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.
Kipshidze
Nicholas N
NN
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
Porter
Thomas R
TR
Dangas
George
G
Yazdi
Hamid
H
Tio
Fermin
F
Xie
Feng
F
Hellinga
David
D
Fournadjiev
Jana
J
Wolfram
Roswitha
R
Seabron
Rufus
R
Waksman
Ron
R
Abizaid
Alexander
A
Roubin
Gary
G
Iyer
Sriram
S
Leon
Martin B
MB
Moses
Jeffrey W
JW
Iversen
Patrick
P
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