Protein-anchored near-infrared heptamethine cyanine photosensitizer with ultralong retention for phototherapy of large tumors.

Abstract

Conventional photosensitizers frequently exhibit nonspecific accumulation in organs and are rapidly cleared from tumor sites, posing significant challenges to the precision and efficacy of in vivo phototherapy. This study presents a novel photosensitizer that markedly enhances tumor-specific accumulation and retention for up to 25 days, outperforming all existing photosensitizers. The photosensitizers are synthesized by incorporating two 3,5-dioxocyclohexanecarboxylic acid moieties onto the heptamethine cyanine scaffold. Notably, the photothermal conversion efficiency (58.28 %) and ROS generation of the synthesized Cy7DA are significantly enhanced in the NIR range (808 nm) compared to IR780 derivatives, through assembly-mediated intermolecular aggregation effect. The intrinsic tumor-targeted Cy7DA preferentially accumulates within the mitochondria of cancer cells, where it forms irreversible covalent interactions with overexpressed sulfonic acid proteins. This interaction resulted in ultralong tumor retention and nearly complete growth inhibition of large tumors (approximately 300 mm³) in vivo, following single-dose administration and three laser irradiation sessions. This research represents the first example of single-molecule photosensitizers for ultralong NIR fluorescence imaging of tumors, coupled with integrated photodynamic and photothermal therapy.