{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T15:24:31Z","timestamp":1764084271996,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T00:00:00Z","timestamp":1685491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Research Foundation","award":["HE6317\/2-1","RA969\/12-1","FU356\/12-2","VA 1183\/2-1"],"award-info":[{"award-number":["HE6317\/2-1","RA969\/12-1","FU356\/12-2","VA 1183\/2-1"]}]},{"name":"Medical Faculty of the University Duisburg-Essen","award":["HE6317\/2-1","RA969\/12-1","FU356\/12-2","VA 1183\/2-1"],"award-info":[{"award-number":["HE6317\/2-1","RA969\/12-1","FU356\/12-2","VA 1183\/2-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>The cardiac bioavailability of peptide drugs that inhibit harmful intracellular protein\u2013protein 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\u201359 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.<\/jats:p>","DOI":"10.3390\/ph16060824","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T03:06:00Z","timestamp":1685588760000},"page":"824","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Demonstration of the Early Cardiac Bioavailability of a Non-Specific Cell-Targeted Peptide Using Radionuclide-Based Imaging In Vivo"],"prefix":"10.3390","volume":"16","author":[{"given":"Stephan","family":"Settelmeier","sequence":"first","affiliation":[{"name":"Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, Medical Faculty, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5485-3186","authenticated-orcid":false,"given":"Zohreh","family":"Varasteh","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Medical Faculty, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"Department of Nuclear Medicine, Klinikum rechts der Isar der TUM, 81675 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Staniszewska","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Medical Faculty, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna-Lena","family":"Beerlage","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, Medical Faculty, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1613-4850","authenticated-orcid":false,"given":"Fadi","family":"Zarrad","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Medical Faculty, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang P.","family":"Fendler","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Medical Faculty, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Rischpler","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Medical Faculty, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3964-3391","authenticated-orcid":false,"given":"Johannes","family":"Notni","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Medical Faculty, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"TRIMT GmbH, 01454 Radeberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Totzeck","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, Medical Faculty, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Medical Faculty, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8001-0265","authenticated-orcid":false,"given":"Tienush","family":"Rassaf","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, Medical Faculty, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrike B.","family":"Hendgen-Cotta","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, Medical Faculty, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.1016\/j.jacc.2020.11.010","article-title":"Global 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