Tumor Microenvironment-Responsive, Multistaged Liposome Induces Apoptosis and Ferroptosis by Amplifying Oxidative Stress for Enhanced Cancer Therapy

作者：Longfa Kou, Rui Sun, Xinyu Jiang, Xinlu Lin, Huirong Huang, Shihui Bao, Youting Zhang, Chao Li, Ruijie Chen, Qing Yao · 发表于：ACS Applied Materials & Interfaces · 年份：2020 · DOI：10.1021/acsami.0c03564 · 被引用次数：74 · 研究领域：Nanoplatforms for cancer theranostics、Nanoparticle-Based Drug Delivery、Ferroptosis and cancer prognosis

Tumor cells usually display metabolic, genetic, and microenvironment-related alterations, which are beneficial to tumor proliferation, tumor development, and resistance occurrence. Many transporters and enzymes, including ATB 0,+, xCT, and matrix metalloproteinases (MMPs), are involved in the altered cell metabolism and tumor microenvironment and often abnormally upregulated in malignant tumors. Meanwhile, these dysregulated transporters and enzymes provide targets not only for a pharmacological blockage to suppress tumor progress but also for tumor-specific delivery. Although transporters and MMPs have been widely reported for antitumor drug delivery, the feasibility of utilizing two strategies has never been elucidated yet. Herein, we developed an M MP2-activated and A TB 0,+ -targeted l ipo s ome with d oxorubicin and s orafenib (DS@MA-LS) loaded for optimal tumor drug delivery for cancer therapy. DS@MA-LS was designed to prolong blood circulation and deshield the PEG shell from MMP2 cleavage to expose lysine and target overexpressed ATB 0,+ for enhanced tumor distribution and cancer cellular uptake. Besides the anticancer effects of loaded drugs, the endocytosed liposomes could further increase ROS production and suppress the antioxidant system to amplify oxidative stress. As expected, DS@MA-LS displayed enhanced targeted drug delivery to tumor sites with the MMP2-controlled ligand exposure and ATB 0,+ -mediated uptake. More importantly, DS@MA-LS successfully inhibited th...