的抑制肿瘤耐药性体系的设计提供新思路。

Tumor therapy always suffers from the barrier of drug resistance upon chemotherapy with undersired side effects. In this project, we designed amphiphilic peptide-based matrix metalloproteinase 2 (MMP-2)-triggered tumor cellular/subcellular organelles dual-targeted drug delivery systems to overcome drug resistance. Trinitarian therapeutical stragety will be proposed to ablation of drug resistant cells, i.e., improved cellular uptake of hydrophobic drug in drug resistant cells via MMP-2 responsive drug delivery, combined chemical and photodynamic therapies, and suppression of drug active efflux mediated by decreased expression level of drug resistance related bioactive substances such as adenosine triphosphate (ATP). In vitro studies in terms of the MMP-2 responsive cell targeting, integrity of subcellular organelles, drug uptake and efflux, MTT assay and in vivo antitumor effect will be extensively studied to evaluate the inhibition of drug resistance. Moreover, the relationship among the light irradiation time, the amount of ATP and the cell viability in drug resistant tumor cells will be tested systematically. And the potential mechanism of subcellular organelles destruction in overcoming drug resistance will be proposed. We hope this strategy can open a new window in the design of overcoming drug resistance systems.