Hybrid Nitric Oxide Donor and its Carrier for the Treatment of Peripheral Arterial Diseases

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.

Hybrid Compound SA-2 is Neuroprotective in Animal Models of Retinal Ganglion Cell Death

“…Under conditions of H 2 O 2 -induced oxidative stress, the hybrid compound SA-2 protected the HUVECs with an EC 50 of 0.354 lM, scavenged the ROS, and maintained physiologically relevant level of eNOS. 28 We also demonstrated earlier that, compound SA-2 increased the SOD enzyme levels in 661W mouse photoreceptor neural cells 21 and in primary human trabecular meshwork cells (Stankowska DL, Acharya S, unpublished observations, 2018).…”

“…In summary, a small hybrid compound SA-2 with the potential of maintaining a physiological concentration of NO and effectively scavenging the ROS as shown by us in endothelial cells 28 was neuroprotective in the retina. Compound SA-2 was effective both therapeutically and prophylactically in three separate acute models of RGC death, including hypoxia, ONC, and I/R model and the neuroprotective activity is mediated by upregulation of SOD levels in the retinas following ONC.…”

Nanoparticles in Medicine: A Focus on Vascular Oxidative Stress

“…However, the ischemic event during peripheral ischemia produces O 2 − and diminishes the bioavailability of NO by forming ONOO − . An interesting recent study [ 132 ] developed a hybrid molecule consisting of a copolymer poly (lactic-co-glycolic acid) (PLGA) nanoparticle loaded with SA-2 and which contains both antioxidant and NO donor functionalities and provides a sufficiently therapeutic level of NO to treat peripheral arterial diseases.…”

Nanomagnetite-embedded PLGA Spheres for Multipurpose Medical Applications

“…The successful experimental use of unconventional pharmaceutical formulations based on this particular PLGA copolymer was reported in modern strategies for diabetes-related conditions [21,22], HIV management [23,24], vaccine therapy [25], therapeutic angiogenesis [26,27], and tissue engineering [28,29,30]. Relevant examples of PLGA-based anti-infective strategies include treatment of streptococcal infections [31], ocular infection management [32], treatment of vaginal infection [33], and systemic antibiotherapy [34].…”