Systemic targeted delivery of antisense with perflourobutane gas microbubble carrier reduced neointimal formation in the porcine coronary restenosis model

Nicholas N. Kipshidze, Thomas Richard Porter, George Dangas, Hamid Yazdi, Fermin Tio, Feng Xie, David Hellinga, Jana Fournadjiev, Roswitha Wolfram, Rufus Seabron, Ron Waksman, Alexander Abizaid, Gary Roubin, Sriram Iyer, Martin B. Leon, Jeffrey W. Moses, Patrick Iversen

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Hypothesis: 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). Conclusion: In the porcine coronary stent model, systemic targeted delivery of AVI-4126 using PGMC carrier significantly inhibited neointimal formation.

Original languageEnglish (US)
Pages (from-to)152-159
Number of pages8
JournalCardiovascular Radiation Medicine
Volume4
Issue number3
DOIs
StatePublished - Jan 1 2003

Fingerprint

Coronary Restenosis
Microbubbles
Swine
Gases
Stents
Fluorocarbons
High Pressure Liquid Chromatography
Western Blotting
Poloxamer
Morpholinos
Injections
AVI-4126
Blood Vessels
Catheters
Animal Models
Arteries
Gels

Keywords

  • Antisense
  • Nanoparticles
  • Restenosis
  • Stents

ASJC Scopus subject areas

  • Surgery
  • Molecular Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Systemic targeted delivery of antisense with perflourobutane gas microbubble carrier reduced neointimal formation in the porcine coronary restenosis model. / Kipshidze, Nicholas N.; Porter, Thomas Richard; Dangas, George; Yazdi, Hamid; Tio, Fermin; Xie, Feng; Hellinga, David; Fournadjiev, Jana; Wolfram, Roswitha; Seabron, Rufus; Waksman, Ron; Abizaid, Alexander; Roubin, Gary; Iyer, Sriram; Leon, Martin B.; Moses, Jeffrey W.; Iversen, Patrick.

In: Cardiovascular Radiation Medicine, Vol. 4, No. 3, 01.01.2003, p. 152-159.

Research output: Contribution to journalArticle

Kipshidze, NN, Porter, TR, Dangas, G, Yazdi, H, Tio, F, Xie, F, Hellinga, D, Fournadjiev, J, Wolfram, R, Seabron, R, Waksman, R, Abizaid, A, Roubin, G, Iyer, S, Leon, MB, Moses, JW & Iversen, P 2003, 'Systemic targeted delivery of antisense with perflourobutane gas microbubble carrier reduced neointimal formation in the porcine coronary restenosis model', Cardiovascular Radiation Medicine, vol. 4, no. 3, pp. 152-159. https://doi.org/10.1016/S1522-1865(03)00184-7
Kipshidze, Nicholas N. ; Porter, Thomas Richard ; Dangas, George ; Yazdi, Hamid ; Tio, Fermin ; Xie, Feng ; Hellinga, David ; Fournadjiev, Jana ; Wolfram, Roswitha ; Seabron, Rufus ; Waksman, Ron ; Abizaid, Alexander ; Roubin, Gary ; Iyer, Sriram ; Leon, Martin B. ; Moses, Jeffrey W. ; Iversen, Patrick. / Systemic targeted delivery of antisense with perflourobutane gas microbubble carrier reduced neointimal formation in the porcine coronary restenosis model. In: Cardiovascular Radiation Medicine. 2003 ; Vol. 4, No. 3. pp. 152-159.
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abstract = "Hypothesis: 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). Conclusion: In the porcine coronary stent model, systemic targeted delivery of AVI-4126 using PGMC carrier significantly inhibited neointimal formation.",
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AU - Kipshidze, Nicholas N.

AU - Porter, Thomas Richard

AU - Dangas, George

AU - Yazdi, Hamid

AU - Tio, Fermin

AU - Xie, Feng

AU - Hellinga, David

AU - Fournadjiev, Jana

AU - Wolfram, Roswitha

AU - Seabron, Rufus

AU - Waksman, Ron

AU - Abizaid, Alexander

AU - Roubin, Gary

AU - Iyer, Sriram

AU - Leon, Martin B.

AU - Moses, Jeffrey W.

AU - Iversen, Patrick

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N2 - Hypothesis: 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). Conclusion: In the porcine coronary stent model, systemic targeted delivery of AVI-4126 using PGMC carrier significantly inhibited neointimal formation.

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