Hybrid Nitric Oxide Donor and its Carrier for the Treatment of Peripheral Arterial Diseases
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Abstract
Nitric oxide (NO) has been known to promote physiological angiogenesis to treat peripheral arterial diseases (PAD) by increasing the vascular endothelial growth factor (VEGF) level in endothelial cells (ECs) and preventing platelet adherence and leukocyte chemotaxis. However, the ongoing ischemic event during peripheral ischemia produces superoxide and diminishes the NO bioavailability by forming toxic peroxynitrite anion. Here we disclose an efficacious hybrid molecule 4-(5-Amino-1,2,3-oxadiazol-3-yl)-2,2,6,6-tetramethyl-1-piperidinol (SA-2) containing both antioxidant and NO donor functionalities that provide a therapeutic level of NO necessary to promote angiogenesis and to protect ECs against hydrogen peroxide-induced oxidative stress. Compound SA-2 scavenged reactive oxygen species, inhibited proliferation and migration of smooth muscle cells (SMCs) and promoted the tube formation from ECs. Copolymer poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with SA-2 provided a sustained release of NO over days, improved aqueous stability in serum, protected ECs against oxidative stress, and enhanced angiogenesis under stress conditions as compared to that of the control in the in vitro matrigel tube formation assay. These results indicated the potential use of SA-2 nanoparticles as an alternative therapy to treat PAD.
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Blood Vessels / metabolism
Cell Hypoxia / drug effects
Cell Movement / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Human Umbilical Vein Endothelial Cells / drug effects
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Myocytes, Smooth Muscle / drug effects
Myocytes, Smooth Muscle / metabolism
Nanoparticles / chemistry
Nanoparticles / ultrastructure
Neovascularization, Physiologic / drug effects
Nitric Oxide Donors / chemistry
Nitric Oxide Donors / pharmacology
Nitric Oxide Donors / therapeutic use
Oxidative Stress / drug effects
Peripheral Arterial Disease / drug therapy
Peripheral Arterial Disease / pathology