title: Methotraxate-Loaded Hybrid Nanoconstructs Target Vascular Lesions and Inhibit Atherosclerosis Progression in ApoE-/-Mice.
abstract: Atherosclerosis is an inflammatory disorder characterized by the progressive thickening of blood vessel walls eventually resulting in acute vascular syndromes. Here, intravenously injectable hybrid nanoconstructs are synthesized for tempering immune cell inflammation locally and systemically. Lipid and polymer chains are nanoprecipitated to form 100 nm spherical polymeric nanoconstructs (SPNs), loaded with methotrexate (MTX) and subsequently labeled with Cu64and fluorescent probes for combined nuclear/optical imaging. Upon engulfment into macrophages, MTX SPNs intracellularly release their anti-inflammatory cargo significantly lowering the production of proinflammatory cytokine (interleukin 6 and tumor necrosis factor α) already at 0.06 mg mL-1of MTX. In ApoE-/-mice, fed with high-fat diet up to 17 weeks, nuclear and optical imaging demonstrates specific accumulation of SPNs within lipid-rich plaques along the arterial tree. Histological analyses confirm SPN uptake into macrophages residing within atherosclerotic plaques. A 4-week treatment with biweekly administration of MTX SPNs is sufficient to reduce the plaque burden in ApoE-/-mice by 50%, kept on high-fat diet for 10 weeks. Systemic delivery of MTX to macrophages via multifunctional, hybrid nanoconstructs constitutes an effective strategy to inhibit atherosclerosis progression and induce, potentially, the resorption of vascular lesions.
authors.affiliation: Department of Translational Imaging & Nanomedicine, Houston Methodist Research Institute, Houston, TX, 77030, USA.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Stigliano
authors.affiliation: Department of Translational Imaging & Nanomedicine, Houston Methodist Research Institute, Houston, TX, 77030, USA.
authors.forename: Maricela R
authors.initials: MR
authors.lastname: Ramirez
authors.affiliation: Department of Translational Imaging & Nanomedicine, Houston Methodist Research Institute, Houston, TX, 77030, USA.
authors.forename: Jaykrishna V
authors.initials: JV
authors.lastname: Singh
authors.affiliation: Department of Chemistry, Nanotechnology Innovation Center of Kansas State (NICKS), Kansas State University, Manhattan, KS, 66506, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Aryal
authors.affiliation: Department of Biomedical Engineering, Yonsei University, Wonju, Gangwon-do, 220-710, Republic of Korea.
authors.forename: Jaehong
authors.initials: J
authors.lastname: Key
authors.affiliation: Department of Translational Imaging & Nanomedicine, Houston Methodist Research Institute, Houston, TX, 77030, USA.
authors.forename: Elvin
authors.initials: E
authors.lastname: Blanco
authors.affiliation: Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, Genoa, 16163, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Decuzzi
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003301:Copper Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D008727:Methotrexate / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D061848:Optical Imaging / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D003301:Copper Radioisotopes; D004337:Drug Carriers; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D008727:Methotrexate
keywords: cardiovascular diseases; hybrid nanoparticles; macrophage; methotrexate; nanomedicine