AMPHIPHILIC PEROXYNITRITE DECOMPOSITION CATALYSTS in LIPOSOMAL ASSEMBLIES

Julianne A. Hunt, Jinbo Lee and John T. Groves

Chemistry & Biology 1997, in press.

Background: Peroxynitrite (ONOO-), a toxic oxidant produced by the direct and rapid combination of nitric oxide and superoxide, reacts with a wide range of biological substrates, and has been implicated in many pathophysiological conditions. The synthetic, water-soluble porphyrins 5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphinatoiron(III) (FeTMPyP) and 5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphinatomanganese(III) (MnTMPyP) have recently emerged as potential drugs for ONOO- detoxification, and FeTMPyP has demonstrated profound activity in biological models of ONOO- related disease states. We set out to design and prepare amphiphilic analogs of FeTMPyP and MnTMPyP that would be amenable to liposomal delivery in sterically stabilized liposomes (SLs).

Results: We prepared three amphiphilic iron porphyrins 1a-c and three amphiphilic manganese porphyrins 2a-c that bound to liposomes and catalyzed the decomposition of ONOO-. The polyethylene glycol-linked tetradodecylpyridinium metalloporphyrins 1b and 2b proved to be the most effective of these catalysts, rapidly decomposing ONOO- with second-order rate constants (kcat) of 2.9 x 105 M-1s-1 and 5.0 x 105 M-1s-1, respectively, in conventional DMPC liposomes. Catalysts 1b and 2b also bound to SLs, and these metalloporphyrin-SL constructs efficiently catalyzed ONOO- decomposition, with kcat = 2.3 x 105 M-1s-1 for 1b-SL and kcat = 1.9 x 105 M-1s-1 for 2b-SL.

Conclusions: The amphiphilic analogs of FeTMPyP and MnTMPyP effectively catalyze the decomposition of ONOO- when situated at the interface of the vesicle lipid membrane and the bulk solution (as in 1b and 2b), but are much less effective when tied to the surface of the lipid membrane (as in compounds 1a and 2a), demonstrating that the polarity of the environment of the porphyrin headgroup is intimately related to the efficiency of the catalyst. As potential therapeutic agents, 1b and 2b possess an important advantage over their water-soluble TMPyP analogs: they bind to phospholipid vesicles and thus can 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.

Editted by Jinbo Lee

Last updated on Oct. 7, 1997.