{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T01:00:18Z","timestamp":1755219618665,"version":"3.43.0"},"reference-count":47,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2025,7,6]],"date-time":"2025-07-06T00:00:00Z","timestamp":1751760000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Prostate"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p><jats:italic>N<\/jats:italic>\u2010terminus 15 amino acid (MC16) of Annexin A1 (ANXA1) is an effective therapeutic target for tumors and tumor vasculature as it specifically localizes to the cell surface of tumor cells and tumor vascular endothelial cells. We identified the <jats:sc>d<\/jats:sc>\u2010type peptide (hpnevrs, dhp7) by mirror\u2010image phage display targeting <jats:sc>l<\/jats:sc>\u2010type MC16 and tested the hypothesis that intravenously injected c(vcMMAE)dhp7 eradicates prostate tumor in mice with less adverse side effects than that of mc\u2010Val\u2010Cit\u2010PAB\u2010monomethyl auristatin (vcMMAE) alone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The binding affinity of dhp7 to MC16 of ANXA1 was analyzed by biolayer interferometry and <jats:italic>in silico<\/jats:italic> conformational analysis. c(vcMMAE)dhp7 was synthesized by coupling dhp7 to vcMMAE to evaluate the antitumor effects. A subcutaneous tumor model was generated by inoculating the luciferase\u2010expressing prostate cancer PC\u20103 cell line, PC\u20103\u2010hLuc\u2010PSMA, into the nude mice. 1.25\u2009mg\/kg vcMMAE or 2.14\u2009mg\/kg c(vcMMAE)dhp7, the equal dose as 1.25\u2009mg\/kg vcMMAE, was administered intravenously every 3 or 4 days and growth of tumors was assessed by photon count using an IVIS system.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The dhp7 bound specifically to <jats:sc>l<\/jats:sc>\u2010type MC16 (KD 0.48\u2009\u03bcM) but not bound to <jats:sc>d<\/jats:sc>\u2010type MC16 and mutant <jats:sc>l<\/jats:sc>\u2010type MC16. Both in vitro and <jats:italic>in silico<\/jats:italic> interaction analysis indicating the <jats:italic>\u03b1<\/jats:italic>\u2010helix of the <jats:sc>l<\/jats:sc>\u2010type MC16 may be important for dhp7 binding. Fluorescence labeled\u2010dhp7 accumulated in both ANXA1 positive cells and subcutaneous prostate tumor. To evaluate the antitumor effect, c(vcMMAE)dhp7 was synthesized by coupling dhp7 with mc\u2010Val\u2010Cit\u2010PAB\u2010monomethyl auristatin E (vcMMAE) as a payload. The IC50\u2009s of vcMMAE (129.9\u2009ng) and c(vcMMAE)dhp7 (122.7\u2009ng) against prostate cancer cells showed almost equivalent in vitro drug sensitivity. The c(vcMMAE)dhp7\u2010treated mice showed significant antitumor effects including complete responses at the same dose of MMAE (1.25\u2009mg\/kg) as mice treated with vcMMAE alone. Pathological analysis of the residual tumor showed that CD31 density of the c(vcMMAE)dhp7 treated group was significantly higher than that of the vcMMAE group, and the Ki\u201067 index was significantly lower than that of the vcMMAE alone. Clinical chemistry tests showed side effects of MMAE significantly improved in terms of hepatic\/biliary toxicity in c(vcMMAE)dhp7\u2010treated group.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The c(vcMMAE)dhp7 conjugate exerts a better antitumor effect than vcMMAE on ANXA1\u2010positive prostate cancer.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pros.70007","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T02:33:36Z","timestamp":1751855616000},"page":"1208-1221","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Annexin A1\u2010Targeted <scp>d<\/scp>\u2010Peptide\u2010Monomethyl Auristatin E Conjugate Enhanced Antitumor Effect of Monomethyl Auristatin E for Chemotherapy of Prostate Cancer"],"prefix":"10.1002","volume":"85","author":[{"given":"Kai","family":"Ozaki","sequence":"first","affiliation":[{"name":"Department of Urology Hirosaki University Graduate School of Medicine, Hirosaki Aomori Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1098-407X","authenticated-orcid":false,"given":"Tohru","family":"Yoneyama","sequence":"additional","affiliation":[{"name":"Department of Glycotechnology Hirosaki University Graduate School of Medicine, Hirosaki Aomori Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuka","family":"Kubota","sequence":"additional","affiliation":[{"name":"Department of Urology Hirosaki University Graduate School of Medicine, Hirosaki Aomori Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0598-7030","authenticated-orcid":false,"given":"Mihoko Sutoh","family":"Yoneyama","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and Cell Biology Oyokyo Kidney Research Institute Hirosaki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8487-6485","authenticated-orcid":false,"given":"Motohiro","family":"Nonaka","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry Human Health Sciences, Graduate School of Medicine, Kyoto University Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomonori","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Faculty of Life Sciences Tokyo University of Agriculture, Setagaya Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryuma","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Urology Hirosaki University Graduate School of Medicine, Hirosaki Aomori Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chikara","family":"Ohyama","sequence":"additional","affiliation":[{"name":"Department of Advanced Transplant and Regenerative Medicine Hirosaki University Graduate School of Medicine Hirosaki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0026-4079","authenticated-orcid":false,"given":"Shingo","family":"Hatakeyama","sequence":"additional","affiliation":[{"name":"Department of Urology Hirosaki University Graduate School of Medicine, Hirosaki Aomori Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,6]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.18.1.813"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02580"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3623"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/18.6.1516"},{"issue":"2","key":"e_1_2_12_6_1","first-page":"450","article-title":"A Peptide Mimic of E\u2010Selectin Ligand Inhibits Sialyl Lewis X\u2010Dependent Lung Colonization of Tumor Cells","volume":"60","author":"Fukuda M. 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