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New drug candidates often fail due to a combination of poor pharmacokinetics as well as an inability to address the complex, multifactorial nature of osteoarthritis. To address these issues, we developed a zwitterionic poly-carboxybetaine acrylamide-dexamethasone (pCBAA-DEX) conjugate showing good cartilage penetration as well as anti-inflammatory and lubricating properties in previous in vitro studies. Here, we investigate the therapeutic potential of pCBAA-DEX in the collagenase-induced osteoarthritis (CIOA) model in rats. Upon induction of the model, animals received one-time, unilateral injections of either saline, DEX or pCBAA-DEX on day 4 (<jats:italic>N<\/jats:italic>\u2009=\u20098). On day 70, joint tissues were harvested and analyzed. While pCBAA-DEX achieved\u2009~\u200950% cartilage retention at the terminal timepoint, it did not prevent cartilage degeneration, synovial inflammation and synovial fibrosis, nor did DEX alone. Nevertheless, DEX and pCBAA-DEX slightly decreased the fibrosis levels in the synovium with DEX also decreasing the number of synovial lining layers. For the cartilage, DEX did not cause any notable differences, instead we observed an increase in cartilage degeneration in the pCBAA-DEX group. These findings challenge the previous in vitro results and motivate a substantial redesign of these conjugates and associated in vitro methods to reconsider them for the treatment of osteoarthritis.<\/jats:p>","DOI":"10.1038\/s41598-025-93247-3","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T13:15:45Z","timestamp":1751375745000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Zwitterionic poly-carboxybetaine-dexamethasone conjugates do not alleviate cartilage degeneration and synovitis in the collagenase-induced osteoarthritis model in rats"],"prefix":"10.1038","volume":"15","author":[{"given":"Patrick","family":"Weber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Asadikorayem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shipin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Fercher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kajetana","family":"Bevc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami","family":"Kauppinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuomas","family":"Frondelius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianqi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Fonti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gon\u00e7alo","family":"Barreto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikko A.J.","family":"Finnil\u00e4","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcy","family":"Zenobi-Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"93247_CR1","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1002\/art.42089","volume":"74","author":"H Long","year":"2022","unstructured":"Long, H. et al. 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