title: Alendronate-loaded nanoparticles deplete monocytes and attenuate restenosis.
abstract: Systemic transient depletion of monocytes and macrophages by liposome-encapsulated bisphosphonates (BPs), reduces neointimal formation in experimental restenosis. The aim of this study was to examine the antirestenotic effect of a polymeric nanoparticulate formulation containing the BP alendronate (ALN). The BP was successfully formulated in polylactide-co-glycolide (PLGA) nanoparticles (NP). ALN NP with negative charge, size of 223+/-64 nm, and high entrapment efficiency (55.1%) have been formulated. ALN NP exhibited a significant cytotoxic effect, in a dose-response relationship, on macrophage-like RAW264 cells in cell culture. Subcutaneously (SC) administrated ALN NP (1.5 mg/kg on days -1 and +6) resulted in a significant attenuation of neointima to media ratio (N/M) by 52.7% and stenosis by 39.7% 28 days after balloon injury in the hypercholesterolemic rabbit model. Moreover, a good correlation was found between macrophage abundance in the injured arteries and the extent of stenosis. ALN NP treatment resulted in the reduction of both interleukin-1beta and matrix metalloproteinases (2 and 9). It is concluded that a particulated dosage form of polymeric NP loaded with ALN reduce neointimal formation in vivo by systemic transient depletion of monocytes.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel.
authors.forename: Einat
authors.initials: E
authors.lastname: Cohen-Sela
authors.forename: Ohad
authors.initials: O
authors.lastname: Rosenzweig
authors.forename: Jianchuan
authors.initials: J
authors.lastname: Gao
authors.forename: Hila
authors.initials: H
authors.lastname: Epstein
authors.forename: Irith
authors.initials: I
authors.lastname: Gati
authors.forename: Reuven
authors.initials: R
authors.lastname: Reich
authors.forename: Haim D
authors.initials: HD
authors.lastname: Danenberg
authors.forename: Gershon
authors.initials: G
authors.lastname: Golomb
mesh_terms: D019386:Alendronate / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003251:Constriction, Pathologic / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000473:pathology; D007279:Injections, Subcutaneous; D019344:Lactic Acid / Q000737:chemistry; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000187:drug effects* / Q000473:pathology; D049329:Nanostructures / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry; D011817:Rabbits; D013997:Time Factors
chemical_list: D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D019386:Alendronate