title: Localization and photodynamic efficacy of two cationic porphyrins varying in charge distributions.
abstract: Two meso-tetraphenylporphyrin derivatives bearing adjacent: 5,10-di[4-(N-trimethylaminophenyl)-15,20-diphenylporphyrin (DADP-a) or opposite: 5,15-di[4-(N-trimethylaminophenyl)-10,20-diphenylporphyrin (DADP-o) cationic-N-(CH3)3+ groups on two of the para-phenyl positions were examined with regard to photodynamic properties as a function of charge distribution. The two adjacent positive charges in the DADP-a structure result in a molecular distortion (asymmetry), likely from electrostatic repulsion. This could be responsible for the unusual interaction of this compound with some solvents and detergent micelles. In contrast, DADP-o is a much more symmetric molecule. In a cellular environment, fluorescence spectra of the two agents were essentially identical. Subcellular localization played a major role in photodynamic efficacy. DADP-a localized in mitochondria, and irradiation of photosensitized cells (640-650 nm) resulted in a rapid loss of the mitochondrial membrane potential (delta(psi)m), usually a prelude to apoptotic cell death. In contrast, DADP-o localized in lysosomes, and extensive lysosomal photodamage was observed after irradiation. Both steady-state accumulation levels and absorbance spectra favored DADP-o, but the light dose required for a 90% cell kill was two-fold greater for DADP-o than for DADP-a, at a constant extracellular sensitizer concentration. These data indicate that, on a photons/cell basis, DADP-a was five-fold more efficacious. Fluorescence emission spectra in different solvents and detergents demonstrated a tendency for DADP-a association. We interpret these results to indicate partition of both drugs to membrane loci, with mitochondriabeing the more lethal site for photodamage.
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA. dhkessel@med.wayne.edu
authors.forename: David
authors.initials: D
authors.lastname: Kessel
authors.forename: Raymond
authors.initials: R
authors.lastname: Luguya
authors.forename: M Graça H
authors.initials: MG
authors.lastname: Vicente
mesh_terms: D002412:Cations; D008856:Microscopy, Fluorescence; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry*; D011166:Porphyrins / Q000737:chemistry*; D013050:Spectrometry, Fluorescence
chemical_list: D002412:Cations; D017319:Photosensitizing Agents; D011166:Porphyrins