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

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 encapsulatied within folate-modified and disulfide-containing nano-micelles. Upon targeted delivery and selective release, positive 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 within 1 nm. This configuration profoundly boosts the ICET efficiency, achieving potent PDT even at low endogenous levels of H₂O₂. Moreover, the tumor-specific decomposition of the nano-micelles eliminating aggregation caused quenching effect and removing the diffusion barrier of 1O2, while in normal tissues the integrality of nano-micelles shields 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.