title: The use of MMP2 antibody-conjugated cationic microbubble to target the ischemic myocardium, enhance Timp3 gene transfection and improve cardiac function.
abstract: The objective of this study was to synthesize a cationic microbubble (CMB) conjugated with an antibody against matrix metalloproteinase 2 (CMBMMP2) to increase microbubble accumulation and gene transfection in the infarcted myocardium and to restore ventricular function following an ischemic insult. We previously reported that our CMBs enhanced the efficiency of gene transfection following ultrasound-targeted microbubble destruction (UTMD) in rodent hearts. Therefore, we conjugated a thiolated MMP2 antibody to the PEG chains on the CMB surface, which was verified by fluorescent microscopy. Rats underwent ischemia/reperfusion injury 3 days prior to UTMD delivery of the control or Timp3 plasmid. The CMBMMP2 improved microbubble accumulation in the infarct region, with 57% more contrast intensity compared to the non-conjugated CMB. UTMD-mediated CMBMMP2 delivery of the Timp3 gene significantly increased TIMP3 protein levels in the infarct scar and border zone at 3 days post-UTMD compared to delivery by the non-conjugated CMB. Both MMP2 and MMP9 activity were reduced in the CMBMMP2Timp3 group, which resulted in smaller and thicker infarcts and improved cardiac function. UTMD therapy with this CMBMMP2 provides an efficient platform for the targeted delivery of factors intended to preserve ventricular structure and improve cardiac function after ischemic injury.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Division of Cardiovascular Surgery and Toronto General Research Institute, University Health Network, Toronto, ON, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Ping
authors.initials: P
authors.lastname: Yan
authors.forename: Ko-Jie
authors.initials: KJ
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.forename: Hsing-Wen
authors.initials: HW
authors.lastname: Sung
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000818:Animals; D018796:Immunoconjugates / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D045423:Microbubbles; D017202:Myocardial Ischemia / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D010714:Phosphatidylethanolamines / Q000737:chemistry; D010957:Plasmids / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*; D014162:Transfection
chemical_list: C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D018796:Immunoconjugates; D010714:Phosphatidylethanolamines; D019717:Tissue Inhibitor of Metalloproteinase-3; D011092:Polyethylene Glycols; D020778:Matrix Metalloproteinase 2
keywords: Gene transfection; Ischemic myocardium; MMP; Matrix modulation; TIMP; Targeted microbubble