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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Prostate-specific membrane antigen (PSMA) is a validated theranostic target with clinical relevance extending beyond prostate cancer to PSMA-expressing neovasculature in solid tumors. Despite the success of 177Lu-PSMA therapy, a significant proportion of patients experience disease recurrence or partial responses, motivating the development of targeted alpha therapy (TAT) approaches. In this study, novel monomeric and dimeric 225Ac-labeled PSMA inhibitors, [225Ac]Ac-DOTA-iPSMA ([225Ac]Ac-D-iPSMA) and [225Ac]Ac-MACROPA-iPSMA ([225Ac]Ac-M-iPSMA), were designed through receptor-based computational screening, synthesized, radiolabeled, and evaluated in vitro and in vivo. Radiolabeling achieved high radiochemical purities (&gt;96%), and saturation binding assays using lanthanum(III) surrogates confirmed cooperative nanomolar PSMA affinity. The binding affinities were Kd = 8.28 \u00b1 0.51 nM (La-D-iPSMA) and Kd = 16.76 \u00b1 2.51 nM (La-M-iPSMA). PSMA-specific uptake was validated in 4T1 breast cancer and HCT116 colorectal cancer cells. D-iPSMA induced superior late apoptosis (41.74% at 2 Gy), associated with reductions in GSK-3 \u03b1\/\u03b2 (Glycogen Synthase Kinase-3) and WNK1 (With No Lysine Kinase 1) phosphorylation, \u03b2-catenin downregulation, and dose-dependent DNA double-strand breaks (72.08% \u03b3-H2AX [\u03b3-phosphorylated histone]-positive cells at 6 Gy). [225Ac]Ac-M-iPSMA biodistribution in 4T1 tumor-bearing BALB\/c mice revealed rapid blood clearance, a tumor-to-kidney dose ratio of 54:1, and a high tumor-absorbed dose. A combination of [177Lu]Lu-D-iPSMA with [225Ac]Ac-M-iPSMA maximized reactive oxygen species generation. These findings support both conjugates as promising TAT candidates for PSMA-expressing tumors.<\/jats:p>","DOI":"10.3390\/ijms27177785","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:48:36Z","timestamp":1788256116000},"page":"7785","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["[225Ac]Ac-iPSMA Radiopharmaceuticals for Targeted Alpha Therapy: Design, Synthesis, and Preclinical Evaluation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2893-1911","authenticated-orcid":false,"given":"Daniel","family":"Garc\u00eda-Arce","sequence":"first","affiliation":[{"name":"Department of Radioactive Materials, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico"},{"name":"Faculty of Chemistry, Universidad Aut\u00f3noma del Estado de M\u00e9xico, Toluca 50180, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4082-3816","authenticated-orcid":false,"given":"Myrna","family":"Luna-Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Department of Radioactive Materials, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Pedro","family":"Cruz-Nova","sequence":"additional","affiliation":[{"name":"Department of Radioactive Materials, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5674-7881","authenticated-orcid":false,"given":"Abraham","family":"Vidal-Limon","sequence":"additional","affiliation":[{"name":"Red de Estudios Moleculares Avanzados, Instituto de Ecolog\u00eda A.C. (INECOL), El Haya, Xalapa 91073, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9480-4621","authenticated-orcid":false,"given":"Nallely","family":"Jim\u00e9nez-Mancilla","sequence":"additional","affiliation":[{"name":"IxM SECIHTI-ININ, Department of Radioactive Materials, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4066-2327","authenticated-orcid":false,"given":"Liliana","family":"Aranda-Lara","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Universidad Aut\u00f3noma del Estado de M\u00e9xico, Toluca 50180, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7520-461X","authenticated-orcid":false,"given":"Erika","family":"Azor\u00edn-Vega","sequence":"additional","affiliation":[{"name":"Department of Radioactive Materials, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8471-6791","authenticated-orcid":false,"given":"Enrique","family":"Morales-Avila","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Universidad Aut\u00f3noma del Estado de M\u00e9xico, Toluca 50180, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Paola","family":"Rodr\u00edguez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Department of Radioactive Materials, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico"},{"name":"Faculty of Chemistry, Universidad Aut\u00f3noma del Estado de M\u00e9xico, Toluca 50180, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5903-1598","authenticated-orcid":false,"given":"Clara","family":"Santos-Cuevas","sequence":"additional","affiliation":[{"name":"Department of Radioactive Materials, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0296-7605","authenticated-orcid":false,"given":"Guillermina","family":"Ferro-Flores","sequence":"additional","affiliation":[{"name":"Department of Radioactive Materials, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5831-8412","authenticated-orcid":false,"given":"Blanca","family":"Ocampo-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Department of Radioactive Materials, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1002\/jcb.10661","article-title":"Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer","volume":"91","author":"Ghosh","year":"2004","journal-title":"J. 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