Cardiomyocyte-Targeting Peptide to Deliver Amiodarone.

Area of Science:

• Cardiology
• Pharmacology
• Biomedical Engineering

Background:

• Amiodarone, an antiarrhythmic drug, is limited by significant off-target toxicities.
• Targeted delivery strategies are needed to improve amiodarone's therapeutic index.

Purpose of the Study:

• To develop and evaluate a novel amiodarone conjugate utilizing a cardiomyocyte-targeting peptide (CTP).
• To assess the efficacy and cardiac electrophysiological effects of CTP-amiodarone in a guinea pig model.

Main Methods:

• CTP was synthesized and conjugated to amiodarone.
• The conjugate's stability was assessed.
• Guinea pigs received vehicle, amiodarone, CTP-amiodarone, or CTP.
• Cardiac electrophysiology (conduction velocity, action potential duration, Ca2+ transient duration) was measured.
• RNA sequencing was performed on heart tissue.

Main Results:

• CTP-amiodarone conjugate demonstrated stability up to 21 days at 37°C.
• A ~1/15th dose of CTP-amiodarone significantly slowed cardiac conduction velocity, comparable to amiodarone alone.
• CTP-amiodarone and CTP significantly decreased action potential duration and Ca2+ transient duration.
• CTP alone increased expression of Ca-handling genes (DHPR, SERCA2a) and decreased proinflammatory genes.

Conclusions:

• CTP facilitates amiodarone delivery to cardiomyocytes at a significantly lower dose.
• CTP-mediated reduction in action potential and Ca2+ transient durations may involve modulation of Ca-handling genes.
• This targeted approach holds promise for reducing amiodarone's toxicity while preserving its antiarrhythmic effects.