title: Periadventitial application of rapamycin-loaded nanoparticles produces sustained inhibition of vascular restenosis.
abstract: Open vascular reconstructions frequently fail due to the development of recurrent disease or intimal hyperplasia (IH). This paper reports a novel drug delivery method using a rapamycin-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs)/pluronic gel system that can be applied periadventitially around the carotid artery immediately following the open surgery. In vitro studies revealed that rapamycin dispersed in pluronic gel was rapidly released over 3 days whereas release of rapamycin from rapamycin-loaded PLGA NPs embedded in pluronic gel was more gradual over 4 weeks. In cultured rat vascular smooth muscle cells (SMCs), rapamycin-loaded NPs produced durable (14 days versus 3 days for free rapamycin) inhibition of phosphorylation of S6 kinase (S6K1), a downstream target in the mTOR pathway. In a rat balloon injury model, periadventitial delivery of rapamycin-loaded NPs produced inhibition of phospho-S6K1 14 days after balloon injury. Immunostaining revealed that rapamycin-loaded NPs reduced SMC proliferation at both 14 and 28 days whereas rapamycin alone suppressed proliferation at day 14 only. Moreover, rapamycin-loaded NPs sustainably suppressed IH for at least 28 days following treatment, whereas rapamycin alone produced suppression on day 14 with rebound of IH by day 28. Since rapamycin, PLGA, and pluronic gel have all been approved by the FDA for other human therapies, this drug delivery method could potentially be translated into human use quickly to prevent failure of open vascular reconstructions.
authors.affiliation: Department of Surgery, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, United States of America.
authors.forename: Xudong
authors.initials: X
authors.lastname: Shi
authors.affiliation: Wisconsin Institutes for Discovery, University of Wisconsin, Madison, Wisconsin, United States of America ; Materials Science Program, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Guojun
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Surgery, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, United States of America.
authors.forename: Lian-Wang
authors.initials: LW
authors.lastname: Guo
authors.affiliation: Department of Surgery, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Si
authors.affiliation: Wisconsin Institutes for Discovery, University of Wisconsin, Madison, Wisconsin, United States of America ; Materials Science Program, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Men
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Wisconsin Institutes for Discovery, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Pilla
authors.affiliation: Department of Surgery, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, United States of America.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Wisconsin Institutes for Discovery, University of Wisconsin, Madison, Wisconsin, United States of America ; Materials Science Program, University of Wisconsin, Madison, Wisconsin, United States of America ; Department of Biomedical Engineering, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Shaoqin
authors.initials: S
authors.lastname: Gong
authors.affiliation: Department of Surgery, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, United States of America.
authors.forename: K Craig
authors.initials: KC
authors.lastname: Kent
mesh_terms: D063194:Adventitia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053758:Nanoparticles / Q000008:administration & dosage*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage*
chemical_list: D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus