Rational Design of Efficient Organic Phototherapeutic Agents via Perturbation Theory for Enhancing Anticancer Therapeutics

The development of efficient phototherapeutic agents (PTA) through rational and specific principles exhibits great potential to the biomedical field. In this study, a facile and rational strategy was used to design PTA through perturbation theory. According to the theory, both the intersystem crossing rate for singlet oxygen generation and nonradiative transition for photothermal conversion efficiency can be simultaneously enhanced by the rational optimization of donor–acceptor groups, heavy atom number, and their functional positions, which can effectively decrease the energy gap between the singlet and triplet states and increase the spin‐orbit coupling constant. Finally, efficient PTA were obtained that showed excellent performance in multimode‐imaging‐guided synergetic photodynamic/photothermal therapy. This study therefore expands the intrinsic mechanism of organic PTA and should help guide the rational design of future organic PTA via perturbation theory. Illuminating research: The aza‐BODIPY (C‐4)‐based phototherapeutic agent (PTA) with enhanced anticancer efficacy was rationally designed by perturbation theory. According to the theory, C‐4, which has improved singlet oxygen generation and photothermal conversion efficiency, was obtained through a rational structure‐optimization approach. Finally, this PTA was found to successfully cure tumors without recurrence under multimode‐imaging‐guided phototherapy.