S-nitrosothiol-modified dendrimers as nitric oxide delivery vehicles.
The synthesis and characterization of two generation-4 polyamidoamine (PAMAM) dendrimers with S-nitrosothiol exteriors are reported. The hyperbranched macromolecules were modified with either N-acetyl-D, L-penicillamine (NAP) or N-acetyl-L-cysteine (NACys) and analyzed via 1H and 13C NMR, UV absorption spectroscopy, MALDI-TOF mass spectrometry, and size exclusion chromatography. Treatment of the dendritic thiols with nitrite solutions yielded the corresponding S-nitrosothiol nitric oxide (NO) donors (G4-SNAP, G4-NACysNO). Chemiluminescent NO detection demonstrated that the dendrimers were capable of storing approximately 2 micromol NO x mg (-1) when exposed to triggers of S-nitrosothiol decomposition (e.g., light and copper). The kinetics of NO release were found to be highly dependent on the structure of the nitrosothiol (i.e., tertiary vs primary) and exhibited similar NO release characteristics to classical small molecule nitrosothiols reported in the literature. As a demonstration of utility, the ability of G4-SNAP to inhibit thrombin-mediated platelet aggregation was assayed. At equivalent nitrosothiol concentrations (25 microM), the G4-SNAP dendrimer resulted in a 62% inhibition of platelet aggregation, compared to only 17% for the small molecule NO donor. The multivalent NO storage, the dendritic effects exerted on nitrosothiol stability and reactivity, and the utility of dendrimers as drug delivery vehicles highlight the potential of these constructs as clinically useful S-nitrosothiol-based therapeutics.
Stasko
Nathan A
NA
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Fischer
Thomas H
TH
Schoenfisch
Mark H
MH
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry; D003692:Delayed-Action Preparations; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008027:Light; D009569:Nitric Oxide / Q000008:administration & dosage*; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009757:Nylons / Q000737:chemistry; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014677:Pharmaceutical Vehicles / Q000138:chemical synthesis / Q000737:chemistry* / Q000528:radiation effects; D010974:Platelet Aggregation / Q000187:drug effects; D026403:S-Nitrosothiols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D003692:Delayed-Action Preparations; D050091:Dendrimers; C528059:G4-S-nitroso-N-acetylcysteine; C528058:G4-S-nitroso-N-acetylpenicillamine; D020030:Nitric Oxide Donors; D009757:Nylons; C520550:PAMAM-G4; D014677:Pharmaceutical Vehicles; D026403:S-Nitrosothiols; D009569:Nitric Oxide; D003300:Copper; D010396:Penicillamine; D000111:Acetylcysteine