Donor-PeT Control of Intersystem Crossing Enables ALDH1A1-Activated Photodynamic Therapy.

ABSTRACT: Aldehyde dehydrogenase 1A1 (ALDH1A1) is highly expressed in therapy-resistant and metastatic cancers and represents a clinically relevant biomarker for selective activation strategies. We report AAP, an OFF-ON photosensitizer activated through ALDH1A1-mediated oxidation that produces singlet oxygen upon light exposure. AAP uses a donor photoinduced electron transfer (d-PeT) mechanism to suppress intersystem crossing in its unreacted benzaldehyde form, which minimizes background activity. Oxidation by ALDH1A1 disrupts d-PeT and restores phototoxicity. AAP showed minimal off-target activation by other ALDH isoforms or oxidative stress. In vivo, AAP suppressed tumor growth in two non-small cell lung cancer (NSCLC) models. In the first, intratumoral delivery into established tumors conf

SUBMITTER: Forzano JA 

PROVIDER: S-EPMC12842602 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature