{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T09:02:44Z","timestamp":1789635764311,"version":"4.0.0"},"reference-count":31,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Scientific Research Project of Jiangsu Maternal and Child Health","award":["F2019017"],"award-info":[{"award-number":["F2019017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy. Single-targeted ADCs\/PDCs are limited by \u201con-target, off-tumor\u201d toxicity. We developed FMM-66, a dual-ligand peptide-drug conjugate targeting FOLR1 and c-Met, to improve tumor-selective drug delivery. Methods: FMM-66 was rationally designed by integrating FOLR1- and c-Met-targeting peptide ligands into a single PDC architecture. Binding and cellular internalization assays were performed in ovarian cancer cell lines with different FOLR1\/c-Met expression profiles, as well as in engineered overexpression cell models, to comprehensively evaluate the targeting properties of FMM-66. Antitumor efficacy, intratumoral pharmacokinetics, and biodistribution were evaluated in female BALB\/c nude mice bearing Caov3 xenografts, with the single-ligand PDCs FA-MMAE and GE137-MMAE as comparators. Normal-tissue biodistribution and systemic safety were further assessed in female Sprague\u2013Dawley rats. Results: FMM-66 demonstrated enhanced binding affinity and significantly increased cellular internalization compared with single-ligand PDCs in vitro. Receptor-blocking experiments confirmed contributions from both FOLR1 and c-Met, whereas internalization was driven predominantly by FOLR1. In vivo studies revealed potent tumor growth inhibition and superior tumor accumulation in FOLR1\/c-Met double-positive ovarian tumors than the single-ligand comparators. Furthermore, FMM-66 exhibited rapid systemic clearance while released MMAE showed prolonged intratumoral exposure. At the therapeutic-equivalent dose in rats, no significant biochemical abnormalities or body-weight loss were observed; transient ALT, AST, creatinine, and urea elevations at the higher dose largely resolved by Day 14. Conclusions: FMM-66 demonstrated enhanced tumor accumulation and potent antitumor efficacy, with preliminary tolerability at the tested dose levels. These findings support dual-ligand targeting as a promising strategy for improving tumor-selective payload delivery and warrant further preclinical evaluation of FMM-66.<\/jats:p>","DOI":"10.3390\/cancers18183013","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T08:03:17Z","timestamp":1789632197000},"page":"3013","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Dual-Ligand PDC Co-Targeting FOLR1 and c-Met Enhances Tumor Accumulation and Antitumor Efficacy in Ovarian Cancer"],"prefix":"10.3390","volume":"18","author":[{"given":"Honghong","family":"Cai","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou 215005, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"software","vocabulary":"credit"}]},{"given":"Tian","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou 215005, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"given":"Yuan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou 215005, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Xiuwu","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou 215005, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Youguo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou 215005, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"He","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou 215005, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","first-page":"12","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA A Cancer J. 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