Inhibition of vein graft stenosis with a c-jun targeting DNAzyme in a cationic liposomal formulation containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)
Name
Hammond_Inhibition of.pdf
Size
3.45 MB
Format
Adobe PDF
Checksum (MD5)
683db39c138aed2b369a624faa840349
Author(s)
Li, Yue
Bhindi, Ravinay
Deng, Zhou J.
Morton, Stephen Winford
Khachigian, Levon M.
Hammond, Paula T
Date Issued
July 2013
Journal
International Journal of Cardiology
Citation
Li, Yue, Ravinay Bhindi, Zhou J. Deng, Stephen W. Morton, Paula T. Hammond, and Levon M. Khachigian. “Inhibition of Vein Graft Stenosis with a c-Jun Targeting DNAzyme in a Cationic Liposomal Formulation Containing 1,2-Dioleoyl-3-Trimethylammonium Propane (DOTAP)/1,2-Dioleoyl-Sn-Glycero-3-Phosphoethanolamine (DOPE).” International Journal of Cardiology 168, no. 4 (October 2013): 3659–3664.
Version
Author's final manuscript
Abstract
Background/objectives
Coronary artery bypass grafting (CABG) is among the most commonly performed heart surgical procedures. Saphenous vein graft failure due to stenosis impedes the longer-term success of CABG. A key cellular event in the process of vein graft stenosis is smooth muscle cell hyperplasia. In this study, we evaluated the effect of a DNAzyme (Dz13) targeting the transcription factor c-Jun in a rabbit model of vein graft stenosis in a cationic liposomal formulation containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Dz13 in DOTAP/DOPE has undergone preclinical toxicological testing, and a Phase I clinical trial we recently conducted in basal cell carcinoma cancer patients demonstrates that it is safe and well tolerated after local administration.
Methods
Effects of Dz13 in a formulation containing DOTAP/DOPE on smooth muscle cell (SMC) growth and c-Jun expression were assessed. Dz13 transfection was determined by cellular uptake of carboxyfluorescein-labeled Dz13. Autologous jugular vein to carotid artery transplantation was performed in New Zealand White rabbits to investigate the effect of the Dz13 in DOTAP/DOPE formulation on intimal hyperplasia.
Results
Dz13/DOTAP/DOPE reduced SMC proliferation and c-Jun protein expression in vitro compared with an impotent form of Dz13 bearing a point mutation in its catalytic domain (Dz13.G > C). The Dz13(500 μg)/DOTAP/DOPE formed lipoplexes that were colloidally stable for up to 1 h on ice (0 °C) and 30 min at 37 °C, allowing sufficient uptake by the veins. Dz13 (500 μg) inhibited neointima formation 28 d after end-to-side transplantation.
Conclusions
This formulation applied to veins prior to transplantation may potentially be useful in efforts to reduce graft failure.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.ijcard.2013.05.092
