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A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma |
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| Authors: | Katsunori Matsushita Takumi Okuda Dr. Shohei Mori Dr. Masamitsu Konno Dr. Hidetoshi Eguchi Dr. Ayumu Asai Dr. Jun Koseki Dr. Yoshifumi Iwagami Dr. Daisaku Yamada Dr. Hirofumi Akita Dr. Tadafumi Asaoka Dr. Takehiro Noda Dr. Koichi Kawamoto Dr. Kunihito Gotoh Dr. Shogo Kobayashi Dr. Yuuya Kasahara Dr. Kunihiko Morihiro Prof. Dr. Taroh Satoh Prof. Dr. Yuichiro Doki Prof. Dr. Masaki Mori Prof. Dr. Hideshi Ishii Prof. Dr. Satoshi Obika |
| Affiliation: | 1. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan). Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan These authors contributed equally to this work.;2. Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871 Japan;3. Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871 Japan These authors contributed equally to this work.;4. Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan;5. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan).;6. Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan Department of Medical Data Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan;7. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan). Present address: Department of Digestive Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, Osaka, 541-8567 Japan;8. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan). Present address: Kinki Regional Bureau of Health and Welfare, Ministry of Health, Labour and Welfare, 4-1-76 Nonin Bashi, Chuo-ku, Osaka, Osaka, 540-0008 Japan;9. Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871 Japan National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085 Japan;10. Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871 Japan National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085 Japan Present address: Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656 Japan;11. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan). Present address: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan;12. Department of Medical Data Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan |
| Abstract: | The main concern in the use of anticancer chemotherapeutic drugs is host toxicity. Patients need to interrupt or change chemotherapy due to adverse effects. In this study, we aimed to decrease adverse events with gemcitabine (GEM) in the treatment of pancreatic ductal adenocarcinoma and focused on the difference of hydrogen peroxide levels in normal versus cancer cells. We designed and synthesized a novel boronate-ester-caged prodrug that is activated by the high H2O2 concentrations found in cancer cells to release GEM. An H2O2-activatable GEM (A-GEM) has higher selectivity for H2O2 over other reactive oxygen species (ROS) and cytotoxic effects corresponding to the H2O2 concentration in vitro. A xenograft model of immunodeficient mice indicated that the effect of A-GEM was not inferior to that of GEM when administered in vivo. In particular, myelosuppression was significantly decreased following A-GEM treatment compared with that following GEM treatment. |
| Keywords: | chemoselectivity chemotherapy gemcitabine pancreatic cancer prodrugs |