Cardiomyocyte Targeting Peptide to Deliver Amiodarone

Area of Science:

• Cardiovascular Pharmacology
• Drug Delivery Systems
• Molecular Cardiology

Background:

• Amiodarone, an antiarrhythmic drug, is underutilized due to significant off-target toxicities.
• A cardiomyocyte targeting peptide (CTP) was developed to facilitate targeted cardiac delivery of amiodarone.
• Hypothesis: Targeted delivery of amiodarone via CTP will allow for a lower, safer effective dose.

Approach:

• CTP was synthesized and conjugated to amiodarone.
• The CTP-amiodarone conjugate stability was assessed.
• Guinea pigs received vehicle, amiodarone, CTP-amiodarone, or CTP.
• Cardiac function was evaluated using electrophysiological measurements (conduction velocity, action potential duration) and calcium transient analysis.
• RNA sequencing was performed on heart tissue.

Key Points:

• CTP-amiodarone conjugate demonstrated stability up to 21 days.
• At approximately 1/15th the dose, CTP-amiodarone significantly slowed conduction velocity, comparable to amiodarone alone.
• CTP-amiodarone decreased action potential duration and calcium transient duration.
• RNA-seq revealed CTP upregulated calcium-handling genes (DHPR, SERCA2a) and downregulated inflammatory genes.

Conclusions:

• CTP enables amiodarone delivery to cardiomyocytes at a significantly reduced molar dose.
• CTP-mediated reduction in action potential and calcium transient durations may involve modulation of calcium-handling genes.
• This targeted approach holds promise for safer amiodarone therapy.