On the Correlation Between Hydrophobicity, Liposome Binding and Cellular Uptake of Porphyrin Sensitizers

Abstract

A crucial factor in choosing a porphyrin or analogous photosensitizer for photodynamic therapy (PDT) is its ability to incorporate into the cells. For hydrophobic compounds that partition passively into the cytoplasmic membrane, a partition coefficient between an organic solvent and water, P, is one factor that could be used to predict the molecule's ability to diffuse into biomembranes. We synthesized several porphyrins, modified with two, three or four meso-substituents and studied their spectroscopic and photophysical properties. The octanol-water partitioning coefficients, log P, were calculated as a parameter for hydrophobicity. We found these porphyrins to be very hydrophobic, with log P values in the range of 8.9-11.8. These were correlated with the binding constants of these porphyrins into liposomes, K(b), as well as to their uptake by cells. The correlation between the estimated log P and K(b) is nearly linear but negative, indicating, apparently, that there is lesser binding to liposomes with increased hydrophobicity. On the other hand, all of the studied porphyrins are taken up by cells, but there is no clear correlation between cellular uptake and the log P or K(b). Lipinski's pharmacological "rule of 5" predicts poor permeation of drugs into cells when log P is greater than five. This may be relevant for diffusional binding to liposomes, where aqueous aggregation can interfere strongly with cellular uptake. In such extreme conditions, neither liposome binding nor other rules seem to predict porphyrin behavior in vitro.

Photodynamic treatment with phenothiazinium photosensitizers kills both ungerminated and germinated microconidia of the pathogenic fungi Fusarium oxysporum, Fusarium moniliforme and Fusarium solani

“…Several studies have shown that the cell membrane is one of the targets of ROS generated during the photodynamic process [41,[48][49][50][51]. PI is widely used to evaluate the membrane integrity [52,53].…”

Synthesis and Crystal Structure of a Meso-Meso Directly Linked Bisporphyrin

“…Likewise, only limited studies on the preparation of unsymmetrical systems thereof or porphyrin arrays amenable to further 3 functionalization have been published. In the context of our interest in the preparation of near-IR absorbers for applications in photodynamic therapy (PDT) [10] we have begun to explore the chemistry of these compounds with the goal in mind to make unsymmetrical and amphiphilic systems for use in preclinical studies [11][12][13].…”

Chemical Synthesis and Medicinal Applications of Glycoporphyrins

“…This allowed the synthesis of an extensive glycoporphyrin library which has been biologically evaluated and used to identify the intracellular localization of glycoporphyrins depending on the carbohydrate unit present [33] . For example, these preliminary results in biological testing showed that triglycosubstituted porphyrins lack the ability to be taken up by esophageal cancer cells possibly due to their high water solubility and reinforced that amphiphilicity of such systems is key to their ability to cross the lipid membrane [34][35][36][37][38][39][40][41][42] .…”