Auger Electron Therapy Enhanced by Heat-Triggered Release of I-125-Labeled DNA-Targeted Compounds within the Tumor Microenvironment.

In Auger electron therapy, the effective delivery of Auger electron-emitting radionuclides to the nuclei of cancer cells is essential for achieving high therapeutic efficacy. In this study, we developed a novel strategy that combined thermosensitive liposomes (TSLs) encapsulating 125I-labeled DNA-targeted compounds. This approach enabled enhanced tumor accumulation via TSL-mediated delivery and efficient nuclear translocation of radioactivity by releasing an 125I-labeled doxorubicin derivative ([125I]I-DOX) within the tumor microenvironment. [125I]I-DOX exhibited high cellular and nuclear uptake, producing potent cytotoxicity through Auger electrons emitted from 125I. [125I]I-DOX-loaded TSLs efficiently released [125I]I-DOX at 43 °C, enhancing its cellular uptake by Colon-26 cells. Tumor accumulation of radioactivity in the heating group was much higher than in the nonheating group, and the accumulation was maintained for up to 48 h postinjection. Intravenous injection of [125I]I-DOX-loaded TSLs (5.0 MBq) and localized tumor heating significantly inhibited tumor growth without body weight loss. The combination of [125I]I-DOX-loaded TSLs and hyperthermia represents a promising strategy for Auger electron therapy targeting the nuclei of cancer cells.