Design, Synthesis, and Biological Evaluation of BODIPY-Caged Resiquimod as a Dual-Acting Phototherapeutic

Resiquimod, an imidazoquinoline scaffold, exhibits potent
immunotherapeutic
activity but is associated with off-target effects, limiting its clinical
utility. To address this limitation, we developed a novel BODIPY-caged
resiquimod that is responsive to red light, combining photocaging
and photodynamic therapy functionalities. Molecular docking studies
guided identification of the optimal caging site for resiquimod, effectively
masking its immune activity. BODIPY-caged resiquimod remained inactive
under dark conditions, effectively masking resiquimod’s immunostimulatory
effects. However, red light irradiation precisely uncaged resiquimod,
inducing robust immune activation, even in the presence of N-acetyl cysteine as an antioxidant. Notably, the attachment
of resiquimod to BODIPY reduced the dark toxicity typically associated
with BODIPY as a photosensitizer. In 3D spheroid models of HeLa and
A549 cells, BODIPY-caged resiquimod demonstrated spatiotemporal control
over cytotoxicity, significantly enhancing cell death only upon irradiation.
This dual-function therapeutic approach highlights a “win–win”
strategy: precise, red-light-mediated control of immune activation
and photodynamic efficacy with reduced collateral toxicity.