Latest studies highlight boron-dipyrromethene (BODIPY) with a meso-methyl moiety as a promising photoremovable protecting group due to its activation within the phototherapeutic window. While BODIPYs inherently generate ROS and act as photosensitizers, few studies have explored combining their photouncaging capability with photodynamic therapy (PDT). Herein, we developed novel meso-methyl-BODIPY conjugates of the DNA alkylator Boc-seco-CBI and the multikinase inhibitor cabozantinib derivative activated by green or red light. To enhance the photodecaging efficiency of the conjugates, heavy atoms (Br, I) were introduced, and the boron atom was alkylated. The synthesized compounds were characterized for key photophysical and photochemical properties, including quantum yields of singlet oxygen generation, fluorescence, photolysis, and cytostatic release. It was shown that green-light irradiation of halogenated Boc-seco-CBI conjugates enabled rapid cytostatic release (<1 min), though with modest drug yields due to competing photodegradation. However, efficient uncaging of the cytostatic from the BODIPY-cabozantinib conjugate was achieved only after extended photoirradiation (∼80 min) with red light. In vitro evaluation using tumor (MDA-MB-231, A-431) and normal (HEK293) cell lines with various EGFR/c-Met expressions demonstrated that the BODIPY-cabozantinib conjugate exhibited predominant photosensitizing effects, with minimal cytostatic contribution. During this study, we encountered significant synthetic challenges in developing red-light-absorbing conjugates, coupled with their photodegradation under prolonged irradiation. Our observations reveal key considerations for developing conjugates based on meso-methyl-BODIPY that combine PDT with light-controlled drug release toward antitumor therapy.
Kuzmina et al. (Wed,) studied this question.