Amphiphilic peroxynitrite decomposition catalysts in liposomal assemblies

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.