A highly effective self-supplying photosensitizer drug for the treatment of deep-tissue metastatic tumors

Abstract

Due to the inherent defects of photodynamic therapy (PDT), its application in the treatment of deep-tissue metastatic tumors remains challenging. To extend the applicability of PDT, a novel chemiexcited photosensitizer, Cy7-EOM, was developed by covalently coupling the photosensitizer Cy7 with a peroxycatechol derivative and encapsulating it within folate-modified and disulfide-containing nano-micelles. Upon targeted delivery and selective release, positively charged Cy7-EOM would target the mitochondria and efficiently generate singlet oxygen (¹O₂) through intramolecular chemical energy transfer (ICET), directly inducing mitochondrial damage and cell apoptosis, realizing an efficient PDT for deep-tissue metastatic tumors. Remarkably, the covalent tethering of the photosensitizer to the peroxyoxalate ensures their spatial proximity to within 1 nm. This configuration profoundly boosts the efficiency of ICET, achieving potent PDT even at low endogenous levels of H₂O₂. Moreover, the tumor-specific decomposition of the nano-micelles eliminates the quenching effect caused by aggregation and removes the diffusion barrier to ¹O₂, while in normal tissues the integrity of the nano-micelles shields the tissues against the lethal effects of ¹O₂. This method provides a new strategy for transforming adjuvant photosensitizers into direct therapeutic drugs, with significant potential for clinical application in the treatment of metastatic tumors.