ABSTRACT
Investigation of a series of tetra(3,4-pyrido)porphyrazines (TPyPzs) substituted with hydrophilic substituents revealed important structure-activity relationships for their use in photodynamic therapy (PDT). Among them, a cationic TPyPz derivative with total of 12 cationic charges above, below and in the plane of the core featured a unique spatial arrangement that caught the hydrophobic core in a cage, thereby protecting it fully from aggregation in water. This derivative exhibited exceptionally effective photodynamic activity on a number of tumor cell lines (HeLa, SK-MEL-28, A549, MCF-7) with effective concentrations (EC50) typically below 5 nM, at least an order of magnitude better than the EC50 values obtained for the clinically approved photosensitizers verteporfin, temoporfin, protoporphyrin IX, and trisulfonated hydroxyaluminum phthalocyanine. Its very low dark toxicity (TC50 > 400 µM) and high ability to induce photodamage to endothelial cells (EA.hy926) without preincubation suggest the high potential of this cationic TPyPz derivative in vascular-targeted PDT.
Subject(s)
Metalloporphyrins/pharmacology , Photosensitizing Agents/pharmacology , Pyridines/pharmacology , 3T3 Cells , Animals , Cations/chemical synthesis , Cations/chemistry , Cations/pharmacology , Cell Survival/drug effects , Dose-Response Relationship, Drug , Endothelial Cells/drug effects , HeLa Cells , Humans , MCF-7 Cells , Metalloporphyrins/chemical synthesis , Metalloporphyrins/chemistry , Mice , Molecular Structure , Photochemotherapy , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A synthesis procedure for heteroatom-substituted tetra(3,4-pyrido)porphyrazines that absorb light near 800 nm was developed. Based on the observed relationships between the structure and photophysical parameters, a novel highly photodynamically active (IC50 = 0.26 µM) compound was synthesized and biologically characterized.
