Background: Peroxynitrite (ONOO-), a toxic biological oxidant, has been implicated in many pathophysiological conditions. The water-soluble porphyrins 5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphinato iron(III) (FeTMPyP) and manganese(III) (MnTMPyP) have recently emerged as potential drugs for ONOO- detoxification, and FeTMPyP has demonstrated activity in models of ONOO- related disease states. We set out to develop amphiphilic analogs of FeTMPyP and MnTMPyP suitable for liposomal delivery in sterically stabilized liposomes (SLs). Results: Three amphiphilic iron porphyrins (termed 1a-c) and three manganese porphyrins (termed 2a-c) bound to liposomes and catalyzed the decomposition of ONOO-. The polyethylene-glycol-linked metalloporphyrins 1b and 2b proved the most effective of these catalysts, rapidly decomposing ONOO- with second-order rate constants (k(cat)) of 2.9 x 105 M-1 s-1 and 5.0 x 106 M-1 s-1, respectively, in dimyristoylphosphatidylcholine liposomes. Catalysts 1b and 2b also bound to SLs, and these metalloporphyrin-SL constructs efficiently catalyzed ONOO- decomposition (k(cat) ≃ 2 x 105 M-1 s-1). The analogous metalloporphyrins 1a and 2a, which are not separated from the vesicle membrane surface by polyethylene glycol linkers, were significantly less effective (kcat ≃ 3.5 x 104 M-1 s-1). Conclusions: For these amphiphilic analogs of FeTMPyP and MnTMPyP, the polarity of the environment of the metalloporphyrin headgroup is intimately related to the efficiency of the catalyst; a polar aqueous environment is essential for effective catalysis of ONOO- decomposition. Thus, catalysts 1b and 2b react rapidly with ONOO- and are potential therapeutic agents that, unlike their water-soluble TMPyP analogs, could be administered as liposomal formulations in SLs. These SL-bound amphiphilic metalloporphyrins may prove to be highly effective in the exploration and treatment of ONOO- related disease states.
Hunt, J. A., Lee, J., & Groves, J. T. (1997). Amphiphilic peroxynitrite decomposition catalysts in liposomal assemblies. Chemistry and Biology, 4(11), 845–858. https://doi.org/10.1016/S1074-5521(97)90117-4