title: Electrosprayed Montelukast/poly (lactic-co-glycolic acid) particle based coating: A new therapeutic approach towards the prevention of in-stent restenosis.
abstract: Drug-eluting stents (DESs), have shown promising results in prevention of in-stent restenosis after percutaneous coronary intervention (PCI). The elevated level of leukotrienes (LTs) detected in injured arteries after PCI, together with the potential role of LTs in inflammatory cascades and structural alterations in arterial wall provides the rationale for development of therapeutic strategies for prevention of in-stent restenosis using LTs receptor antagonists. Montelukast (MK) is a selective cysLT1 receptor antagonist, with anti-inflammatory and anti-proliferative properties, which has been used for treatment of various diseases. Here, we report on the fabrication of MK/PLGA particles by electrospraying, aiming towards the development of particle based coating of DESs. The electrosprayed particles incorporated with 3% and 6% w/w MK exhibited fairly spherical shape with smooth surfaces and narrow size distribution. Sustained release of MK for up to 40days was obtained for both formulations, with higher initial burst release and drug release rate for the particles with higher drug loading. The LTD4 induced proliferation and migration of human coronary artery smooth muscle cells (HCASMCs) by 35% and 85%, respectively, which was substantially antagonized using MK incorporated particles. Nevertheless, MK antagonism preserved the normal proliferation and migration of human coronary artery endothelial cells (HCAECs). Moreover, MK antagonism inhibited the LTD4 induced phenotypic transition of HCASMCs from contractile to synthetic type. The electrosprayed MK-PLGA particles can be employed as a coating for DESs to inhibit the formation of neointimal hyperplasia responsible for in-stent restenosis, yet preserve the healing rate of the stented vessel.
  
  
  
  Montelukast (MK) is a selective cysLT1 receptor antagonist, with anti-inflammatory and anti-proliferative properties. The LTD4 induced proliferation and migration of human coronary artery smooth muscle cells by 35% and 85%, respectively, which was substantially antagonized using MK incorporated particles. MK antagonism preserved the normal proliferation and migration of human coronary artery endothelial cells. The MK antagonism inhibited the phenotypic transition of human coronary artery smooth muscle cells from contractile to synthetic one induced by LTD4. The electrosprayed MK-PLGA particles can be employed as coating for DESs to inhibit formation of neointimal hyperplasia, responsible for in-stent restenosis.
authors.affiliation: Department of Mechanical Engineering, National University of Singapore, 2 Engineering Drive 3, Singapore 117576, Singapore. Electronic address: maedeh.zamani@u.nus.edu.
authors.forename: Maedeh
authors.initials: M
authors.lastname: Zamani
authors.affiliation: Department of Mechanical Engineering, National University of Singapore, 2 Engineering Drive 3, Singapore 117576, Singapore. Electronic address: nanotechmpp@gmail.com.
authors.forename: Molamma P
authors.initials: MP
authors.lastname: Prabhakaran
authors.affiliation: Department of Pharmaceutics, Novel Drug Delivery Systems Research Centre and School of Pharmacy, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran. Electronic address: varshosaz@pharm.mui.ac.ir.
authors.forename: Jaleh
authors.initials: J
authors.lastname: Varshosaz
authors.affiliation: School of Materials and Science Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore. Electronic address: smpriya@ntu.edu.sg.
authors.forename: Priyadarshini S
authors.initials: PS
authors.lastname: Mhaisalkar
authors.affiliation: Department of Mechanical Engineering, National University of Singapore, 2 Engineering Drive 3, Singapore 117576, Singapore. Electronic address: seeram@nus.edu.sg.
authors.forename: Seeram
authors.initials: S
authors.lastname: Ramakrishna
mesh_terms: D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use*; D002152:Calorimetry, Differential Scanning; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020099:Coated Materials, Biocompatible / Q000737:chemistry*; D023903:Coronary Restenosis / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000473:pathology; D003521:Cyclopropanes; D065546:Drug Liberation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D018077:Receptors, Leukotriene / Q000378:metabolism; D015607:Stents; D013440:Sulfides
chemical_list: D000085:Acetates; D020099:Coated Materials, Biocompatible; D003521:Cyclopropanes; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C083169:leukotriene D4 receptor; C093875:montelukast
keywords: Drug-eluting stents; Electrospraying; In-stent restenosis; Montelukast; Poly (lactic-co-glycolic acid)