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)
Author(s)Li, Yue; Bhindi, Ravinay; Deng, Zhou J.; Morton, Stephen Winford; Hammond, Paula T.; Khachigian, Levon M.; ... Show more Show less
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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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Chemical Engineering
International Journal of Cardiology
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.
Author's final manuscript