Construction of an uricase/catalase/curcumin-co-loaded drug delivery system and its effect on hyper-uric acid-induced kidney injury

Abstract

Hyper-uric acid (UA)-induced kidney injury (HAKI) is caused by the deposition of excess blood UA into the kidneys. We confined molecules of uricase (URI), catalase (CAT), and curcumin (Cur) to a single structure (UC/Cur) while retaining their enzymatic activities via a cross-linking complexation reaction between tannic acid and FeCl3 for treating HAKI. Simultaneously, bovine serum albumin (BSA)-UC/Cur nanoparticles were successfully prepared by interlinking the disulfide bonds of BSA with the enzyme complex via Tris(2-carboxyethyl) phosphine(TCEP) to form sulfhydryl groups. BSA-UC/Cur significantly attenuated MSU-induced NLRP3 inflammasome pathway activation and apoptosis in NRK-52e cells by eliminating UA crystals and intracellular reactive oxygen species. More importantly, treatment with BSA-UC/Cur stabilized blood UA concentrations and lowered proximal tubular protein levels, mitochondrial swelling, and fibrotic areas, renducing the expression of matrix metalloproteinase (MMP)2, MMP9, and NLRP3 while, increasing the expression of tight-junction proteins ZO1 and occludin as well as that of TIMP-1, in HAKI model rats. In addition, BSA-UC/Cur nanoparticles reduced the subpopulation ratios of CD8+ T cells and M1 macrophages and increased those of M2 macrophages and Treg cells. Preliminary in-vivo trials showed that long-term intravenous treatment with BSA-UC/Cur is safe. Therefore, BSA-UC/Cur could be a potential nanotherapeutic agent for HAKI.

Keywords

• Hyper-uric acid-induced kidney injury
• Uricase
• Catalase
• Curcumin
• Metal organic framework