Acid-activatable photosensitizers for photodynamic therapy using self-aggregates of chlorophyll‒peptide conjugates

Abstract Photodynamic therapy is useful due to its high antitumor efficacy, spatiotemporal selectivity, and noninvasiveness and has garnered significant attention in the field of cancer treatment. When photoexcited by light irradiation, photosensitizers produce reactive oxygen species (ROS) that damage tumor tissues. However, photosensitizers can also accumulate in normal tissues, leading to side effects such as skin photosensitivity. To mitigate these side effects, we report the development of chlorophyll‒peptide conjugates as tumor-selective photosensitizers. These conjugates bearing histidine and lysine residues self-assemble into nanoparticles that are expected to accumulate selectively in tumors and reduce ROS generation through self-quenching under the neutral conditions typical of normal tissues. In contrast, these aggregated conjugates partially disassemble under weakly acidic conditions, such as those found in tumor tissues, resulting in phototoxicity. We anticipate that these acid-activatable conjugates have the potential to serve as cancer-selective photosensitizers, thereby reducing phototoxicity in normal tissues.