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Although biologics offer a target\u2010specific therapy, it raises the risk of serious infections and even cancer due to immune system suppression. We introduce an anti\u2010inflammatory arthritis MTX ester prodrug using a long\u2010circulating biocompatible polymeric macromolecule: folic acid (FA) functionalized hyperbranched polyglycerol (HPG). In vitro the drug MTX is incrementally released through pH and enzymatic degradation over 2 weeks. The role of matrix metalloproteinases (MMPs) in site\u2010specific prodrug activation was verified using synovial fluid (SF) of 26 rheumatology patients and 4 healthy controls. Elevated levels of specific MMPs\u2010markers of joint inflammation\u2010positively correlated with enhanced prodrug release explained by acid\u2010catalyzed hydrolysis of esters by proteases. Intravenously administered <jats:sup>111<\/jats:sup>In\u2010radiolabeled prodrug confirmed by SPECT\/CT imaging that it accumulated preferentially in inflamed joints while reducing off\u2010target side\u2010effects in a mouse model of rheumatoid arthritis (RA). Added FA as a targeting vector prolonged prodrug action; prodrug with 4x less MTX applied every 2 weeks was as effective as weekly MTX therapy. The preclinical results suggest a prodrug\u2010based strategy for the treatment of inflammatory joint diseases, with potential for other chronic inflammatory diseases and cancer.<\/jats:p>","DOI":"10.1002\/adhm.202401936","type":"journal-article","created":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T03:11:00Z","timestamp":1728443460000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Prodrug Nanomedicine for Synovium Targeted Therapy of Inflammatory Arthritis: Insights from Animal Model and Human Synovial Joint Fluid"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7092-942X","authenticated-orcid":false,"given":"Zeynab","family":"Nosrati","sequence":"first","affiliation":[{"name":"Faculty of Pharmaceutical Sciences University of British Columbia  2405 Wesbrook Mall Vancouver BC V5Z 3P2 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun 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