The popular anticancer drug cisplatin causes many adverse side effects, the most serious of which is acute kidney injury (AKI). Emerging evidence from laboratory and clinical studies suggests that the AKI pathogenesis involves oxidative stress pathways; therefore, regulating such pathways may offer protection. Urolithin A (UA), a gut metabolite of the dietary tannin ellagic acid, possesses antioxidant properties and has shown promise in mouse models of AKI. However, therapeutic potential of UA is constrained by poor bioavailability. We aimed to improve oral bioavailability of UA by formulating it into biodegradable nanoparticles that use a surface-conjugated ligand targeting the gut-expressed transferrin receptor. Nanoparticle encapsulation of UA led to a sevenfold enhancement in oral bioavailability compared with native UA. Treatment with nanoparticle UA also significantly attenuated the histopathological hallmarks of cisplatin-induced AKI and reduced mortality by 63% in the mouse model. Expression analyses indicated that nanoparticle UA therapy coincided with oxidative stress mitigation and downregulation of nuclear factor erythroid 2-related factor 2- and P53-inducible genes. Additionally, normalization of miRNA (miR-192-5p and miR-140-5p) implicated in AKI, poly(ADP-ribose) polymerase 1 levels, antiapoptotic signaling, intracellular NAD+, and mitochondrial oxidative phosphorylation were observed in the treatment group. Our findings suggest that nanoparticles greatly increase the oral bioavailability of UA, leading to improved survival rates in AKI mice, in part by reducing renal oxidative and apoptotic stress.
Cyclosporine A (CsA) is a powerful immunosuppressant, but it is an ineffective stand-alone treatment for systemic lupus erythematosus (SLE) due to poor target tissue distribution and renal toxicity. We hypothesized that CD71 (transferrin receptor 1)–directed delivery of CsA to the lymphatic system would improve SLE outcomes in a murine model. We synthesized biodegradable, ligand-conjugated nanoparticles [P2Ns–gambogic acid (GA)] targeting CD71. GA conjugation substantially increased nanoparticle association with CD3+ or CD20+ lymphocytes and with intestinal lymphoid tissues. In orally dosed MRL-lpr mice, P2Ns-GA–encapsulated CsA increased lymphatic drug delivery 4- to 18-fold over the ligand-free formulation and a commercial CsA capsule, respectively. Improved lymphatic bioavailability of CsA was paralleled by normalization of anti–double-stranded DNA immunoglobulin G titer, plasma cytokines, and glomerulonephritis. Thus, this study demonstrates the translational potential of nanoparticles that enhance the targeting of lymphatic tissues, transforming CsA into a potent single therapeutic for SLE.
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