Graduate Student Brett Berger

"Two-Photon Excitable Fluorophores for Photodynamic Therapy"

Cancer is a leading cause of death around the world each year, and typical treatments can be highly invasive with numerous side effects. Photodynamic therapy (PDT) relies on photosensitizers to generate reactive oxygen species (ROS) directly at the tumor site that are capable of causing cell death in a minimally invasive and controlled manner. Normally, PDT is limited to areas that can be reached easily by a fiber optic cable to apply the necessary light due to the poor penetration of high-energy visible light through the skin. Two-photon PDT can utilize longer near-infrared light that has much greater tissue penetration, allowing for the treatment in areas that would traditionally require a much more invasive clinical approach. Fang et al. create the first ever metal-free thermally activated delayed fluorescence (TADF) photosensitizer for two-photon PDT that demonstrates a high efficiency in ROS generation, potent cytotoxicity, with limited side effects that also has potential for use as an imaging probe in normal fluorescent microscopy.1 Human carboxylesterase 2 (hCES2) is a common target for chemical therapeutics, given that it has an increased expression within cancer cells. However, some patients lack elevated hCES2 levels and thus are resistant to hCES2-targeting medications. Kailass et al. developed a two-photon photosensitizer that is only active in the low hCES2 environments that, when combined with targeted light application, allows for the reduction of tumor mass in vitro and in 3D tumor models.2 Given the high reproduction rate of cancerous cells and the low supporting vasculature in the tumor microenvironment, there is a localized region of low oxygen concentrations. Wang et al. have developed a photosensitizer that is specifically activated by the low-oxygen environment to control side effects throughout the body while still being able to induce cell death.3 In conclusion, two-photon photodynamic therapy has the potential to improve patient outcomes with its minimally invasive yet potent cytotoxicity that can be controlled to just the tumor environment.

References:

(1) Fang, F.; Yuan, Y.; Wan, Y.; Li, J.; Song, Y.; Chen, W.; Zhao, D.; Chi, Y.; Li, M.; Lee, C.; Zhang, J. Near‐Infrared Thermally Activated Delayed Fluorescence Nanoparticle: A Metal‐Free Photosensitizer for Two‐Photon‐Activated Photodynamic Therapy at the Cell and Small Animal Levels. Small 2022, 18 (6), 2106215. https://doi.org/10.1002/smll.202106215.
(2) Kailass, K.; Sadovski, O.; Zipfel, W. R.; Beharry, A. A. Two-Photon Photodynamic Therapy Targeting Cancers with Low Carboxylesterase 2 Activity Guided by Ratiometric Fluorescence. J. Med. Chem. 2022, 65 (13), 8855–8868. https://doi.org/10.1021/acs.jmedchem.1c01965.
(3) Wang, Y.; Shi, X.; Fang, H.; Han, Z.; Yuan, H.; Zhu, Z.; Dong, L.; Guo, Z.; Wang, X. Platinum-Based Two-Photon Photosensitizer Responsive to NIR Light in Tumor Hypoxia Microenvironment. J. Med. Chem. 2022, 65 (11), 7786–7798. https://doi.org/10.1021/acs.jmedchem.2c00141.