Background/Purpose: Many types of inflammatory arthritis (IA) are treated with systemic therapy. In situations where only one or a few joints are active, intra-articular drug administration may offer distinct advantages over starting or escalating systemic therapy by increasing drug bioavailability locally and reducing the potential for drug-induced systemic toxicity. However, local delivery of therapeutics is limited by short intra-articular half-lives. A drug delivery method that generates a local drug depot and titrates drug release to arthritis activity would represent an attractive solution to this problem. We investigated the utility of hydrogels generated from a generally recognized as safe (GRAS) compound for inflammation-responsive local drug delivery in a mouse model of IA.

Methods: Hydrogels were generated from triglycerol monostearate (TG-18) and loaded with triamcinolone acetonide (TA) or a fluorescent dye (DiR). TA-loaded hydrogels were incubated in vitro with defined enzymatic activities or human synovial fluid. TA release was measured using high performance liquid chromatography. IA was induced in C57BL/6 mice by two i.p. injections of K/BxN serum. DiR-loaded hydrogels were injected into the right hindpaw prior to disease induction and fluorescence signal decay was measured by IVIS imaging. To test therapeutic efficacy, TA-loaded hydrogel, blank hydrogel or free TA were injected into the right hindpaw immediately after disease induction, and disease severity was assessed by measuring paw thickness with calipers and clinical scoring.

Results: TG-18 hydrogels efficiently and stably encapsulate TA. In vitro, TA-loaded hydrogels released drug on-demand upon exposure to enzymes including matrix metalloproteases or synovial fluid from patients with rheumatoid arthritis. In mice with K/BxN serum transfer arthritis, locally injected DiR-hydrogels demonstrated loss of fluorescence over time due to hydrogel disassembly that correlated with arthritis severity. Moreover, a single dose of TA-loaded hydrogel but not the equivalent dose of locally injected free TA reduced arthritis activity in the injected paw.

Conclusion: Our results suggest that an inflammation-responsive hydrogel as self-titrating on-demand drug delivery system can offer improved therapeutic benefit in IA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/an-on-demand-drug-delivery-system-for-the-treatment-of-inflammatory-arthritis/