{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:07:39Z","timestamp":1791846459163,"version":"4.3.4"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Targeted alpha therapy with\n                      <jats:sup>225<\/jats:sup>\n                      Ac-PSMA-617 is a promising strategy for metastatic prostate cancer. However, physiological uptake in dose-limiting organs, particularly the salivary glands and kidneys, necessitates precise dosimetry to define the therapeutic window. Therefore, the objective of this study was to perform integrated dosimetry, quantify the therapeutic index (TI), and establish dose-response relationships for the tumor control and organ toxicity of\n                      <jats:sup>225<\/jats:sup>\n                      Ac-PSMA-617 in a PSMA-positive xenograft model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In male nude mice bearing C4-2 xenografts, a dosimetry group (n = 32) received 5\u00a0kBq\n                      <jats:sup>225<\/jats:sup>\n                      Ac-PSMA-617 for multi-time-point biodistribution. Time-activity curves were fitted with bi-exponential models, and absorbed doses were calculated using the MIRD formalism. A therapy group (n = 12\/arm) received a single 40\u00a0kBq dose of the therapy or vehicle. Efficacy was assessed by tumor growth inhibition (TGI) and time-to-progression (TTP) of 500\u00a0mm\n                      <jats:sup>3<\/jats:sup>\n                      . Toxicity was evaluated via renal function, histopathology (kidney: Day 56; salivary glands: Day 28), and pilocarpine-stimulated salivary secretion. The therapeutic index (TI_min) and Spearman correlations between absorbed dose and biological endpoints were calculated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The radiopharmaceutical demonstrated high purity and stability. Dosimetry revealed favorable pharmacokinetics, with the highest absorbed dose coefficient for the tumor (588\u00a0Gy\/GBq). The mean absorbed dose to the parotid gland (0.56\u00a0Gy at 5\u00a0kBq) exceeded that to the kidneys (0.29\u00a0Gy). The TI_min was &amp;gt;1 for all animals. The 40\u00a0kBq dose induced significant tumor growth inhibition (TGI: 75.2%, P &amp;lt; 0.001) and delayed progression (P &amp;lt; 0.001). While renal function remained normal, histology revealed mild tubular injury. Salivary gland function, however, showed a profound and sustained decrease (&amp;gt;60%, P &amp;lt; 0.001). Strong correlations were found between tumor dose and TGI (\u03c1 = 0.720), kidney dose and histology score (\u03c1 = 0.643), and salivary gland dose and functional impairment (\u03c1 = 0.776) (all P &amp;lt; 0.05).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:sup>225<\/jats:sup>\n                      Ac-PSMA-617 provides a significant therapeutic window (TI &amp;gt; 1) with potent efficacy. The salivary glands, not the kidneys, are identified as the primary dose-limiting organ based on severe functional toxicity strongly correlated with absorbed dose. These quantitative dose-response correlations establish a foundation for clinical dose optimization.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1807913","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:05:19Z","timestamp":1775801119000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Salivary glands as the primary dose-limiting organ: an integrated dosimetry, efficacy, and toxicity study of 225Ac-PSMA-617 in prostate cancer xenografts"],"prefix":"10.3389","volume":"17","author":[{"given":"Chenchen","family":"Cai","sequence":"first","affiliation":[{"name":"School of Pharmacy and Laboratory of Drug Discovery from Natural Resources and Industrialization, Macau University of Science and Technology","place":["Macau, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peishang","family":"Li","sequence":"additional","affiliation":[{"name":"Mednovo Group Co., Ltd.","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqian","family":"Wang","sequence":"additional","affiliation":[{"name":"Mednovo Group Co., Ltd.","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiling","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Laboratory of Drug Discovery from Natural Resources and Industrialization, Macau University of Science and Technology","place":["Macau, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunmiao","family":"Qu","sequence":"additional","affiliation":[{"name":"Mednovo Group Co., Ltd.","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlei","family":"Jin","sequence":"additional","affiliation":[{"name":"Mednovo Group Co., Ltd.","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangsheng","family":"Kong","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Laboratory of Drug Discovery from Natural Resources and Industrialization, Macau University of Science and Technology","place":["Macau, China"]},{"name":"Mednovo Group Co., Ltd.","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S66","DOI":"10.1088\/0026-1394\/52\/3\/S66","article-title":"Uncertainties in nuclear decay data evaluations","volume":"52","author":"B\u00e9","year":"2015","journal-title":"Metrologia"},{"key":"B2","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.eururo.2023.11.018","article-title":"Prostate-specific membrane antigen\u2013targeted therapies for prostate cancer: towards improving therapeutic outcomes","volume":"85","author":"Corpetti","year":"2024","journal-title":"Eur. 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