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.
Highlights
Peripheral arterial diseases (PAD), the occlusive arterial disorder in the lower extremities of the body, is prevalent in elderly people
We investigated the approach of combining “spontaneous” or pH-responsive Nitric Oxide (NO) donor[24] and superoxide dismutase (SOD) mimetic functional groups (SA-2, Fig. 1a) to both maintain a therapeutic level of NO and scavenge superoxide[25], respectively
We have studied the effects of standard pH-responsive NO donor (3-(4-Morpholino)-sydnonimine hydrochloride, SIN-1, Fig. 1a), SOD mimetic nitroxide (4-Amino TEMPO, SA-3, Fig. 1a) or mitochondrial enzymes-dependent No donor hybrid compound[26] (4-nitro TEMPOL, SA-5, Fig. 1a) to compare their effects and validate the advantages of our hybrid molecule SA-2 on inhibiting smooth muscle cells (SMCs) migration and proliferation as well as preventing endothelial cells (ECs) dysfunction
Summary
Peripheral arterial diseases (PAD), the occlusive arterial disorder in the lower extremities of the body, is prevalent in elderly people. Ischemia related to PAD occlusions has high rates of amputations and mortalities worldwide Common treatments such as bypass grafts, endovascular and percutaneous interventions are feasible methods in restoring sufficient perfusion to maintain normal vessel functions, yet they often cause frequent late thrombosis and restenosis in arteries[2, 3]. Therapeutic angiogenesis, the sprouting of new blood vessels from pre-existing vasculatures[4], has proven to be a potential strategy to mitigate PAD patients’ symptoms as it promotes vessel formation and lowers blood pressure while supplying oxygen-rich blood and nutrients to tissues in deficits[5] This treatment route requires the administration of exogenous pro-angiogenic factors to trigger EC proliferation and migration and to remodel the extracellular matrix (ECM) for tubule formation and expansion[6]. A sustainable delivery system consisting of SA-2, SA-2-loaded PLGA nanoparticles (SA-2 NPs), was synthesized, characterized and confirmed for a sustained release of SA-2 to further provide the improved EC survival and enhanced angiogenesis under stress conditions
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