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      • Intracellular Mechanistic Understanding of 2D MoS<sub>2</sub> Nanosheets for Anti-Exocytosis-Enhanced Synergistic Cancer Therapy

        Zhu, Xianbing,Ji, Xiaoyuan,Kong, Na,Chen, Yunhan,Mahmoudi, Morteza,Xu, Xiaoding,Ding, Li,Tao, Wei,Cai, Ting,Li, Yujing,Gan, Tian,Barrett, Austin,Bharwani, Zameer,Chen, Hongbo,Farokhzad, Omid C. American Chemical Society 2018 ACS NANO Vol.12 No.3

        <P>Emerging two-dimensional (2D) nanomaterials, such as transition-metal dichalcogenide (TMD) nanosheets (NSs), have shown tremendous potential for use in a wide variety of fields including cancer nanomedicine. The interaction of nanomaterials with biosystems is of critical importance for their safe and efficient application. However, a cellular-level understanding of the nano-bio interactions of these emerging 2D nanomaterials (<I>i</I>.<I>e</I>., intracellular mechanisms) remains elusive. Here we chose molybdenum disulfide (MoS<SUB>2</SUB>) NSs as representative 2D nanomaterials to gain a better understanding of their intracellular mechanisms of action in cancer cells, which play a significant role in both their fate and efficacy. MoS<SUB>2</SUB> NSs were found to be internalized through three pathways: clathrin → early endosomes → lysosomes, caveolae → early endosomes → lysosomes, and macropinocytosis → late endosomes → lysosomes. We also observed autophagy-mediated accumulation in the lysosomes and exocytosis-induced efflux of MoS<SUB>2</SUB> NSs. Based on these findings, we developed a strategy to achieve effective and synergistic <I>in vivo</I> cancer therapy with MoS<SUB>2</SUB> NSs loaded with low doses of drug through inhibiting exocytosis pathway-induced loss. To the best of our knowledge, this is the first systematic experimental report on the nano-bio interaction of 2D nanomaterials in cells and their application for anti-exocytosis-enhanced synergistic cancer therapy.</P> [FIG OMISSION]</BR>

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