Sustained intra-articular delivery of IL-1Ra from a thermally-responsive elastin-like polypeptide as a therapy for post-traumatic arthritis

Abstract

Post-traumatic arthritis (PTA) is a rapidly progressive form of arthritis that develops due to joint injury, including articular fracture. Current treatments are limited to surgical restoration and stabilization of the joint; however, evidence suggests that PTA progression is mediated by the upregulation of pro-inflammatory cytokines, such as interleukin-1 (IL-1) or tumor necrosis factor-α (TNF-α). Although these cytokines provide potential therapeutic targets for PTA, intra-articular injections of anti-cytokine therapies have proven difficult due to rapid clearance from the joint space. In this study, we examined the ability of a cross-linked elastin-like polypeptide (xELP) drug depot to provide sustained intra-articular delivery of IL-1 and TNF-α inhibitors as a beneficial therapy. Mice sustained a closed intra-articular tibial plateau fracture; treatment groups received a single intra-articular injection of drug encapsulated in xELP. Arthritic changes were assessed 4 and 8 weeks after fracture. Inhibition of IL-1 significantly reduced the severity of cartilage degeneration and synovitis. Inhibition of TNF-α alone or with IL-1 led to deleterious effects in bone morphology, articular cartilage degeneration, and synovitis. These findings suggest that IL-1 plays a critical role in the pathogenesis of PTA following articular fracture, and sustained intra-articular cytokine inhibition may provide a therapeutic approach for reducing or preventing joint degeneration following trauma.

Dexamethasone Release from Within Engineered Cartilage as a Chondroprotective Strategy Against Interleukin-1α

“…By releasing dex from within engineered cartilage, our therapeutic strategy targets the complicated autocrine control system of chondrolysis, through which cartilage damage is triggered by proinflammatory cytokines produced from leukocytes and the synovium. 70,71 Compared to strategies that target specific proinflammatory cytokines, such as IL-1 receptor antagonist, 72,73 dex has been shown to mitigate the deleterious effects of IL, TNF-a, and other cytokines associated with inflammation. Once internalized, dex acts directly and indirectly by activating anti-inflammatory proteins, 74,75 upregulating their production through glucocorticoidresponsive elements located on DNA, 76,77 and by interfering with the translocation of other transcriptional factors, such as nuclear factor-kappa B.…”

“…While simplistic, the use of a single proinflammatory cytokine, IL-1a, is a well-established culture model for OA 38,40,71,72,[96][97][98] proven to provide valuable insight on the impact of cytokines on articular cartilage. The use of IL-1, specifically, exploits the cytokine's importance in inflammation.…”

Post-traumatic arthritis: overview on pathogenic mechanisms and role of inflammation

“…Recently, the use of lentiviral-mediated RNA interference silencing of IL-1b and TNF to treat PTA in rabbits displayed reduced cartilage damage and speed of degeneration 87. However, although both cytokines play a role in the post-traumatic acute phase, different studies performed in mouse models assert that intra-articular inhibition of IL-1, rather than TNF, may reduce the development of chronic PTA 54 88 89…”

Sustained intra-cartilage delivery of low dose dexamethasone using a cationic carrier for treatment of post traumatic osteoarthritis

“…It is critical for drugs to penetrate the full depth of cartilage in order to reach the chondrocytes and ECM targets involved in OA pathogenesis (Evans, 2016). Drug carrier systems proposed so far, including polymeric microparticles (Bodick et al , 2015), liposomes (Dong et al , 2013) and drug-loaded hydrogels (Kimmerling et al , 2015; Petit et al , 2015), have prolonged joint residence time due to their large size or aggregating properties; however, they are not able to penetrate into and through the joint cartilage. While these drug carriers can be useful in providing extended pain and inflammation relief through enhanced delivery to targets in the synovium, preclinical and clinical studies strongly suggest that certain DMOADs must be delivered to chondrocytes or ECM components to achieve cartilage protection (Chevalier et al , 2009; Cohen et al , 2011).…”