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Intracellular Mechanistic Understanding of 2D MoS₂ Nanosheets for Anti-Exocytosis-Enhanced Synergistic Cancer Therapy

ACS Nano2018Vol. 12(3), pp. 2922–2938

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Xianbing Zhu, Xiaoyuan Ji, Na Kong, Yunhan Chen, Morteza Mahmoudi, Xiaoding Xu, Li Ding, Wei Tao, Ting Cai, Yujing Li, Gan Tian, Austin John Barrett, Zameer Bharwani, Hongbo Chen, Omid C. Farokhzad

Abstract

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. e., intracellular mechanisms) remains elusive. Here we chose molybdenum disulfide (MoS₂) 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. MoS₂ 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 MoS₂ NSs. Based on these findings, we developed a strategy to achieve effective and synergistic in vivo cancer therapy with MoS₂ 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.

Citations Over TimeTop 1% of 2018 papers

Abstract

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