An on demand drug delivery depot for the treatment of inflammatory arthritis

摘要

Introduction: 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 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. Materials and Methods: Release studies were performed in vitro to study on-demand delivery of TA in response to ⅰ) (MMP-2/ MMP-9/ esterase), ⅱ) enzymes secreted from activated macrophages and ⅲ) synovial fluid (SF) collected from arthritic patient's joint. TA loaded gels were evaluated in vitro for biocompatibility using chondrocytes and synoviocytes, and for anti-inflammatory efficacy using activated human macrophages. Therapeutic efficacy of TA loaded gels was evaluated in vivo using K/BxN serum model of IA developed in C57BI/6 mice, and was compared to the therapeutic efficacy of Kenalog, the current clinically used formulation of TA. Results and Discussions: Gels released TA 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 (Fig.1A and 1B). Incubation in PBS at 37oC 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 (Fig.1C). In addition, gel released TA in response to SF collected from arthritic joints, but not when incubated with normal SF (Fig.1 D). TA loaded gels showed excellent biocompatibility with both chondrocytes and synoviocytes at 10 mg/ml concentration 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 (Fig. 2). Finally, an in vivo efficacy 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) (Fig. 3). Conclusions: Overall, our results suggest that an inflammation responsive hydrogel as self-titrating drug delivery system can offer improved therapeutic benefit in inflammatory arthritis.