mZD7349 peptide-conjugated PLGA nanoparticles directed against VCAM-1 for targeted delivery of simvastatin to restore dysfunctional HUVECs

• Published in: Microvascular research Vol. 112; pp. 14 - 19
• Main Authors: Imanparast, Fatemeh, Faramarzi, Mohammad Ali, Vatannejad, Akram, Paknejad, Maliheh, Deiham, Behnas, Kobarfard, Farzad, Amani, Amir, Doosti, Mahmood
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2017
• Subjects: Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - metabolism; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - toxicity; Cells, Cultured; Drug Carriers; Drug Compounding; Drug Liberation; Endothelium; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Human Umbilical Vein Endothelial Cells - pathology; Humans; HUVECs; Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry; Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - toxicity; Inflammation - metabolism; Inflammation - pathology; Inflammation - prevention & control; Lactic Acid - chemistry; Lactic Acid - toxicity; mZD7349 peptide; Nanoparticles; Nitric Oxide Synthase Type III - metabolism; Peptides, Cyclic - chemistry; Peptides, Cyclic - metabolism; Peptides, Cyclic - toxicity; Phospho-eNOS (Ser1177); Phosphorylation; Poly (dl-lactic-co-glycolic acid) nanoparticles; Polyglycolic Acid - chemistry; Polyglycolic Acid - toxicity; Serine; Simvastatin; Simvastatin - chemistry; Simvastatin - metabolism; Simvastatin - pharmacology; Simvastatin - toxicity; Solubility; Time Factors; Tumor Necrosis Factor-alpha - pharmacology; Vascular Cell Adhesion Molecule-1 - metabolism; Vascular cell-adhesion molecule-1; Simvastatin; Phospho-eNOS (Ser1177); mZD7349 peptide; Poly (dl-lactic-co-glycolic acid) nanoparticles; Vascular cell-adhesion molecule-1; HUVECs; Endothelium
• ISSN: 0026-2862; 1095-9319
• DOI: 10.1016/j.mvr.2017.02.002

Endothelial dysfunction is initial and critical step of atherosclerosis. Impaired bioavailability of endothelial nitric oxide synthase (eNOS) is one of the main reasons of endothelial dysfunction. Improving bioavailability of eNOS by increasing its expression or activity using statins is an effective therapeutic strategy in restoring endothelial dysfunction. In this study, simvastatin (SIM) as a poorly water-soluble drug was loaded in poly (lactic-co-glycolic acid) (PLGA) nanoparticles (SIM-PLGA-NPs). NPs were then conjugated with mZD7349 peptide (mZD7349-SIM-PLGA-NPs) and directed against vascular cell adhesion molecule 1 (VCAM-1). In vitro evaluation of the NPs for targeted delivery of SIM was performed on activated Human Umbilical Cord Vascular Endothelial Cells (HUVECs) by tumor necrosis factor alpha (TNF-α). Effect of mZD7349-SIM-PLGA-NPs and SIM-PLGA-NPs was compared on eNOS phosphorylation (ser-1177). Results of western blot showed SIM post-treatment increased significantly phosphor-eNOS (Ser1177) expression but no total eNOS expression. The study showed that mZD7349-SIM-PLGA-NPs have particle size, zeta potential value, polydispersity index (PDI) and encapsulation efficacy % of 233±18nm, −9.6±1.1mV, 0.59±0.066 and 69±17.3%, respectively. Also phosphor-eNOS (Ser1177) expression in activated HUVECs treated with mZD7349-SIM-PLGA-NPs was significantly (p<0.05) better than treated cells with SIM-PLGA-NPs. The results suggest that mZD7349-SIM-PLGA-NPs may be usable as an appropriate drug carrier for restoring endothelial dysfunction. •Simvastatin (SIM) was loaded in PLGA NPs, then, conjugated with mZD7349 peptide to direct against VCAM-1.•SIM treatment showed increased phosphor - eNOS (Ser1177) expression.•p- eNOS expression in activated HUVECs treated with conjugated NPs was better those treated with unconjugated NPs.•The results suggest that conjugated NPs may be usable as an appropriate drug carrier for restoring endothelial dysfunction.