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Published on: October 3, 2017
Prevention of neointimal formation after angioplasty using nuclear factor-κB decoy oligodeoxynucleotide-coated
Takashi Miyake1, Shinya Ihara1, Tetsuo Miyake1
1From the Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Osaka, Japan (T.M., T.M., R.M.); Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Osaka, Japan (T.M., H.N.); AnGes MG, Inc, Osaka, Japan (S.I., H.W.); Pharmaceutical and Beauty Science Research Center, Hosokawa Micron Corporation, Osaka, Japan (Y.T., H.T.); and Togo Medikit Co, Ltd, Miyazaki, Japan (H.M., H.K.).
Background:
Despite the advent of drug-eluting stents, restenosis after endovascular intervention is still a major limitation in the treatment of cardiovascular disease. To regulate the multiple biological mechanisms underlying restenosis, we focused on inhibition of an important transcription factor, nuclear factor-kappaB (NFκB), using a decoy strategy.
Methods And Results:
For site-specific application of NFκB decoy oligodeoxynucleotides into target vessels during angioplasty, we developed a balloon catheter-based delivery system combined with biocompatible nanoparticles as oligodeoxynucleotides carriers. To clarify the therapeutic effect at the site of neointima, balloon angioplasty of the rabbit carotid arteries was performed at 4 weeks after initial endothelial denudation. This delivery system exhibited successful transfer of fluorescence-labeled nanospheres into the neointima in short-term contact with target vessels, and fluorescence could be detected ≥1 week after angioplasty. Consistently, local application of NFκB decoy oligodeoxynucleotides -loaded nanospheres resulted in significant inhibition of neointimal formation, associated with inhibition of NFκB binding activity in the injured arteries. The therapeutic effects were caused by inhibition of macrophage recruitment through the suppression of monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, and CC chemokine ligand 4 expression and inhibition of vascular smooth muscle cell growth via a decrease in the expression of cyclin A and proliferating cell nuclear antigen. Importantly, application of NFκB nanospheres accelerated restoration of the endothelial cell monolayer, associated with enhanced expression of phosphorylated Bcl-2 in endothelial cells.
Conclusions:
A drug-coated balloon catheter using NFκB decoy oligodeoxynucleotides significantly inhibited the development of neointimal hyperplasia in rabbits. The present study indicates the possibility of a novel therapeutic option to prevent restenosis after angioplasty.
Insights
A novel balloon catheter system effectively delivered nuclear factor-kappaB (NFκB) decoy nanoparticles to inhibit restenosis after angioplasty. This approach significantly reduced neointimal hyperplasia and promoted endothelial restoration in rabbit arteries.
Area of Science:
- Cardiovascular Research
- Biomedical Engineering
- Molecular Biology
Background:
- Restenosis remains a significant challenge in cardiovascular disease treatment despite current interventions.
- Nuclear factor-kappaB (NFκB) is a key transcription factor involved in the biological mechanisms of restenosis.
Purpose of the Study:
- To develop and evaluate a novel drug delivery system for NFκB decoy oligodeoxynucleotides to prevent restenosis.
- To investigate the therapeutic efficacy of NFκB decoy delivery in a rabbit carotid artery model.
Main Methods:
- A balloon catheter-based system was developed using biocompatible nanoparticles to deliver NFκB decoy oligodeoxynucleotides.
- Rabbit carotid arteries underwent balloon angioplasty, followed by local application of NFκB decoy-loaded nanospheres.
- Neointimal formation, NFκB binding activity, inflammatory markers, and cell proliferation were assessed.
Main Results:
- The delivery system successfully transferred nanospheres into the neointima, with detectable fluorescence for over a week.
- NFκB decoy-loaded nanospheres significantly inhibited neointimal hyperplasia and NFκB binding activity.
- Therapeutic effects included reduced macrophage recruitment and suppressed vascular smooth muscle cell proliferation.
- Endothelial cell monolayer restoration was accelerated, with enhanced phosphorylated Bcl-2 expression.
Conclusions:
- A drug-coated balloon catheter utilizing NFκB decoy oligodeoxynucleotides effectively inhibits neointimal hyperplasia in a rabbit model.
- This study presents a promising novel therapeutic strategy for preventing post-angioplasty restenosis.
