Reactive Oxygen Species–Activatable Liposomes Regulating Hypoxic Tumor Microenvironment for Synergistic Photo/Chemodynamic Therapies
Zhihao Zhao1, Weiqi Wang2, Chenxi Li1, Yiqiu Zhang1, Tianrong Yu1, Renfei Wu1, Jiayue Zhao1, Zhuang Liu1, Jian Liu,* 1 and Haijun Yu*3
1Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu Province 215123, China;
2School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226001, China;
3State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Tumors have adapted various cellular antidotes and microenvironmental conditions to subsist against photodynamic therapy (PDT) and chemodynamic therapy (CDT). Here, the development of reactive oxygen species (ROS)-activatable Liposomes (RALP) for therapeutic enhancement by simultaneously addressing the critical questions in PDT and CDT is reported. The design of RALP@HOC@Fe3O4 features ROS-cleavable linker molecules for improved tumor penetration/uptake and ondemand cargo releasing, and integration of Fe3O4 and an oxaliplatin prodrug for smart regulation of hypoxia tumor microenvironment. Glutathione stored by the tumor cells is consumed by the prodrug to produce highly toxic oxaliplatin. Depletion of glutathione not only avoids the undesired annihilation of ROS in PDT, but also modulates the chemical specie equilibria in tumors for H2O2 promotion, leading to greatly relieved tumor hypoxia and PDT enhancement. Synergistically, Fe (II) in the hybrid RALP formulation can be fuelled by H2O2 to generate •OH in the Fenton reaction, thus elevating CDT efficiency. This work offers a strategy for harnessing smart, responsive, and biocompatible liposomes to enhance PDT and CDT by regulating tumor microenvironment, highlighting a potential clinical translation beneficial to patients with cancer.