Combination of chemotherapeutics with redox nanoparticles for colon cancer

Abstract

Event Abstract Back to Event Combination of chemotherapeutics with redox nanoparticles for colon cancer Long Vong1*, Toru Yoshitomi1*, Hirofumi Matsui2, 3* and Yukio Nagasaki1, 2, 4* 1 University of Tsukuba, Department of Materials Science, Graduate School of Pure and Applied Sciences, Japan 2 University of Tsukuba, Master’s School of Medical Sciences, Graduate School of Comprehensive Human Sciences, Japan 3 University of Tsukuba, Division of Gastroenterology, Graduate School of Comprehensive Human Sciences, Japan 4 National Institute for Materials Science, Satellite Laboratory, International Center of Materials Nanoarchitectonics, Japan Conventional chemotherapeutic drugs such as doxorubicin (DOX) and irrinotecan (IRI) cause severe adverse effects to healthy tissues due to excessive generation of reactive oxygen species (ROS). ROS are also reported to induce drug resistance in cancer cells. Antioxidant compounds and free radical scavengers have been used to improve anticancer efficacy of chemotherapy and minimize the adverse effect in vitro. However, these low-molecular-weight (LMW) antioxidants have failed so miserably in clinical practice due to low stability and non-specific distribution in vivo environments. Moreover, LMW compounds facilely internalize into the healthy cells to disturb the important redox reactions in mitochondrial respiratory chain, leading to cellular dysfunctions and adverse effects. In order to prevent the nonspecific accumulation of LMW antioxidant to healthy tissues, we have recently developed a core–shell-type redox nanoparticles (RNP) covalently conjugating nitroxide radicals (TEMPO) as ROS scavengers in the core of nanoparticle with 40 nm in diameter [1]. It was confirmed that RNP does not internalize into healthy cells, resulting in an extremely low adverse effects to healthy tissues on models of mice and zebra fish as compared to LWM nitroxide radicals. RNP exhibited long blood circulation via intravenous administration, while it accumulates in gastrointestinal tract after oral administration due to its high colloidal stability as compared to LMW nitroxide radical (TEMPOL) [1],[2]. We investigated that RNP enhances the anticancer drug uptake in cancer cells by scavenging overproduced ROS in inflamed and cancer sites, significantly improving anticancer efficacies of DOX and IRI in colitis-associated colon cancer mice [3],[4]. In addition, RNP effectively suppressed DOX-induced cardiotoxicity and IRI-induced intestinal injury. Based on these results, RNP is a promising antioxidant nanotherapeutics to improve cancer chemotherapy with minimal adverse effects. A part of this work was supported by Grant-in-Aid for Scientific Research S (25220203) and the World Premier International Research Center Initiative (WPI Initiative) on Materials Nanoarchitronics of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; Long B. Vong would like to express his sincere appreciation for the Research Fellowship of the Japan Society for the Promotion of Science (JSPS) for Young Scientists.