Demonstration of the Early Cardiac Bioavailability of a Non-Specific Cell-Targeted Peptide Using Radionuclide-Based...

Area of Science:

• Pharmacology
• Biotechnology
• Cardiovascular Research

Background:

• Delivering peptide drugs to the heart for cardiovascular diseases is challenging.
• Intracellular protein-protein interactions are key targets in cardiovascular disease therapy.
• Efficient drug delivery to the heart is crucial for therapeutic efficacy.

Purpose of the Study:

• To evaluate the cardiac bioavailability of a novel cell-targeted peptide drug.
• To establish a stepwise nuclear molecular imaging approach for assessing cardiac drug delivery.
• To investigate the real-time cardiac delivery of ⁶⁸Ga-NODAGA-TAT-heart8P in vivo.

Main Methods:

• Pharmacokinetic studies of TAT-heart8P in dogs and rats.
• In vitro cellular internalization assays of TAT-heart8P-Cy(5.5) in cardiomyocytes.
• In vivo PET/CT imaging of ⁶⁸Ga-NODAGA-TAT-heart8P in mice under physiological and pathological conditions.

Main Results:

• TAT-heart8P exhibited fast blood clearance and high liver extraction but rapid internalization into cardiomyocytes.
• ⁶⁸Ga-NODAGA-TAT-heart8P demonstrated rapid cardiac uptake, with significant bioavailability observed as early as 10 minutes post-injection.
• Cardiac uptake was saturable and unaffected by cell membrane toxicity models, indicating specific targeting.

Conclusions:

• A stepwise nuclear imaging workflow effectively evaluates cardiac delivery of hydrophilic, non-specific cell-targeting peptides.
• ⁶⁸Ga-NODAGA-TAT-heart8P achieves rapid accumulation in cardiac tissue, supporting its potential for cardiovascular drug development.
• PET/CT imaging is a valuable tool for assessing temporal cardiac uptake of drug candidates.