title: Nanoparticles Effectively Target Rapamycin Delivery to Sites of Experimental Aortic Aneurysm in Rats.
abstract: Several drugs targeting the pathogenesis of aortic aneurysm have shown efficacy in model systems but not in clinical trials, potentially owing to the lack of targeted drug delivery. Here, we designed a novel drug delivery system using nanoparticles to target the disrupted aortic aneurysm micro-structure. We generated poly(ethylene glycol)-shelled nanoparticles incorporating rapamycin that exhibited uniform diameter and long-term stability. When injected intravenously into a rat model in which abdominal aortic aneurysm (AAA) had been induced by infusing elastase, labeled rapamycin nanoparticles specifically accumulated in the AAA. Microscopic analysis revealed that rapamycin nanoparticles were mainly distributed in the media and adventitia where the wall structures were damaged. Co-localization of rapamycin nanoparticles with macrophages was also noted. Rapamycin nanoparticles injected during the process of AAA formation evinced significant suppression of AAA formation and mural inflammation at 7 days after elastase infusion, as compared with rapamycin treatment alone. Correspondingly, the activities of matrix metalloproteinases and the expression of inflammatory cytokines were significantly suppressed by rapamycin nanoparticle treatment. Our findings suggest that the nanoparticle-based delivery system achieves specific delivery of rapamycin to the rat AAA and might contribute to establishing a drug therapy approach targeting aortic aneurysm.
authors.affiliation: Division of Vascular Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Shirasu
authors.affiliation: Division of Vascular Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Translational Research Center, The University of Tokyo Hospital, Tokyo, Japan.|Department of Vascular Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koyama
authors.affiliation: Departments of Materials Engineering and Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.|Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Miura
authors.affiliation: Division of Vascular Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Hoshina
authors.affiliation: Departments of Materials Engineering and Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.|Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Division of Vascular Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D001014:Aortic Aneurysm / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D018093:Gelatinases / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008856:Microscopy, Fluorescence; D057054:Molecular Imaging; D053758:Nanoparticles; D051381:Rats; D020123:Sirolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D018093:Gelatinases; D020123:Sirolimus