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ATP-responsive hollow nanocapsules for DOX/GOx delivery to enable tumor inhibition with suppressed P-glycoprotein

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Abstract

Multidrug resistance (MDR) restricts chemotherapy efficacy due to P-glycoprotein (P-gp) mediated drug efflux, whereas current approaches to suppressing P-gp expression suffer from intrinsic challenges, such as low transfection, high toxicity and poor specificity. Here, hollow ferric-tannic acid complex nanocapsules (HFe-TA), which can be effectively degraded by the reaction with adenosine triphosphate (ATP), are synthesized for the delivery of glucose oxidase (GOx) and doxorubicin (DOX) for tumor treatment. The findings indicate that the intracellular ATP is significantly decreased due to the combined effect of HFe-TA degradation and GOx-mediated glucose consumption. Along with this ATP down-regulation, P-gp expression of tumor cells is suppressed remarkably, which in turn promotes the intracellular accumulation and anticancer efficacy of DOX. In addition, the production of •OH by Fe ions released from HFe-TA is promoted by the by-products of the oxidation of glucose process by GOx. In consequence, HFe-TA nanocapsules loaded with DOX and GOx enable significant inhibition effect to tumors both in vitro and in vivo due to the synergistic effect of cascade reactions. This study has therefore provided an alternative therapeutic platform for effective tumor inhibition with the potential in overcoming intrinsic MDR.

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (Nos. 51672247 and 51902288), Provincial Key research program of Zhejiang Province (No. 2020C04005), ‘111’ Program funded by Education Ministry of China and Sate Bureau of Foreign Experts Affairs (No. B16043), China Postdoctoral Science Foundation (No. 2018M640555), Fundamental Research Funds for the Central Universities and ZJU-Hangzhou Global Scientific and Technological Innovation Center.

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  1. Huimin Zhu, Guodong Cao, and Yike Fu contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Silicon Materials, School of Materials Science and Engineering, Zhejiang University, Hangzhou, 310027, China

    Huimin Zhu, Yike Fu, Chao Fang, Qiang Chu, Xiang Li & Gaorong Han

  2. Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310000, China

    Guodong Cao & Yulian Wu

  3. ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, 311200, China

    Yike Fu & Xiang Li

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  1. Huimin Zhu
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Correspondence to Xiang Li or Yulian Wu.

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Zhu, H., Cao, G., Fu, Y. et al. ATP-responsive hollow nanocapsules for DOX/GOx delivery to enable tumor inhibition with suppressed P-glycoprotein. Nano Res. 14, 222–231 (2021). https://doi.org/10.1007/s12274-020-3071-7

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