Abstract 2102: Uniform-Field Induced Magnetization Enables Efficient Targeting of Adenovirus-Impregnated Magnetic Nanoparticles to Stented Arteries in the Rat Carotid Model of Restenosis
Introduction The translation of experimental gene therapy strategies into clinically used methods for the treatment for cardiovascular disease has remained unrealized due to suboptimal safety and efficacy. Their low therapeutic index resulting from the poor localization of the vector to its site of action can potentially be addressed by using magnetically targeted nanoparticles (MNP) as gene delivery vector carriers. However both the formulation of such MNP and design of a magnetic guidance system for targeting injured blood vessels have been challenging. We hypothesized that the efficiency of adenoviral (Ad) gene transfer to an injured artery can be increased by combining novel Ad-loaded MNP with a uniform magnetic field-controlled delivery approach previously shown to provide efficient cell targeting to stents (PNAS 2008).
Methods Ad-loaded MNP (305±7 nm) were formulated by controlled aggregation of magnetite nanocrystals in the presence of luciferase-encoding Ad. Rat carotid arteries were injured by a Fogarty catheter prior to deployment of a 304-grade stainless steel stent. MNP at a dose of 2.4±109 viral particles were delivered to the arteries via the aortic arch under a uniform field (1200 G). Free Ad or MNP delivered under non-magnetic conditions were used as controls. Reporter gene expression was assayed by bioluminescence after 2 and 9 days (n≥8). The tissue distribution of luciferase was determined 2 days post surgery (n=3).
Results Magnetically targeted MNP delivery resulted in a significantly enhanced transduction of stented arteries at both timepoints (7- to 14-fold higher luciferase signal compared to controls, p<0.05). After 2 days the weight-normalized reporter signal in magnetically treated arteries was 28- and 31-fold higher than in liver or spleen (compared to the respective ratios of 0.8 and 1.9 in the non-magnetic control group). No transduction was observed in the lungs.
Conclusions Site-specific delivery of Ad-loaded MNP using a novel uniform field-controlled targeting approach significantly enhanced adenoviral transduction of injured arteries in the rat carotid stenting model.
This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).