Oral Presentation 18th International Congress on Photobiology 2024

What makes the strength of very phototoxic photosensitizers (#30)

Zoe A. Arnaut 1 , Lígia C. Gomes-da-Silva 1 , Sara M.A. Pinto 1 , Luis G. Arnaut 1 , Mariette M Pereira 1
  1. Department of Chemistry, CQC-IMS, University of Coimbra, Coimbra, Portugal

Higher phototoxicity in vitro is readily associated with photosensitizers with higher yields of generation of reactive oxygen species (ROS) in cell media. Although photosensitizers that generate high yields of ROS, notably high singlet oxygen quantum yields (F∆), tend to be more phototoxic to cells, cell uptake and subcellular localization are also important determinants of phototoxicity. For example, atropisomers of redaporfin with nearly identical F∆ have phototoxicities that differ by more than one order of magnitude due to differences in cell uptake.1 In this work, we explore eukaryotic cell uptake of porphyrins that are precursors of photosensitizers known for their high in vitro phototoxicity. These include porphyrin precursors of Foscan® (IC50=200 nM @ 1J/cm2 for CT26 cells),2 of IC-H-Me2+ (IC50≈500nM @ 5J/cm2 for HEK cells),3 and of a new bacteriochlorin named LUZ51B (IC50=6nM @ 1J/cm2 for CT26 cells).4 IC-H-Me2+ is a chlorin very effective in the photoinactivation of gram-positive and gram-negative bacteria, and viruses (e.g., SARS-CoV-2). LUZ51B is a carboxamide bacteriochlorin phototoxic to cancer cells and gram-positive bacteria.

This work aims to elucidate the underlying mechanisms that contribute to the phototoxicity of photosensitizers in diverse applications. We report the cellular uptake of the previously mentioned porphyrin precursors of photosensitizers with widely different molecular structures in the JEG-3 cell line. Additionally, we report the uptake of porphyrins lacking therapeutic effects. These porphyrins were selected from a series employed in a screening of antivirals for the Zika virus that included a variety of molecular sizes, charge distributions and functional groups. The screening of antivirals that prevent replication in infected cells, offered clues to differences in cell uptake and to therapeutic efficiency that are discussed in this work.


Acknowledgments

The authors thank FCT for financial support (PTDC/QUI-OUT/0303/2021) and Eureka 2024, Z.A.A. thanks FCT for a PhD grant (2021.09454.BD).

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  2. L. G. Arnaut, M. M. Pereira, J. M. Dabrowski, E. F. F. Silva, F. A. Schaberle, A. R. Abreu, L. B. Rocha, M. M. Barsan, K. Urbanska, G. Stochel, C. M. A. Brett, Photodynamic Therapy Efficacy Enhanced by Dynamics: The Role of Charge Transfer and Photostability in the Selection of Photosensitizers. Chem. Eur. J., 20 (2014) 5346-5357
  3. Z. A. Arnaut, S. M. A. Pinto, R. T. Aroso, et al. Selective, broad-spectrum antiviral photodynamic disinfection with dicationic imidazolyl chlorin photosensitizers. Photochemical and Photobiological Sciences 22, 2607–2620 (2023).
  4. G. P. N. Costa, N. P. F. Gonçalves, C. J. P. Monteiro, A. C. R. Abreu, H. T. Soares, L. B. Rocha, F. A. Schaberle, M. M. Pereira, L. G. Arnaut Moreira. Low molecular weight derivatives of carboxamide halogenated porphyrins, namely chlorins and bacteriochlorins, and their applications in photodynamic therapy. PCT/IB2016/052606. WO2016178191