{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T03:37:08Z","timestamp":1788233828371,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Secretary of Science, Humanities, Technology, and Innovation","award":["CBF-2025-I-3583"],"award-info":[{"award-number":["CBF-2025-I-3583"]}]},{"name":"Italian Ministry of Health No. 5x1000","award":["project \u201cDECURTA\u201d"],"award-info":[{"award-number":["project \u201cDECURTA\u201d"]}]},{"DOI":"10.13039\/501100004493","name":"International Atomic Energy Agency","doi-asserted-by":"publisher","award":["CRP-F22078"],"award-info":[{"award-number":["CRP-F22078"]}],"id":[{"id":"10.13039\/501100004493","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Castration-resistant prostate cancer presents radiotherapeutic challenges, especially in optimizing the cytosolic internalization of therapeutic radiopharmaceuticals. This research aimed to design and evaluate in vitro, a new dimeric radiopharmaceutical, [177Lu]Lu\u2013iPSMA\u2013iGRP78, which combines PSMA and GRP78 inhibitors in a heterodimeric radioligand to improve the radionuclide internalization and cytotoxicity efficacy. Molecular docking showed that the dimer iPSMA\u2013iGRP78 presents a higher affinity for GRP78 (CNN-docking score: \u221214.0 kcal\u00b7mol\u22121, pKi: 10) and for PSMA (CNN-docking score: \u221217.0 kcal\u00b7mol\u22121, pKi: 11.5) compared to the monomers iGRP78 (CNN-docking score: \u221211.0 kcal\u00b7mol\u22121, pKi: 9.4) and iPSMA (CNN-docking score: \u221213.9 kcal\u00b7mol\u22121, pKi: 10.2). The saturation binding assay using LNCaP cells (PSMA+, CS-GRP78+) showed an affinity (Kd) of 1.883 nM for [177Lu]Lu\u2013iPSMA\u2013iGRP78 and 2.245 nM for [177Lu]Lu\u2013iPSMA. The dimeric radiopharmaceutical achieved 10.44 \u00b1 2.43% cytosolic internalization and 4.81 \u00b1 0.94% nuclear internalization, while the [177Lu]Lu\u2013iPSMA monomer showed 6.45 \u00b1 0.60% cytosolic internalization and no uptake in the cell nucleus. In PC3 cells (PSMA\u2013, CS-GRP78\u2013), [177Lu]Lu\u2013iPSMA\u2013iGRP78 uptake was negligible, demonstrating specificity. Treatment with the dimeric radiopharmaceutical reduced cell viability (69.93 \u00b1 4.85% of dead cells) significantly more than [177Lu]Lu\u2013iPSMA (38.63 \u00b1 6.13% of dead cells). In conclusion, conjugation of a GRP78 inhibitor to [177Lu]Lu\u2013iPSMA improves the radionuclide internalization and cytotoxicity in prostate cancer cells, suggesting that the bispecific radiopharmaceutical is a promising strategy in prostate cancer treatment.<\/jats:p>","DOI":"10.3390\/ijms262411783","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T15:11:24Z","timestamp":1764947484000},"page":"11783","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Enhancing Cytosolic Internalization of [177Lu]Lu\u2013iPSMA in Prostate Cancer Cells: The Effect of Conjugating a GRP78 Inhibitor to the Radiotherapeutic Molecule"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7520-461X","authenticated-orcid":false,"given":"Erika","family":"Azor\u00edn-Vega","sequence":"first","affiliation":[{"name":"Department of Radioactive Materials, Instituto Nacional de Investigaciones Nucleares (ININ), Ocoyoacac 52750, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Garc\u00eda-Arce","sequence":"additional","affiliation":[{"name":"Department of Radioactive Materials, Instituto Nacional de Investigaciones Nucleares (ININ), Ocoyoacac 52750, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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 (ININ), Ocoyoacac 52750, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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 (ININ), Ocoyoacac 52750, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Trujillo-Ben\u00edtez","sequence":"additional","affiliation":[{"name":"Department of Radioactive Materials, Instituto Nacional de Investigaciones Nucleares (ININ), Ocoyoacac 52750, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5674-7881","authenticated-orcid":false,"given":"Abraham","family":"Vidal-Limon","sequence":"additional","affiliation":[{"name":"Network for Advanced Molecular Studies, Instituto de Ecolog\u00eda A.C., Xalapa-Enr\u00edquez 91070, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Griselda","family":"Rodr\u00edguez-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Respiratory Pathogens Research Laboratory, Hospital Infantil de M\u00e9xico Federico G\u00f3mez, Mexico City 06720, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Luisa","family":"Dur\u00e1n-Past\u00e9n","sequence":"additional","affiliation":[{"name":"Channelopathies National Laboratory, Cellular Physiology Institute, UNAM, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0701-3616","authenticated-orcid":false,"given":"Laura","family":"Mel\u00e9ndez-Alafort","sequence":"additional","affiliation":[{"name":"Immunology and Molecular Oncology Diagnostics Unit, Veneto Institute of Oncology IOV\u2013IRCCS, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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 (ININ), Ocoyoacac 52750, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1016\/S1470-2045(25)00189-5","article-title":"Health-related quality of life, pain, and symptomatic skeletal events with [177Lu]Lu-PSMA-617 in patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): An open-label, randomised, phase 3 trial","volume":"26","author":"Fizazi","year":"2025","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1007\/s00259-024-06677-y","article-title":"[177Lu]Lu-PSMA-617 as first-line systemic therapy in patients with metastatic castration-resistant prostate cancer: A real-world study","volume":"51","author":"Satapathy","year":"2024","journal-title":"Eur. 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