Zwitterionic poly-carboxybetaine-dexamethasone conjugates do not alleviate cartilage degeneration and synovitis in the collagenase-induced osteoarthritis model in rats
Weber, Patrick; Asadikorayem, Maryam; Zhang, Shipin; Fercher, David; Bevc, Kajetana; Kauppinen, Sami; Frondelius, Tuomas; Zhang, Tianqi; Fonti, Marina; Barreto, Gonçalo; Finnilä, Mikko A J; Zenobi-Wong, Marcy (2025-07-01)
Springer
01.07.2025
Weber, P., Asadikorayem, M., Zhang, S. et al. Zwitterionic poly-carboxybetaine-dexamethasone conjugates do not alleviate cartilage degeneration and synovitis in the collagenase-induced osteoarthritis model in rats. Sci Rep 15, 20501 (2025). https://doi.org/10.1038/s41598-025-93247-3
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© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
https://creativecommons.org/licenses/by/4.0/
© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202508125296
https://urn.fi/URN:NBN:fi:oulu-202508125296
Tiivistelmä
Abstract
Osteoarthritis is a degenerative joint disease for which there is yet to be a disease-modifying drug available in clinics. 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 (N = 8). On day 70, joint tissues were harvested and analyzed. While pCBAA-DEX achieved ~ 50% 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.
Osteoarthritis is a degenerative joint disease for which there is yet to be a disease-modifying drug available in clinics. 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 (N = 8). On day 70, joint tissues were harvested and analyzed. While pCBAA-DEX achieved ~ 50% 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.
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