Assessment of Some Unsymmetrical Porphyrins as Promising Molecules for Photodynamic Therapy of Cutaneous Disorders

Abstract

In order to select for further development novel photosensitizers for photodynamic therapy in cutaneous disorders, three unsymmetrical porphyrins, namely 5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl) porphyrin (P2.2), 5-(2-hydroxy-5-methoxyphenyl)-10,15,20-tris-(4-carboxymethylphenyl) porphyrin (P3.2), and 5-(2,4-dihydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl) porphyrin (P4.2), along with their fully symmetrical counterparts 5,10,15,20-tetrakis-(4-acetoxy-3-methoxyphenyl) porphyrin (P2.1) and 5,10,15,20-tetrakis-(4-carboxymethylphenyl) porphyrin (P3.1) were comparatively evaluated. The absorption and fluorescence properties, as well as atomic force microscopy measurements were performed to evaluate the photophysical characteristics as well as morphological and textural properties of the mentioned porphyrins. The cellular uptake of compounds and the effect of photodynamic therapy on the viability, proliferation, and necrosis of human HaCaT keratinocytes, human Hs27 skin fibroblasts, human skin SCL II squamous cell carcinoma, and B16F10 melanoma cells were assessed in vitro, in correlation with the structural and photophysical properties of the investigated porphyrins, and with the predictions regarding diffusion through cell membranes and ADMET properties. All samples were found to be isotropic and self-similar, with slightly different degrees of aggregability, had a relatively low predicted toxicity (class V), and a predicted long half-life after systemic administration. The in vitro study performed on non-malignant and malignant skin-relevant cells highlighted that the asymmetric P2.2 porphyrin qualified among the five investigated porphyrins to be a promising photosensitizer candidate for PDT in skin disorders. P2.2 was shown to accumulate well within cells, and induced by PDT a massive decrease in the number of metabolically active skin cells, partly due to cell death by necrosis. P2.2 had in this respect a better behavior than the symmetric P.2.1 compound and the related asymmetric compound P4.2. The strong action of P2.2-mediated PDT on normal skin cells might be an important drawback for further development of this compound. Meanwhile, the P3.1 and P3.2 compounds were not able to accumulate well in skin cells, and did not elicit significant PDT in vitro. Taken together, our experiments suggest that P2.2 can be a promising candidate for the development of novel photosensitizers for PDT in skin disorders.

In Silico and In Vitro Studies on an Asymmetrical Porphyrin Derivative with Therapeutic Potential in Skin Disorders

“…The used software allowed the calculation of the binding energy of P5.2 to the cell membrane (ΔG, kcal/mol) structure, the permeability coefficient (logPerm), and the generation of the transfer energy (ΔG transf ) profile as a function of the distance from the center of the membrane ( Figure 2 ). The prediction results were compared with the transfer energy profiles of two other asymmetrical porphyrin derivatives, 5-(4-hydroxy-3-methoxyphenyl)-10,15,20- tris -(4-acetoxy-3-methoxyphenyl) porphyrin (P2.2) and 5-(2-hydroxy-5-methoxyphenyl)-10,15,20- tris -(4-carboxymethylphenyl) porphyrin (P3.2), examined in our previous work [ 31 ].…”

“…The P5.2 asymmetrical porphyrin was synthesized according to the method proposed by the authors [ 45 ]. The compounds used as references, P2.2 and P3.2, were also reported elsewhere [ 31 , 32 ].…”

“…The binding energy (ΔG, kcal/mol) and permeability coefficient (logPerm) were calculated, and the transfer energy profile was generated as a function of the distance from the membrane center. The results were compared with two other porphyrin derivatives that were investigated in our previous study, P2.2 and P3.2 [ 31 ].…”

“…Using ecological and versatile approaches, our research group obtained and characterized a panel of new asymmetrical porphyrins with a general profile suitable for theranostics applications [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ].…”