title: Nanoparticles for localized delivery of hyaluronan oligomers towards regenerative repair of elastic matrix.
abstract: Abdominal aortic aneurysms (AAAs) are rupture-prone progressive dilations of the infrarenal aorta due to a loss of elastic matrix that lead to weakening of the aortic wall. Therapies to coax biomimetic regenerative repair of the elastic matrix by resident, diseased vascular cells may thus be useful to slow, arrest or regress AAA growth. Hyaluronan oligomers (HA-o) have been shown to induce elastic matrix synthesis by healthy and aneurysmal rat aortic smooth muscle cells (SMCs) in vitro but only via exogenous dosing, which potentially has side-effects and limitations to in vivo delivery towards therapy. In this paper, we describe the development of HA-o loaded poly(lactide-co-glycolide) nanoparticles (NPs) for targeted, controlled and sustained delivery of HA-o towards the elastogenic induction of aneurysmal rat aortic SMCs. These NPs were able to deliver HA-o over an extended period (>30 days) at previously determined elastogenic doses (0.2-20 μg ml(-1)). HA-o released from the NPs led to dose-dependent increases in elastic matrix synthesis, and the recruitment and activity of lysyl oxidase, the enzyme which cross-links elastin precursor molecules into mature fibers/matrix. Therefore, we were able to successfully develop a nanoparticle-based system for controlled and sustained HA-o delivery for the in vitro elastogenic induction of aneurysmal rat aortic smooth muscle cells.
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Department of Biomedical Engineering, The Cleveland Clinic, 9500 Euclid Avenue, ND 20, Cleveland, OH 44195, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sylvester
authors.forename: Balakrishnan
authors.initials: B
authors.lastname: Sivaraman
authors.forename: Partha
authors.initials: P
authors.lastname: Deb
authors.forename: Anand
authors.initials: A
authors.lastname: Ramamurthi
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001014:Aortic Aneurysm / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D004549:Elastin / Q000378:metabolism* / Q000648:ultrastructure; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D005455:Fluorescent Antibody Technique; D006820:Hyaluronic Acid / Q000494:pharmacology*; D007700:Kinetics; D019344:Lactic Acid / Q000737:chemistry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011142:Polyvinyl Alcohol / Q000737:chemistry; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D051381:Rats; D012038:Regeneration / Q000187:drug effects*; D055672:Static Electricity
chemical_list: D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011142:Polyvinyl Alcohol; D006820:Hyaluronic Acid; D004549:Elastin; D008249:Protein-Lysine 6-Oxidase; D020778:Matrix Metalloproteinase 2
keywords: Drug delivery; Elastic matrix; Hyaluronan oligomers; Nanoparticles; Regenerative matrix repair
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