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 (31nM corresponding to 2microM 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]=1.28microM NO/mg) at 500microM GSH. Reperfusion experiments conducted with 500microM GSH further lowered the optimal therapeutic G4-SNAP dose to 230pM (i.e., 15nM SNAP). The unique combination of G4-SNAP dendrimer and glutathione trigger represents a novel strategy with possible clinical relevance toward salvaging ischemic tissue.
Johnson
Timothy A
TA
Virginia Tech Carilion School of Medicine, Roanoke, VA, USA. TAJohnson@carilion.clinic.org <TAJohnson@carilion.clinic.org>
Stasko
Nathan A
NA
Matthews
Jessica L
JL
Cascio
Wayne E
WE
Holmuhamedov
Ekhson L
EL
Johnson
C Bryce
CB
Schoenfisch
Mark H
MH
D000818:Animals; D002478:Cells, Cultured; D050091:Dendrimers / Q000494:pharmacology*; D004195:Disease Models, Animal; D005978:Glutathione / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D011073:Polyamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*
D050091:Dendrimers; D011073:Polyamines; D009569:Nitric Oxide; D005978:Glutathione