title: Targeting and Treatment of Tumor Hypoxia by Newly Designed Prodrug Possessing High Permeability in Solid Tumors.
abstract: Tumor hypoxia, which is associated with poor prognosis in cancer, is known to lead to resistance to radiotherapy and anticancer chemotherapy. Impaired drug penetration in hypoxic regions has been recognized as an essential barrier to drug development in solid tumors. Here, we propose novel hypoxia-activated prodrugs, which drastically improved the penetration property of commonly used anticancer drugs in the hypoxic region. In this design, conventional anticancer drugs were modified with 2-nitroimidazole derivatives. The most important point of this study was that the prodrug designed formed a 6-membered cyclic structure to allow liberation of the active drug in the hypoxic region. This design markedly increased the selectivity of the hypoxia-targeted prodrug, resulting in significant reduction of adverse effects in the normoxic region. In vitro studies confirmed the selective activation under hypoxic conditions. In vivo studies showed drastic reduction of adverse effects associated with conventional anticancer drugs and improvement of the survival rate of mice. Immunofluorescence analyses confirmed that the designed prodrug had a tendency to localize at the hypoxic region, in contrast to conventional anticancer drugs, which localize only at the normoxic region.
authors.affiliation: Department of Materials Science, Master's School of Medical Sciences, University of Tsukuba , Tennoudai 1-1-1, Tsukuba 305-8573, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Department of Materials Science, Master's School of Medical Sciences, University of Tsukuba , Tennoudai 1-1-1, Tsukuba 305-8573, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Hisano
authors.affiliation: Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University , Midorigaoka Higashi-2-jyo 1-1-1, Asahikawa, Hokkaido 078-8510, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nishikawa
authors.affiliation: Department of Materials Science, Master's School of Medical Sciences, University of Tsukuba , Tennoudai 1-1-1, Tsukuba 305-8573, Japan.|Master's School of Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba , Tennodai 1-1-1, Tsukuba, Ibaraki 305-8573, Japan.|Satellite Laboratory, International Center for Materials Nanoarchitectonics (WPI-MANA), National Institute for Materials Science (NIMS), University of Tsukuba , Tennoudai 1-1-1, Tsukuba 305-8573, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nagasaki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy*; D009593:Nitroimidazoles / Q000494:pharmacology; D010539:Permeability; D011355:Prodrugs / Q000494:pharmacology*; D000072258:Tumor Hypoxia / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D009593:Nitroimidazoles; D011355:Prodrugs
keywords: drug penetration; prodrug; solid tumor; tumor hypoxia