Targeted vascular delivery of antisense molecules using intravenous microbubbles.
OBJECTIVE
Perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles bind the antisense to the c-myc protooncogene (anti-c-myc) which prevents neointimal hyperplasia following vascular endothelial injury. The microbubbles also adhere to sites of damaged vascular endothelium and thus may be a method of systemically targeting delivery of anti-c-myc.


METHODS
Laser scanning microscopy was performed on the aorta of 10 mice (five which were complement depleted) that received intravenous FITC-PESDA following aortic endothelial injury. C-myc expression was quantified following selective intracoronary injury in nine pigs that received intravenous (IV) anti-c-myc bound to PESDA. Finally, neointimal formation was measured following intracoronary stent deployment in 30 pigs that received either IV anti-c-myc alone or the same dose bound to PESDA.


RESULTS
Fluorescent microscopy confirmed selective PESDA microbubble adherence to aortic endothelium in all mice with aortic injury. This binding was nearly abolished when serum complement was depleted prior to injury. C-myc expression at the site of coronary endothelial injury was significantly lower in pigs treated with systemic anti-c-myc bound to PESDA. There was a 33% reduction in % stenosis and a 28% reduction in intimal area at 45 days post-stent deployment in pigs that received IV antisense plus PESDA. The stent margins also had reduced neointimal formation.


CONCLUSIONS
Systemic administration of anti-c-myc bound to PESDA microbubbles may be a good method for preventing coronary neointimal formation within and around implanted stents.
Porter
Thomas R
TR
Section of Cardiology, University of Nebraska Medical Center, Omaha, NE 68198-1165, USA.
Xie
Feng
F
Knapp
Derek
D
Iversen
Patrick
P
Marky
Luis A
LA
Tsutsui
Jeane M
JM
Maiti
Souvik
S
Lof
John
J
Radio
Stanley J
SJ
Kipshidze
Nicholas
N
D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology*; D005466:Fluorocarbons / Q000494:pharmacology; D051379:Mice; D045423:Microbubbles; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012709:Serum Albumin / Q000494:pharmacology; D015607:Stents; D013552:Swine; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology*
D004268:DNA-Binding Proteins; D005466:Fluorocarbons; C116115:MYCBP protein, human; D016376:Oligonucleotides, Antisense; D012709:Serum Albumin; D014157:Transcription Factors