Amiodarone delivery using lipidic nanocapsules for the treatment of atrial fibrillation

Atrial fibrillation (AF) is the most common arrhythmia and is associated with significant morbidity and mortality. As AF progresses, controlling AF gets more and more challenging. Amiodarone (AMD) is considered as the most effective antiarrhythmic drug for maintaining sinus rhythm after cardioversion and it is also recommended for controlling AF in patient with congestive heart failure. However, its pharmacokinetic and metabolic profile require the use of high dosage resulting in many extracardiac side effects which limit prescription of AMD. Therefore, nanoencapsulation of AMD in lipid nanocapsules (LNC) with the ability to target the heart represents a promising strategy to enhance the efficiency of AMD and to limit its toxicity. This work focus on development of antiarrhythmic LNC-AMD nano-formulations and their in vitro toxicity. LNC-AMD are prepared by microfluidic using a low-energy patented process and purified by a tangential flow filtration process. LNC are characterized in terms of size and polydispersity (PDI) by dynamic light scattering, surface charge by electrophoretic mobility, drug loading (DL) and encapsulation efficiency (EE) by UPLC coupled to UV detector. Cell toxicity of LNC-AMD is evaluated on cardiac cells (H9C2 cardiomyoblastes, and isolated cardiomyocytes) and measured by MTT cell viability assay and lactate dehydrogenase (LDH) release. LNC-AMD have a size of 44 nm ± 5 nm with a PDI of 0.15 ± 0.3 and a zeta potential of +18 mV. After purification, DL is about 0.4 mg/mL of suspension of LNC and EE is of 60%. Formulation and purification of LNC-AMD have been optimized for their biological evaluation. Short-term perspectives are the co-encapsulation of AMD with an anti-fibrotic molecule, and the surface functionalization of LNC with a heart-targeting peptide (ZP1609) to ultimately establish proof-of-concept on Langendorff-perfused rat hearts.