mZD7349 peptide-conjugated PLGA nanoparticles directed against VCAM-1 for targeted delivery of simvastatin to restore dysfunctional HUVECs.
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.
Department of Medical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Laboratory Sciences, Faculty of Khomein Medical Sciences, Arak University of Medical Sciences, Arak, Iran.
Fatemeh
F
Imanparast
Department of Pharmaceutical Biotechnology, Faculty of Pharmacy and Biotechnology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Mohammad Ali
MA
Faramarzi
Department of Medical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Akram
A
Vatannejad
Department of Medical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Maliheh
M
Paknejad
Division of Microbiology, Department of Pathobiology, School of Public Health Tehran University of Medical Sciences, Tehran, Iran.
Behnas
B
Deiham
Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Farzad
F
Kobarfard
Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Medical Biomaterials Research Center (MBRC), Tehran University of Medical Sciences, Tehran, Iran. Electronic address: aamani@sina.tums.ac.ir.
Amir
A
Amani
Department of Medical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: Doostimd@sina.tums.ac.ir.
Mahmood
M
Doosti
D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D002478:Cells, Cultured; D004337:Drug Carriers; D004339:Drug Compounding; D065546:Drug Liberation; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019344:Lactic Acid / Q000737:chemistry* / Q000633:toxicity; D053758:Nanoparticles; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D010766:Phosphorylation; D011100:Polyglycolic Acid / Q000737:chemistry* / Q000633:toxicity; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012694:Serine; D019821:Simvastatin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D012995:Solubility; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D004337:Drug Carriers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010456:Peptides, Cyclic; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C418806:ZD7349; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D012694:Serine; D019821:Simvastatin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III
Endothelium; HUVECs; Phospho-eNOS (Ser1177); Poly (dl-lactic-co-glycolic acid) nanoparticles; Simvastatin; Vascular cell-adhesion molecule-1; mZD7349 peptide