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Docetaxel (DTX) is a first-line chemotherapy drug for metastatic castration resistant prostate cancer (mCRPC) and has exhibited promising efficacy. However, DTX usually causes severe side effects. To address this issue, we utilized short-chain poly(ethylene glycol) (PEG) as a monomer to prepare a water-soluble polyester, which was further modified by a PSMA ligand, 2-[3-[5-amino-1-carboxypentyl]-ureido]-pentanedioic acid (DCL) and covalently linked to DTX via a disulfide bond, resulting in a novel PSMA\u2013targeting polyester\u2013drug conjugate (PET\u2013DCL\u2013DTX). Here, the introduction of short-chain PEG into the polyester skeleton could enhance its hydrophilicity and drug-loading capacity. This conjugate is amphiphilic and forms a nanostructure via self-assembly in aqueous solution, allowing it to passively accumulate in tumor tissues via the enhanced permeability and retention (EPR) effect. Particularly, due to the specific recognition of DCL for PSMA, this nanoconjugate exerts a profound inhibitory effect on PSMA-positive PCa cells. After efficiently entering the cells, this nanoconjugate undergoes sensitive cleavage of the disulfide bond owing to the reductive molecules such as glutathione and releases DTX to suppress the PSMA-positive PCa development. Moreover, an improved safety of this nanoconjugate was observed in vivo compared to DTX alone.<\/jats:p>","DOI":"10.1093\/rb\/rbag072","type":"journal-article","created":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T11:36:52Z","timestamp":1775907412000},"source":"Crossref","is-referenced-by-count":0,"title":["A novel polyester\u2013drug nanoconjugate with subtype selectivity for high efficacy against PSMA-positive prostate cancer"],"prefix":"10.1093","volume":"13","author":[{"given":"Shiwei","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Pharmacy, The Affiliated Hospital of Southwest Medical University , Luzhou, Sichuan 646000,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiyan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Southwest Medical University , Luzhou, Sichuan 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Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University , Luzhou, Sichuan 646000,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei","family":"Jing","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Affiliated Hospital of Southwest Medical University , Luzhou, Sichuan 646000,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University , Luzhou, Sichuan 646000,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University , Luzhou, Sichuan 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