Hepatocyte injury is a common pathological effect of cisplatin (CDDP) in various solid tumor therapies. Thus, strategies for minimizing CDDP toxicity are of great clinical interest. N-acetylcysteine (NAC), a known antioxidant, is often used as an antidote for acetaminophen overdose in the clinic due to its ability to increase the levels of glutathione (GSH). In the present study, the aim was to investigate the protective effects of NAC against CDDP-induced apoptosis in human-derived HepG2 cells. The results showed that upon exposure of the cells to CDDP, oxidative stress was significantly induced. DNA damage caused by CDDP was associated with cell apoptosis. NAC pre-treatment significantly reduced the malondialdehyde (MDA) levels and ameliorated the GSH modulation induced by CDDP. NAC also protected against DNA damage and cell apoptosis. These data suggest the protective role of NAC against hepatocyte apoptosis induced by CDDP was achieved through the inhibition of DNA damage and alterations of the redox status in human derived HepG2 cells. These results indicate that NAC administration may protect against CDDP-induced damage.

Rheumatoid arthritis (RA) is an autoimmune disease with unclear pathogenesis. Hydroxychloroquine (HCQ), despite its moderate anti-RA efficacy, is among the few clinical drugs used for RA therapy. Macrophages reportedly play a vital role in RA. Here, we designed and explored macrophage-targeted HCQ nanotherapeutics based on mannose-functionalized polymersomes (MP-HCQ) for RA therapy. Notably, MP-HCQ exhibited favorable properties of less than 50 nm size, glutathione-accelerated HCQ release, and M1 phenotype macrophage (M1M) targetability, leading to repolarization of macrophages to anti-inflammatory M2 phenotype (M2M), reduced secretion of pro-inflammatory cytokines (IL-6), and upregulation of anti-inflammatory cytokines (IL-10). The therapeutic studies in the zymosan-induced RA (ZIA) mouse model showed marked accumulation of MP-HCQ in the inflammation sites, ameliorated symptoms of RA joints, significantly reduced IL-6, TNF-α, and IL-1β, and increased IL-10 and TGF-β compared with free HCQ. The analyses of RA joints disclosed greatly amplified M2M and declined mature DCs, CD4+ T cells, and CD8+ T cells. In accordance, MP-HCQ significantly reduced the damage of RA joints, cartilages, and bones compared to free HCQ and non-targeted controls. Macrophage-targeted HCQ nanotherapeutics therefore appears as a highly potent treatment for RA.

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