International Journal of Nanomedicine (Aug 2020)
Modulation of Tumor Hypoxia by pH-Responsive Liposomes to Inhibit Mitochondrial Respiration for Enhancing Sonodynamic Therapy
Abstract
Nan Zhang1 ,* Yang Tan1 ,* Liwei Yan,2 Chunyang Zhang,1 Ming Xu,1 Huanling Guo,1 Bowen Zhuang,1 Luyao Zhou,1 Xiaoyan Xie1 1Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, People’s Republic of China; 2Department of Microsurgery and Orthopedic Trauma, The First Affiliated Hospital of Sun Yat‐sen University, Guangzhou, Guangdong 510080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoyan XieDepartment of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, People’s Republic of ChinaTel/ Fax +86-20-87765183Email [email protected] and Purpose: Sonodynamic therapy (SDT) has been widely used for the noninvasive treatment of solid tumors, but the hypoxic tumor microenvironment limits its therapeutic effect. The current methods of reoxygenation to enhance SDT have limitations, prompting reconsideration of the design of therapeutic approaches. Here, we developed a tumor microenvironment-responsive nanoplatform by reducing oxygen consumption to overcome hypoxia-induced resistance to cancer therapy.Methods: A pH-responsive drug-loaded liposome (MI-PEOz-lip) was prepared and used to reduce oxygen consumption, attenuating hypoxia-induced resistance to SDT and thereby improving therapeutic efficiency. Photoacoustic imaging (PAI) and fluorescence imaging (FI) of MI-PEOz-lip were evaluated in vitro and in breast xenograft tumor models. The pH-sensitive functionality of MI-PEOz-lip was applied for pH-triggered cargo release, and its capacity was evaluated. The MI-PEOz-lip-mediated SDT effect was compared with other treatments in vivo.Results: MI-PEOz-lip was demonstrated to specifically accumulate in tumors. Metformin molecules in liposomes selectively accumulate in tumors by pH-responsive drug release to inhibit the mitochondrial respiratory chain while releasing IR780 to the tumor area. These pH-responsive liposomes demonstrated PAI and FI imaging capabilities in vitro and in vivo, providing potential for treatment guidance and monitoring. In particular, the prepared MI-PEOz-lip combined with ultrasound irradiation effectively inhibited breast tumors by producing toxic reactive singlet oxygen species (ROS), while the introduction of metformin inhibited mitochondrial respiration and reduced tumor oxygen consumption, resulting in excellent sonodynamic therapy performance compared with other treatments.Conclusion: In this study, we present a novel strategy to achieve high therapeutic efficacy of SDT by the rational design of multifunctional nanoplatforms. This work provides a new strategy that can solve the current problems of inefficient oxygen delivery strategies and weaken resistance to various oxygen-dependent therapies.Keywords: sonodynamic therapy, pH-responsive liposomes, tumor hypoxia relief, metformin, nanomedicine
