| Title: |
Demonstration of the Early Cardiac Bioavailability of a Non-Specific Cell-Targeted Peptide Using Radionuclide-Based Imaging In Vivo |
| Authors: |
Settelmeier, Stephan; Varasteh, Zohreh; Staniszewska, Magdalena; Beerlage, Anna-Lena; Zarrad, Fadi; Fendler, Wolfgang P.; Rischpler, Christoph; Notni, Johannes; Totzeck, Matthias; Herrmann, Ken; Rassaf, Tienush; Hendgen-Cotta, Ulrike B. |
| Publication Year: |
2023 |
| Collection: |
University of Duisburg-Essen: DuEPublico (Duisburg Essen Publications online) |
| Subject Terms: |
ScholarlyArticle; ddc:610; Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Kardiologie und Angiologie; Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Nuklearmedizin; nuclear cardiology -- peptide drug -- PET/CT -- preclinical drug development -- protein–protein interactions |
| Description: |
The cardiac bioavailability of peptide drugs that inhibit harmful intracellular protein–protein interactions in cardiovascular diseases remains a challenging task in drug development. This study investigates whether a non-specific cell-targeted peptide drug is available in a timely manner at its intended biological destination, the heart, using a combined stepwise nuclear molecular imaging approach. An octapeptide (heart8P) was covalently coupled with the trans-activator of transcription (TAT) protein transduction domain residues 48–59 of human immunodeficiency virus-1 (TAT-heart8P) for efficient internalization into mammalian cells. The pharmacokinetics of TAT-heart8P were evaluated in dogs and rats. The cellular internalization of TAT-heart8P-Cy(5.5) was examined on cardiomyocytes. The real-time cardiac delivery of 68Ga-NODAGA-TAT-heart8P was tested in mice under physiological and pathological conditions. Pharmacokinetic studies of TAT-heart8P in dogs and rats revealed a fast blood clearance, high tissue distribution, and high extraction by the liver. TAT-heart-8P-Cy(5.5) was rapidly internalized in mouse and human cardiomyocytes. Correspondingly, organ uptake of hydrophilic 68Ga-NODAGA-TAT-heart8P occurred rapidly after injection with an initial cardiac bioavailability already 10 min post-injection. The saturable cardiac uptake was revailed by the pre-injection of the unlabeled compound. The cardiac uptake of 68Ga-NODAGA-TAT-heart8P did not change in a model of cell membrane toxicity. This study provides a sequential stepwise workflow to evaluate the cardiac delivery of a hydrophilic, non-specific cell-targeting peptide. 68Ga-NODAGA-TAT-heart8P showed rapid accumulation in the target tissue early after injection. The implementation of PET/CT radionuclide-based imaging methodology as a means to assess effective and temporal cardiac uptake represents a useful and critical application in drug development and pharmacological research and can be extended to the evaluation of comparable drug candidates. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://doi.org/10.3390/ph16060824 |
| DOI: |
10.3390/ph16060824 |
| Availability: |
https://doi.org/10.3390/ph16060824; https://nbn-resolving.org/urn:nbn:de:hbz:465-20230901-153110-0; https://duepublico2.uni-due.de/receive/duepublico_mods_00078728; https://duepublico2.uni-due.de/servlets/MCRFileNodeServlet/duepublico_derivate_00078547/pharmaceuticals_2023-16-00824.pdf |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ ; info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.E51A205E |
| Database: |
BASE |