{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T14:06:19Z","timestamp":1779458779698,"version":"3.53.1"},"reference-count":28,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CAMS Innovation Fund for Medical Sciences","award":["2025-I2M-KJ-018"],"award-info":[{"award-number":["2025-I2M-KJ-018"]}]},{"name":"R&D Center of Mednovo Group Co., Ltd, Suzhou, China","award":["MDN002"],"award-info":[{"award-number":["MDN002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: While 177Lu-DOTATATE has demonstrated clinical efficacy in peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors (NETs), current dosing regimens do not account for potential sex-based pharmacokinetic differences. Our study systematically characterizes sex-dependent pharmacokinetic variations of 177Lu-DOTATATE in preclinical models to provide the first preclinical evidence base informing future sex-stratified clinical investigations. Methods: Sex-stratified pharmacokinetic and biodistribution studies were conducted in male and female SD rats following intravenous administration of 177Lu-DOTATATE at multiple dose levels: 2.86, 5.71, and 11.43 mCi\/kg. Metabolic stability and renal excretion patterns were characterized. Safety assessments included acute toxicity, vascular irritation, hemolysis, and allergenicity testing. Therapeutic efficacy was evaluated exclusively in female AR42J xenograft-bearing CB-17 SCID mice. Results: Significant sex-dependent pharmacokinetic differences were observed at high (11.43 mCi\/kg) and low (2.86 mCi\/kg) dose levels, with females exhibiting 30\u201340% higher AUC and Cmax values compared to males (p &lt; 0.05). Both sexes demonstrated preferential accumulation in SSTR-expressing tissues, particularly the pancreas (females: 10.87 \u00b1 2.51% ID\/g; males: 9.10 \u00b1 0.76% ID\/g) and adrenal glands, with rapid clearance from non-target organs. Radio-HPLC analysis confirmed high metabolic stability with no detectable radiolabeled metabolites, and over 90% of radioactivity was recovered through renal excretion. Safety assessments demonstrated excellent tolerability across dose levels. In female xenograft models, treatment achieved tumor growth inhibition of 92.35\u201396.44% and 100% survival rate versus 10% in controls, though mid\/high doses caused weight loss. Conclusions: Our study provides systematic preclinical evidence of sex-dependent pharmacokinetic differences in 177Lu-DOTATATE, with females demonstrating significantly higher systemic exposure than males at specific dose levels. These findings establish the systematic preclinical evidence base for sex-dependent pharmacokinetic differences in 177Lu-DOTATATE, providing a scientific rationale for incorporating sex as a stratification variable in future dosimetry-guided clinical studies.<\/jats:p>","DOI":"10.3390\/ph19050774","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T13:12:08Z","timestamp":1779455528000},"page":"774","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biological Sex Influences the Pharmacokinetics and Organ Dosimetry of 177Lu-DOTATATE: A Systematic Preclinical Evaluation"],"prefix":"10.3390","volume":"19","author":[{"given":"Xiangsheng","family":"Kong","sequence":"first","affiliation":[{"name":"School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenhe District, Shenyang 110016, China"},{"name":"Mednovo Group Co., Ltd., No. 188 Fuchunjiang Rd., Suzhou New District, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peishang","family":"Li","sequence":"additional","affiliation":[{"name":"Mednovo Group Co., Ltd., No. 188 Fuchunjiang Rd., Suzhou New District, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqian","family":"Wang","sequence":"additional","affiliation":[{"name":"Mednovo Group Co., Ltd., No. 188 Fuchunjiang Rd., Suzhou New District, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenchen","family":"Cai","sequence":"additional","affiliation":[{"name":"Mednovo Group Co., Ltd., No. 188 Fuchunjiang Rd., Suzhou New District, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Mednovo Group Co., Ltd., No. 188 Fuchunjiang Rd., Suzhou New District, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunmiao","family":"Qu","sequence":"additional","affiliation":[{"name":"Mednovo Group Co., Ltd., No. 188 Fuchunjiang Rd., Suzhou New District, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlei","family":"Jin","sequence":"additional","affiliation":[{"name":"Mednovo Group Co., Ltd., No. 188 Fuchunjiang Rd., Suzhou New District, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongzhang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Mednovo Group Co., Ltd., No. 188 Fuchunjiang Rd., Suzhou New District, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeqing","family":"Dong","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6534-3627","authenticated-orcid":false,"given":"Kai","family":"Lv","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Han","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenhe District, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"ref_1","first-page":"471","article-title":"Gastroenteropancreatic Neuroendocrine Tumors","volume":"68","author":"Cives","year":"2018","journal-title":"CA Cancer J. 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Imaging"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/5\/774\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T13:19:35Z","timestamp":1779455975000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/5\/774"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,15]]},"references-count":28,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ph19050774"],"URL":"https:\/\/doi.org\/10.3390\/ph19050774","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,15]]}}}