Systemic targeted delivery of antisense with perflourobutane gas microbubble carrier reduced neointimal formation in the porcine coronary restenosis model.
OBJECTIVE
The antisense phosphorodiamidate morpholino oligomer (PMO), AVI-4126, has been effective in reducing neointimal formation in animal models following delivery by pluronic gels, local delivery catheters and coated stents. Greater flexibility of repeated-dosage regimens and reduced procedure complexity may be provided by systemic injection of AVI-4126 bound to perfluorobutane gas microbubble carriers. The purpose of this study was to investigate the effects of perfluorocarbon gas microbubble carrier (PGMC)-based systemic delivery of AVI-4126 on expression of the c-myc in vascular tissue and restenosis after stent implantation.


METHODS
Seven pigs underwent stent implantation (3 stents/animal). Five pigs received IV injection of PGMC and 2 mg of AVI-4126 (AVI BioPharma). Two served as control. Four hours postprocedure, 3 pigs were sacrificed and stented segments analyzed by high-performance liquid chromatography (HPLC) and Western blot. In chronic experiments, 4 pigs (12 stent sites) were sacrificed at 28 days.


RESULTS
HPLC analysis of plasma samples of treated animals showed minimal presence of AVI-4126. HPLC of the treated arteries demonstrated easily detected concentrations of AVI-4126. Western blot analysis of the stented vessels demonstrated modest inhibition of c-myc. Morphometry showed that the neointimal area was significantly reduced in the AVI-4126/PGMC group compared with control (2.63+/-1.99 vs. 4.77+/-.1.71 mm2, respectively, P<.05).


CONCLUSIONS
In the porcine coronary stent model, systemic targeted delivery of AVI-4126 using PGMC carrier significantly inhibited neointimal formation.
Lenox Hill Heart and Vascular Institute and Cardiovascular Research Foundation, 130 East 77th Street, Black Hall, 9th Floor, New York, NY 10021, USA. nkipshidze@lenoxhill.net
Nicholas N
NN
Kipshidze
Thomas R
TR
Porter
George
G
Dangas
Hamid
H
Yazdi
Fermin
F
Tio
Feng
F
Xie
David
D
Hellinga
Jana
J
Fournadjiev
Roswitha
R
Wolfram
Rufus
R
Seabron
Ron
R
Waksman
Alexander
A
Abizaid
Gary
G
Roubin
Sriram
S
Iyer
Martin B
MB
Leon
Jeffrey W
JW
Moses
Patrick
P
Iversen
D000818:Animals; D019917:Blood Vessel Prosthesis Implantation; D015153:Blotting, Western; D023903:Coronary Restenosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005466:Fluorocarbons / Q000493:pharmacokinetics*; D016259:Genes, myc / Q000187:drug effects; D015918:Infusion Pumps, Implantable; D008297:Male; D045423:Microbubbles; D008955:Models, Cardiovascular; D009025:Morpholines / Q000493:pharmacokinetics; D060172:Morpholinos; D016376:Oligonucleotides, Antisense / Q000493:pharmacokinetics*; D015607:Stents; D013552:Swine; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*
D005466:Fluorocarbons; D009025:Morpholines; D060172:Morpholinos; D016376:Oligonucleotides, Antisense