“Chemical Factory”-Guaranteed Chemodynamic Therapy of Orthotopic Liver Cancer

The liver is a rather well-equipped “chemical factory”, simultaneously operating a myriad of physiological processes. Carrying so many functions, it could also be susceptible to negative stimulation, such as obesity and virus infection, and become diseased and malfunction, and in the worst case, develop tumors^[1]. To date, many experimental therapeutics for liver cancer have been investigated in subcutaneous tumor models rather than orthoptic liver cancer models. However, subcutaneous tumor models cannot accurately recapitulate the actual physiological environment of human liver cancer. Thus, it is not highly clinically relevant for the evaluation of rationally designed therapeutic agents.<br/>The common characteristics of tumor microenvironment, such as acidity^[2], insufficient catalase activity, and intolerance of external reactive oxygen species (ROS)^[3], is present in orthoptic liver tumor models. Importantly, the uniqueness of orthoptic liver tumor models lies in its origin, liver, the central place for iron storage, metabolism, and the primary metabolic sites for most ingested substances. Generally, these characteristics have laid a solid foundation for the introduction of chemodynamic therapy (CDT) strategy^[4], which utilizes the Fenton/Fenton-like reactions <i>in vivo</i> for cancer treatment. Moreover, the presence of all necessary components for Fenton/Fenton-like reactions could enhance the specificity of CDT, and reduce potential adverse effects in normal tissues.<br/>Orthotopic liver cancer model shares many common characteristics with human liver cancer, which can lead to enhanced therapeutic efficacy and facilitate/accelerate clinical translation. In general, the catalyst role of transition metals (e.g. Fe and Cu) in most reported CDT research was fulfilled by the components in the exogenously designed/injected nanoparticles, neglecting the abundant presence of endogenous iron inside the liver^[5]. Employing the iron-enriched microenvironment in the liver could generate more H₂O₂ to kill the tumor cells. More importantly, the coexistence of ROS and Zn²⁺ accumulation could amplify the cell-killing effects of ROS.<br/>In this work, we first established the orthotopic liver tumor model and realized effective cancer therapy through “chemical factory”-guaranteed enhanced Fenton/Fenton-like reactions by using polyethylene glycol-modified zinc peroxide (ZnO₂@PEG) nanoparticles. After intravenous injection into mice, the ZnO₂@PEG nanoparticles could accumulate in the liver and liver cancer tissues. Once inside the tumor tissue, the ZnO₂@PEG nanoparticles will rapidly release Zn²⁺ and H₂O₂ due to mild acidity and low catalase activity, subsequently triggering the enhanced Fenton/Fenton-like reactions with the intrinsic Fe, generating hydroxyl radical which, in the presence of burst increased Zn²⁺, can lead to efficient cancer therapy. As a comparison, in the normal liver tissue, the production of Zn²⁺ and H₂O₂ is rather slow over a prolonged period and the H₂O₂released will be quickly degraded into water and oxygen, which is attributed to the regular catalytic process inside hepatocytes.<br/><br/>[1] Marengo A, Rosso C, Bugianesi E. <i>Annual review of medicine</i>, 2016, 67: 103-117.<br/>[2]] Kato, Yasumasa, <i>et al.</i> <i>Cancer cell international</i> 13.1 (2013): 1-8.<br/>[3] Trachootham, Dunyaporn, Jerome Alexandre, and Peng Huang. <i>Nature reviews Drug discovery</i> 8.7 (2009): 579-591.<br/>[4] Tang, Zhongmin, <i>et al. Angewandte Chemie International Edition</i> 58.4 (2019): 946-956.<br/>[5] Anderson, Gregory J., and David M. Frazer. <i>Seminars in liver disease</i>. Vol. 25. No. 04.