Zwitterionic polymer-dexamethasone conjugates penetrate and protect cartilage from inflammation

• Published in: Materials today bio Vol. 26; p. 101049
• Main Authors: Weber, Patrick, Asadikorayem, Maryam, Surman, František, Zenobi-Wong, Marcy
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2024; Elsevier
• Subjects: Cartilage; Dexamethasone; Full Length; Polymer-drug conjugate; Sustained release; Zwitterionic; CBAA; PEGMA; PCMA; Dexamethasone; C2Pep; DEX-MAHAc; Polymer-drug conjugate; Zwitterionic; Cartilage; DEX; Sustained release; DMA; HPMA; APTAC; DEX-MAES
• ISSN: 2590-0064; 2590-0064
• DOI: 10.1016/j.mtbio.2024.101049

Improving the pharmacokinetics of intra-articularly injected therapeutics is a major challenge in treating joint disease. Small molecules and biologics are often cleared from the joint within hours, which greatly reduces their therapeutic efficacy. Furthermore, they are often injected at high doses, which can lead to local cytotoxicity and systemic side effects. In this study, we present modular polymer-drug conjugates of zwitterionic poly(carboxybetaine acrylamide) (pCBAA) and the anti-inflammatory glucocorticoid dexamethasone (DEX) to create cartilage-targeted carriers with slow-release kinetics. pCBAA polymers showed excellent cartilage penetration (full thickness in 1 h) and retention (>50 % after 2 weeks of washing). DEX was loaded onto the pCBAA polymer by employing two different DEX-bearing comonomers to produce pCBAA-co-DEX conjugates with different release kinetics. The slow-releasing conjugate showed zero-order release kinetics in PBS over 70 days. The conjugates elicited no oxidative stress on chondrocytes compared to dose-matched free DEX and protected bovine cartilage explants from the inflammatory response after treatment with IL-1β. By combining cartilage targeting and sustained drug release properties, the pCBAA-co-DEX conjugates solve many issues of today's intra-articular therapeutics, which could ultimately enable better long-term clinical outcomes with fewer side effects. [Display omitted] •pCBAA polymers penetrate full thickness cartilage within 1 h.•pCBAA polymers are retained in cartilage tissue over >2 weeks.•CBAA-co-DEX conjugates continuously release DEX in PBS over >2 months.•Conjugation protects chondrocytes from oxidative stress elicited by free DEX.•Conjugates protect cartilage from IL-1β induced inflammation.