278 - Treatment of Tumor Hypoxia by Anticancer Prodrug Possessing High Permeability in Solid Tumor

Abstract

Hypoxia is a feature of solid tumors and tumor hypoxia is known to promote mutagenesis, invasiveness. A strategy for targeting the hypoxic region of tumors is highly required; however, several issues such as adverse effects and poor penetration property of drugs have hampered developments. In this study, we developed a novel system in which antitumor prodrug is inactivated by the modification with the functional group and reduces the adverse effect to normal tissues which are generally present under normoxia condition but releases active anticancer drug under hypoxic condition. We have applied this technology to several anticancer drugs. In vivo experiments, doxorubicin prodrug (pro-Dox) was evaluated using tumor bearing mice and significant anti-tumor effect of pro-Dox was observed. Importantly, administration of pro-Dox did not show any apparent adverse effect and drastically improved survival rate of mice. Immunofluorescence analyses confirmed that the designed prodrug localized at the hypoxic region, in contrast to conventional anticancer drugs, which localized only at the normoxic region. These results indicate that the developed prodrug drastically improved the therapeutic effect by reducing adverse effects, improving drug penetration, and specifically activating the drug at hypoxic regions