The ability of photosensitizers to interact with and penetrate cell membranes is crucial for treatment effectiveness, particularly in cellular Photodynamic Therapy (PDT) protocols involving longer intervals between photosensitizer administration and target tissue illumination. These protocols facilitate photosensitizer accumulation in tumors, providing sufficient time for extravasation and cellular uptake.
Redaporfin, a halogenated sulfonamide bacteriochlorin photosensitizer, is characterized by its intense absorption in the NIR region (~750 nm), high phototoxicity, and immunostimulatory properties. However, due to its macromolecular nature (MW: 1134.11 g/mol), redaporfin faces challenges related to cellular internalization (with in vitro studies requiring an incubation a 20-h incubation) and diffusion across the tumor mass, especially in tumors with a dense extracellular matrix and/or restricted vascularization [1].
Redaporfin exists as a mixture of four atropisomers, which differ in the spatial orientation of their sulfonamide groups relative to the macrocycle. Our research has revealed that these atropisomers exhibit markedly different cellular uptake profiles, both in vitro and in vivo, significantly affecting their PDT efficacy. The α4 atropisomer, with all sulfonamide groups on the same side of the macrocycle plane, shows the highest cell uptake and consequently the most potent PDT effects. This enhanced uptake is likely due to its higher amphipathic nature, which facilitates its interaction with the polar head groups of phospholipids on the cell membrane surface, followed by its flipping into the inner layer of the cell membrane, and passive diffusion into the cell [2].
These findings demonstrate that properly oriented polar groups can be strategically incorporated into drug design as effective cell-penetrating motifs. This was further validated by synthesizing novel porphyrin photosensitizers with strapped moieties to restrict the rotation of polar groups and force different atropisomer configurations. Notably, the cis-αα porphyrin, resembling the α4 redaporfin configuration, exhibited enhanced cellular internalization compared to the other conformers [3].
[1] Luis G. Arnaut and Mariette M. Pereira, “Overcoming the Challenges of Infrared Photosensitizers in Photodynamic Therapy: The Making of Redaporfin,” Chemical Communications 59, no. 62 (2023): 9457–68, https://doi.org/10.1039/D3CC02283H.
[2] Claire Donohoe et al., “Unraveling the Pivotal Role of Atropisomerism for Cellular Internalization,” Journal of the American Chemical Society 144, no. 33 (August 24, 2022): 15252–65, https://doi.org/10.1021/jacs.2c05844.
[3] Claire Donohoe et al., “Strapped Porphyrins as Model Systems for Atropisomeric Photosensitizer Drugs,” European Journal of Organic Chemistry 26, no. 15 (April 14, 2023), https://doi.org/10.1002/ejoc.202201453.