title: Prevention of abdominal aortic aneurysm progression by targeted inhibition of matrix metalloproteinase activity with batimastat-loaded nanoparticles.
abstract: BACKGROUND
  Matrix metalloproteinases (MMPs)-mediated extracellular matrix destruction is the major cause of development and progression of abdominal aortic aneurysms. Systemic treatments of MMP inhibitors have shown effectiveness in animal models, but it did not translate to clinical success either because of low doses used or systemic side effects of MMP inhibitors. We propose a targeted nanoparticle (NP)-based delivery of MMP inhibitor at low doses to the abdominal aortic aneurysms site. Such therapy will be an attractive option for preventing expansion of aneurysms in patients without systemic side effects.
  
  
  OBJECTIVE
  Our previous study showed that poly(d,l-lactide) NPs conjugated with an antielastin antibody could be targeted to the site of an aneurysm in a rat model of abdominal aortic aneurysms. In the study reported here, we tested whether such targeted NPs could deliver the MMP inhibitor batimastat (BB-94) to the site of an aneurysm and prevent aneurysmal growth.
  
  
  RESULTS
  Poly(d,l-lactide) NPs were loaded with BB-94 and conjugated with an elastin antibody. Intravenous injections of elastin antibody-conjugated BB-94-loaded NPs targeted the site of aneurysms and delivered BB-94 in a calcium chloride injury-induced abdominal aortic aneurysms in rats. Such targeted delivery inhibited MMP activity, elastin degradation, calcification, and aneurysmal development in the aorta (269% expansion in control versus 40% elastin antibody-conjugated BB-94-loaded NPs) at a low dose of BB-94. The systemic administration of BB-94 alone at the same dose was ineffective in producing MMP inhibition.
  
  
  CONCLUSIONS
  Targeted delivery of MMP inhibitors using NPs may be an attractive strategy to inhibit aneurysmal progression.
authors.affiliation: From the Department of Bioengineering, Clemson University, SC (N.N., P.N.-G., A.S., A.C., P.G., N.R.V.); Department of Biomedical Engineering, Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine (A.S.); and Division of Vascular Surgery, Greenville Health System, SC (C.G.C., B.H.G.).
authors.forename: Nasim
authors.initials: N
authors.lastname: Nosoudi
authors.affiliation: From the Department of Bioengineering, Clemson University, SC (N.N., P.N.-G., A.S., A.C., P.G., N.R.V.); Department of Biomedical Engineering, Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine (A.S.); and Division of Vascular Surgery, Greenville Health System, SC (C.G.C., B.H.G.).
authors.forename: Pranjal
authors.initials: P
authors.lastname: Nahar-Gohad
authors.affiliation: From the Department of Bioengineering, Clemson University, SC (N.N., P.N.-G., A.S., A.C., P.G., N.R.V.); Department of Biomedical Engineering, Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine (A.S.); and Division of Vascular Surgery, Greenville Health System, SC (C.G.C., B.H.G.).
authors.forename: Aditi
authors.initials: A
authors.lastname: Sinha
authors.affiliation: From the Department of Bioengineering, Clemson University, SC (N.N., P.N.-G., A.S., A.C., P.G., N.R.V.); Department of Biomedical Engineering, Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine (A.S.); and Division of Vascular Surgery, Greenville Health System, SC (C.G.C., B.H.G.).
authors.forename: Aniqa
authors.initials: A
authors.lastname: Chowdhury
authors.affiliation: From the Department of Bioengineering, Clemson University, SC (N.N., P.N.-G., A.S., A.C., P.G., N.R.V.); Department of Biomedical Engineering, Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine (A.S.); and Division of Vascular Surgery, Greenville Health System, SC (C.G.C., B.H.G.).
authors.forename: Patrick
authors.initials: P
authors.lastname: Gerard
authors.affiliation: From the Department of Bioengineering, Clemson University, SC (N.N., P.N.-G., A.S., A.C., P.G., N.R.V.); Department of Biomedical Engineering, Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine (A.S.); and Division of Vascular Surgery, Greenville Health System, SC (C.G.C., B.H.G.).
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Carsten
authors.affiliation: From the Department of Bioengineering, Clemson University, SC (N.N., P.N.-G., A.S., A.C., P.G., N.R.V.); Department of Biomedical Engineering, Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine (A.S.); and Division of Vascular Surgery, Greenville Health System, SC (C.G.C., B.H.G.).
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Gray
authors.affiliation: From the Department of Bioengineering, Clemson University, SC (N.N., P.N.-G., A.S., A.C., P.G., N.R.V.); Department of Biomedical Engineering, Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine (A.S.); and Division of Vascular Surgery, Greenville Health System, SC (C.G.C., B.H.G.). narenv@clemson.edu.
authors.forename: Naren R
authors.initials: NR
authors.lastname: Vyavahare
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002122:Calcium Chloride; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D018450:Disease Progression; D004337:Drug Carriers; D004549:Elastin / Q000276:immunology / Q000378:metabolism; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D053758:Nanoparticles; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011091:Polyesters / Q000737:chemistry*; D059748:Proteolysis; D000067996:RAW 264.7 Cells; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D061205:Vascular Calcification / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control
chemical_list: D004337:Drug Carriers; D018796:Immunoconjugates; D061965:Matrix Metalloproteinase Inhibitors; D011091:Polyesters; D013876:Thiophenes; C033616:poly(lactide); D010649:Phenylalanine; D004549:Elastin; C080985:batimastat; D020782:Matrix Metalloproteinases; D002122:Calcium Chloride
keywords: abdominal aortic aneurysm; batimastat; cardiovascular diseases; drug delivery systems; matrix metalloproteinase inhibitors; nanoparticles; vascular remodeling