{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T13:07:26Z","timestamp":1778764046368,"version":"3.51.4"},"reference-count":70,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Envision Sciences Pty Ltd."},{"DOI":"10.13039\/501100001787","name":"University of South Australia","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001787","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Cancer Council SA Beat Cancer Grant"},{"name":"Movember Foundation\/PCa Foundation of Australia\u2019s Research Program"},{"name":"Australian Federal Government","award":["GNT1092904"],"award-info":[{"award-number":["GNT1092904"]}]},{"name":"Australian Federal Government","award":["BTBR200074"],"award-info":[{"award-number":["BTBR200074"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Prostate cancer tissue usually involves either well formed glands, poorly formed glands or a combination of the two morphologies, which can be correlated with metabolic differences and tumor heterogeneity. This is particularly important for metastatic castration-resistant prostate cancer, where the heterogeneity and metabolic changes drive cancer progression and treatment refractory properties. Sortilin and syndecan-1 expression accurately define the two different morphologies in prostate cancer tissue, are critical to the process of metabolic regulation, and exhibit mechanistic\/functional interactions during prostate cancer progression. As trans-membrane proteins that recycle from endocytic compartments to the cell surface, sortilin and syndecan-1 are attractive targets for therapeutic intervention that address the two major forms of prostate cancer. In this study, we describe an antibody-drug conjugate (ADC) strategy that utilizes monoclonal antibodies which bind to specific extracellular domains of these integral membrane proteins to elicit anticancer activity in prostate cancer cell lines. Anti-sortilin (clone 11H8) and anti-syndecan-1 (clone 6D11) monoclonal antibodies demonstrated high specificity for epitopes on the extracellular, N-terminal domains of these respective proteins and were effectively internalized into prostate cancer cell endocytic compartments. Monomethyl aurastatin E (MMAE)-conjugated ADCs exhibited low nanomolar cytotoxicity in LNCaP and PC-3 prostate cancer cells. Mechanistically, 11H8-MMAE and 6D11-MMAE triggered cytotoxicity and morphological alterations in androgen-sensitive and androgen-insensitive cells. However, the uptake of fluorescent labelled 11H8 and 6D11 antibodies appeared to be high, whereas the killing capacity of the MMAE-conjugated antibodies was less impressive, suggesting the need for further ADC development. These promising proof-of-concept ADCs are designed to exploit molecular and metabolic vulnerabilities in prostate cancer and may have utility for overcoming treatment resistance by simultaneously targeting different forms of the cancer.<\/jats:p>","DOI":"10.3390\/ijms262211145","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T12:33:04Z","timestamp":1763469184000},"page":"11145","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting Prostate Cancer Cells Using Anti-Sortilin and Anti-Syndecan-1 Antibody Drug Conjugates"],"prefix":"10.3390","volume":"26","author":[{"given":"Ka Lok","family":"Li","sequence":"first","affiliation":[{"name":"Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3063-531X","authenticated-orcid":false,"given":"Shane M.","family":"Hickey","sequence":"additional","affiliation":[{"name":"Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3951-1866","authenticated-orcid":false,"given":"Hugo","family":"Albrecht","sequence":"additional","affiliation":[{"name":"Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4046-6908","authenticated-orcid":false,"given":"Jessica M.","family":"Logan","sequence":"additional","affiliation":[{"name":"Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanna","family":"Lazniewska","sequence":"additional","affiliation":[{"name":"Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3675-4026","authenticated-orcid":false,"given":"Courtney R.","family":"Moore","sequence":"additional","affiliation":[{"name":"Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert D.","family":"Brooks","sequence":"additional","affiliation":[{"name":"Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7875-3510","authenticated-orcid":false,"given":"Ian R. D.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7311-9326","authenticated-orcid":false,"given":"John J.","family":"O\u2019Leary","sequence":"additional","affiliation":[{"name":"Department of Histopathology, Trinity College Dublin, D02 PN40 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9098-3626","authenticated-orcid":false,"given":"Douglas A.","family":"Brooks","sequence":"additional","affiliation":[{"name":"Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"},{"name":"Department of Histopathology, Trinity College Dublin, D02 PN40 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"63","DOI":"10.14740\/wjon1191","article-title":"Epidemiology of prostate cancer","volume":"10","author":"Rawla","year":"2019","journal-title":"World J. 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