Abstract
Amiodarone is an effective antiarrhythmic drug used to treat and prevent different types of cardiac arrhythmias. However, amiodarone can have considerable side effects resulting from accumulation in off-target tissues. Cardiac macrophages are highly prevalent tissue-resident immune cells with importance in homeostatic functions, including immune response and modulation of cardiac conduction. We hypothesized that amiodarone could be more efficiently delivered to the heart via cardiac macrophages, an important step toward reducing overall dose and off-target tissue accumulation. Toward this goal, we synthesized a nanoparticle drug carrier composed of l-lysine cross-linked succinyl-β-cyclodextrin that demonstrates amiodarone binding through supramolecular host-guest interaction as well as a high macrophage affinity. Biodistribution analyses at the organ and single-cell level demonstrate accumulation of nanoparticles in the heart resulting from rapid uptake by cardiac macrophages. Nanoparticle assisted delivery of amiodarone resulted in a 250% enhancement in the selective delivery of the drug to cardiac tissue in part due to a concomitant decrease of pulmonary accumulation, the main source of off-target toxicity.