Meso-methyl-BODIPY conjugate with cabozantinib as a red-light-activated prodrug for anticancer therapy

Photoactivated chemotherapy is a new strategy for the development of anticancer drugs in which the activity of a chemotherapeutic drug is controlled by light irradiation. This avoids systemic toxicity and reduces side effects. The aim of this work was to evaluate the therapeutic potential of the light-activated prodrug BODIPY-Cab. The tested conjugate consists of cabozantinib, which was used as a cytostatic, and meso-methyl-BODIPY as a photoremovable protecting group (PPG), which is also used as a photosensitizer, allowing for combined therapy.

The photochemical and photophysical properties of the compound were evaluated using a spectrophotometer-spectrofluorometer. To study the biological properties, cell cultures with different expression of target receptors were selected: A-431 (human epidermoid carcinoma), MDA-MB-231 (human breast adenocarcinoma), HEK293 (human embryonic kidney). A laser scanning confocal microscope was used to study the intracellular localization of the BODIPY-Cab. The effect of compounds on cell viability was estimated using the microculture tetrazolium test.

The conjugate has absorption maxima at 368 and 662 nm and a fluorescence maximum at 678 nm. Irradiation of the BODIPY-Cab solution using a red light demonstrated photodegradation of the conjugate and moderate yield of the cabozantinib derivative. Fluorescence quantum yield of BODIPY-Cab was 16%, and the quantum yield of singlet oxygen was 17%. The compound is localized in mitochondria and the endoplasmic reticulum. Activation of the conjugate by light (655−675 nm), increased cytotoxicity, with the generation of ROS, especially superoxide O₂^•−. Cabozantinib derivative exhibited lower toxicity in cells compared to conjugate, suggesting that the photosensitizer should play a predominant role in initiating cellular damage.

The possibility of controlled release of a cytostatic under the action of red light is shown. The results can be used for further optimization of PPG based on meso-methyl-BODIPY.

This work was supported by the Russian Science Foundation under Grant No. 24-13-00179