Co-delivery of indomethacin and uricase as a new strategy for inflammatory diseases associated with high uric acid

Abstract

Uric acid is the final metabolite in humans. High level of uric acid chronically induces urate deposition, aggravates kidney damage, and concomitantly causes an increase in inflammatory factors. Alleviating acute inflammation and decreasing uric acid levels are the key points in the treatment of inflammatory diseases associated with high uric acid. However, a drug delivery system that combines anti-inflammatory and uric acid reduction functions at the same time remains a challenge to be settled. Here, we designed a nanocrystal-based co-delivery platform, IND Nplex, characterized by loading of indomethacin (IND) and uricase. Compared with free IND or uricase, IND Nplex possessed a better anti-inflammatory effect by restraining the release of inflammation-related factors in vitro. In addition, pharmacokinetic and biodistribution studies revealed that IND Nplex significantly prolonged the retention time in vivo and was more concentrated in the kidney. In acute gouty arthritis model rats, IND Nplex markedly relieved ankle joint swelling and mitigated synovial inflammation. In acute kidney injury model rats, IND Nplex indicated better biocompatibility and significant amelioration of renal fibrosis. Moreover, IND Nplex showed the effect of anti-inflammatory and improved renal function via determination of inflammatory factors and biochemical markers in the serum and kidney. In conclusion, these results indicate that IND Nplex exerts anti-inflammatory activity and uric acid-lowering effect and could become a promising candidate for the treatment of uric acid-related diseases. In this study, a stable neutral co-delivery platform (IND Nplex) was fabricated by using a co-delivery strategy, allowing for a combination of the anti-inflammation drug IND and the metabolic enzyme uricase. IND Nplex showed a good therapeutic effect on rats with acute gouty arthritis or acute kidney injury due to the dual effects of anti-inflammatory and uric acid lowering. This platform provided a novel strategy for high uric acid-related illnesses.

Keywords: Anti-inflammatory; Co-delivery nanoplatform; Indomethacin; Uric acid reduction; Uricase.