title: Periadventitial atRA citrate-based polyester membranes reduce neointimal hyperplasia and restenosis after carotid injury in rats.
abstract: Oral all-trans retinoic acid (atRA) has been shown to reduce the formation of neointimal hyperplasia; however, the dose required was 30 times the chemotherapeutic dose, which already has reported side effects. As neointimal formation is a localized process, new approaches to localized delivery are required. This study assessed whether atRA within a citrate-based polyester, poly(1,8 octanediolcitrate) (POC), perivascular membrane would prevent neointimal hyperplasia following arterial injury. atRA-POC membranes were prepared and characterized for atRA release via high-performance liquid chromatography with mass spectrometry detection. Rat adventitial fibroblasts (AF) and vascular smooth muscle cells (VSMC) were exposed to various concentrations of atRA; proliferation, apoptosis, and necrosis were assessed in vitro. The rat carotid artery balloon injury model was used to evaluate the impact of the atRA-POC membranes on neointimal formation, cell proliferation, apoptosis, macrophage infiltration, and vascular cell adhesion molecule 1 (VCAM-1) expression in vivo. atRA-POC membranes released 12 μg of atRA over 2 wk, with 92% of the release occurring in the first week. At 24 h, atRA (200 μmol/l) inhibited [(3)H]-thymidine incorporation into AF and VSMC by 78% and 72%, respectively (*P = 0.001), with negligible apoptosis or necrosis. Histomorphometry analysis showed that atRA-POC membranes inhibited neointimal formation after balloon injury, with a 56%, 57%, and 50% decrease in the intimal area, intima-to-media area ratio, and percent stenosis, respectively (P = 0.001). atRA-POC membranes had no appreciable effect on apoptosis or proliferation at 2 wk. Regarding biocompatibility, we found a 76% decrease in macrophage infiltration in the intima layer (P < 0.003) in animals treated with atRA-POC membranes, with a coinciding 53% reduction in VCAM-1 staining (P < 0.001). In conclusion, perivascular delivery of atRA inhibited neointimal formation and restenosis. These data suggest that atRA-POC membranes may be suitable as localized therapy to inhibit neointimal hyperplasia following open cardiovascular procedures.
authors.affiliation: Division of Vascular Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois;
authors.forename: Elaine K
authors.initials: EK
authors.lastname: Gregory
authors.affiliation: Biomedical Engineering Department, McCormick School of Engineering, Northwestern University, Evanston, Illinois; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois; VesselTek Biomedical, Chicago, Illinois; University of Florida, Gainesville, Florida.
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Webb
authors.affiliation: Division of Vascular Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois;
authors.forename: Janet M
authors.initials: JM
authors.lastname: Vercammen
authors.affiliation: Division of Vascular Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois;
authors.forename: Megan E
authors.initials: ME
authors.lastname: Flynn
authors.affiliation: Biomedical Engineering Department, McCormick School of Engineering, Northwestern University, Evanston, Illinois; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois;
authors.forename: Guillermo A
authors.initials: GA
authors.lastname: Ameer
authors.affiliation: Division of Vascular Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois; mkibbe@nmh.org.
authors.forename: Melina R
authors.initials: MR
authors.lastname: Kibbe
mesh_terms: D063194:Adventitia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D017536:Carotid Artery, Common / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016893:Carotid Stenosis / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002951:Citrates / Q000737:chemistry*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006965:Hyperplasia; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D008567:Membranes, Artificial; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D058426:Neointima; D011108:Polymers / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D013997:Time Factors; D014212:Tretinoin / Q000008:administration & dosage*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D002951:Citrates; D004337:Drug Carriers; D008567:Membranes, Artificial; D011108:Polymers; D019010:Vascular Cell Adhesion Molecule-1; C513817:poly(1,8-octanediol citrate); D014212:Tretinoin
keywords: endothelium/vascular; nitric oxide; peripheral vascular disease; restenosis; smooth muscle cell proliferation and differentiation