An on-Demand Drug Delivery Depot for the Treatment of Inflammatory Arthritis

One of the hallmarks of inflammatory arthritis (IA) is its variable disease activity with exacerbations (flares) of the chronic inflammatory joint process punctuated by periods of low disease activity. Treatment options are limited and often employ corticosteroids—agents with a plethora of toxic side effects. Use of a long acting intra-articular drug delivery method that titrates release to match disease activity would be a paradigm shift. We have developed an injectable inflammation responsive self-assembled hydrogel that can release the encapsulated drugs in response to enzymes, including matrix metalloproteinases (MMP-2 & MMP-9) and esterases, which are upregulated in inflammatory arthritis. Herein, we demonstrate the efficacy of this platform using triamcinolone acetonide (TA), a corticosteroid currently used in the clinic for the treatment of IA.

In vitro release studies showed release of TA from the hydrogel in response to the enzymes that are expressed within arthritic joints (MMP-2, MMP-9 and esterases) as well as in conditioned medium of activated macrophages. Incubation in PBS at 37^oC released moderate amount of drug (<20%) during a 120-day incubation. To evaluate on-demand delivery, enzymes were added to the release medium on day 120, which triggered the release of TA. In addition, gel released TA in response to synovial fluid (SF) collected from arthritic joints, but not when incubated with normal SF.

TA loaded gels showed excellent biocompatibility with both chondrocytes and synoviocytes at 10 mg/ml of TA, which implies that in vivo administration of these gels will not have any detrimental effects to the surrounding cells. TA as a gel formulation demonstrated improved anti-inflammatory activity in vitro in comparison to free TA, as evident by the reduced TNF-α and increased IL-10 secretions from activated human macrophages. Finally, an in vivoefficacy study showed reduced clinical scores for animals treated with TA loaded gels (20 mg TA/ml), compared to the scores observed for untreated animals and animals treated with Kenalog (20 mg TA/ml).

Overall, our results suggest that an inflammation responsive hydrogel as self-titrating drug delivery system can offer improved therapeutic benefit in inflammatory arthritis.