Reduced ischemia/reperfusion injury via glutathione-initiated nitric oxide-releasing dendrimers

We report the therapeutic potential of S-nitroso-N-acetylpenicillamine-derivatized generation-4 polyamidoamine dendrimers (G4-SNAP) for reducing ischemia/reperfusion (I/R) injury in an isolated, perfused rat heart. The use of this dendrimer scaffold to deliver the nitrosothiol therapeutic did not inhibit NO donor activity as the required dose of G4-SNAP to minimize I/R injury (31 nM corresponding to 2 μM SNAP) was consistent with the optimum concentration of small molecule SNAP alone. An exploration of G4-SNAP NO release kinetics in the presence of physiologically relevant concentrations of glutathione (GSH) indicated enhanced NO release (t[NO] = 1.28 μM NO/mg) at 500 μM GSH. Reperfusion experiments conducted with 500 μM GSH further lowered the optimal therapeutic G4-SNAP dose to 230 pM (i.e., 15 nM SNAP). The unique combination of G4-SNAP dendrimer and glutathione trigger represents a novel strategy with possible clinical relevance toward salvaging ischemic tissue.