Fenton-reaction-triggered metabolism of acetaminophen for enhanced cancer therapy

Acetaminophen(APAP), a classic nonsteroidal anti-inflammatory drug(NSAID), has attracted much attention due to the overdose-induced hepatotoxicity in the past several decades. N-Acetyl-p-benzoquinone imine(NAPQI), the P450-dependent metabolism of APAP, leads to GSH depletion, protein binding, mitochondrial oxidative stress, and eventually the liver injury. Herein, we develop a Fe-based metal-organic framework(MOF) to deliver and transform acetaminophen into toxic “chemo” drug through the cascade reaction for enhanced cancer therapy. In the acidic tumor microenvironment, the Fe-based MOF collapses and releases abundant Fe ions to generate hydroxyl radicals(·OH) via Fenton reaction, subsequently catalyzing nontoxic APAP into toxic NAPQI. Meanwhile, NAPQI depletes intracellular glutathione(GSH) rapidly, leading to alleviating the antioxidant ability of cancer cells and amplifying Fenton activity. The intracellular oxidative stress and the toxic metabolite of APAP can provide a synergistic effect on antitumor activity.

In vitro immunomodulation of magnesium on monocytic cell toward anti-inflammatory macrophages

Biodegradable magnesium(Mg)has shown great potential advantages over current bone fixation devices and vascular scaffold technologies;however,there are few reports on the immunomodulation of corrosive Mg products,the micron-sized Mg particles(MgMPs).Human monocytic leukemia cell line THP-1 was set as the in vitro cell model to estimate the immunomodulation of MgMPs on cell proliferation,apoptosis,polarization and inflammatory reaction.Our results indicated highconcentration of Mg^2+ demoted the proliferation of the THP-1 cells and,especially,THP-1-derived macrophages,which was a potential factor that could affect cell function,but meanwhile,cell apoptosis was almost not affected by Mg^2+.In particular,the inflammation regulatory effects of MgMPs were investigated.Macrophages exposed to Mg^2+ exhibited down-regulated expressions of M1 subtype markers and secretions of pro-inflammatory cytokines,up-regulated expression of M2 subtype marker and secretion of anti-inflammatory cytokine.These results indicated Mg^2+ could convert macrophages from M0 to M2 phenotype,and the bioeffects of MgMPs on human inflammatory cells were most likely due to the Mg^2+-induced NF-jB activation reduction.Together,our results proved Mg^2+ could be used as a new anti-inflammatory agent to suppress inflammation in clinical applications,which may provide new ideas for studying the immunomodulation of Mg-based implants on human immune system.