#6744 SELF-ASSEMBLED FISETIN NANOPARTICLES WITH ENHANCED BIOACTIVITIES FOR EFFECTIVE HYPERURICEMIC NEPHROPATHY THERAPY

Abstract

Abstract Background and Aims The prevalence of hyperuricemia is rising rapidly around the world, and increasing evidence demonstrates that hyperuricemia is the independent risk factor for chronic kidney diseases (CKD) development and progression. Hyperuricemia-induced renal injury, namely hyperuricemic nephropathy (HN), is characterized by urate crystal formation, tubulointerstitial fibrosis and glomerulosclerosis, which would eventually progress into end-stage renal disease (ESRD). Up to now, the mechanism of HN remains unclear and the treatment still needs further exploration. Fisetin is a natural flavanol with potent antioxidative and anti-inflammatory properties and showed therapeutic effects in mice with HN. However, the poor water solubility, rapid metabolism, and low bioavailability of fisetin largely hampered its clinical application. Herein, we reported the simple and efficient preparation of fisetin-EGCG nanoparticles (EG/FIS NPs) based on a solvent-mediated disassembly/reassembly strategy. Method The fisetin nano-formulation (FIS/EG NPs) was prepared based on a general solvent-mediated disassembly/reassembly strategy. The physicochemical properties of FIS/EG NPs including morphology, specific surface area and pore size distribution, drug encapsulation rate and loading rate, intracellular distribution were characterized. The potential toxic effects of FIS/EG NPs on RAW264.7 and TCMK-1 cells were investigated by CCK-8. Meanwhile, the anti-oxidative and anti-inflammatory effects of FIS/EG NPs were detected in vivo and in vitro. In vivo small animal imaging was employed to assess the kidney accumulation of FIS/EG NPs. And finally, HN was induced to measure the effect of FIS/EG NPs in mice and PAS staining, Masson staining, RT-qPCR were used to explore underlying mechanisms. Results EG/FIS NPs with stable water dispersion was prepared by using a general solvent-mediated disassembly/reassembly strategy. EG/FIS NPs contains both features of fisetin and EG NPs, and displayed more potent free radical scavenging ability than fisetin and EG NPs. Meanwhile, it was found that both RAW264.7 and TCMK-1 cells were able to uptake EG/FIS NPs and no proliferation toxicity was observed in these two cell types after incubation with various concentrations of EG/FIS NPs. By in vivo and in vitro experiments, fisetin and EG NPs were shown to have synergistic effects in inhibiting LPS-stimulated NO production after encapsulation. Moreover, fluorescence imaging revealed that EG/FIS NPs preferentially accumulated in the injured kidneys of HN mice. Finally, it was observed that EG/FIS NPs exhibited enhanced therapeutic efficiency against HN due to the combined antioxidative, anti-inflammatory, and antifibrotic activities of fisetin and EG NPs Conclusion Collectively, these results suggested that EGCG-based nanocarriers might be a novel strategy for the development of therapeutic drugs for HN.