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Nano Research 2021, 14(7): 2372-2382 https://doi.org/10.1007/s12274-020-3238-2
Research Article | Issue | Published: 05 July 2021

A glutathione-triggered precision explosive system for improving tumor chemosensitivity

Show Author's Information Yuanyuan Nie§,  Yurui Xu§( ),  Ya Gao§,  Jielei He,  Lei Sun,  Jianmei Chen,  Yushuang Cui( ),  Haixiong Ge( ),  Xinghai Ning( )
National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing 210093, China

§ Yuanyuan Nie, Yurui Xu, and Ya Gao contributed equally to this work.

Keywords:
synergistic effects, glutathione-responsive, serum stability, selective intracellular release, explosive reactive oxygen species (ROS) production, enhanced anticancer effects
Topics:
Cardiovascular system Cell proliferation Controlled drug deliveryMammalsManganese oxideOxygenPeptidesTargeted drug delivery
Cite this article:
Nie Y, Xu Y, Gao Y, et al. A glutathione-triggered precision explosive system for improving tumor chemosensitivity. Nano Research, 2021, 14(7): 2372-2382. https://doi.org/10.1007/s12274-020-3238-2
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Abstract Full text Electronic supplementary material About this article

Stimuli-responsive delivery systems hold promise in cancer treatments. However, their application potential has been limited due to undesirable drug leaking during blood circulation and inefficient therapeutic efficacy in tumors, resulting in undesirable therapeutic outcomes. Herein, we have developed a novel redox-sensitive pegylated phospholipid, termed as DOPE-SS-PEG, which can form a glutathione (GSH)-triggered precision explosive system (GPS) for simultaneously improving circulation stability, tumor specificity, and chemosensitivity, leading to explosive anticancer effects. GPS is constructed of liposomal doxorubicin (DOX) functionalized with DOPE-SS-PEG and MnO2 nanoparticles, which can protect liposome structure in the presence of serum GSH (20 μM), whereas converts to cationic liposome in response to intracellular GSH (10 mM), thereby enhancing circulation stability, tumor specificity, endosomal escape, and cytoplasmic delivery. Importantly, GPS can not only generate oxygen to relieve hypoxia and consequently enhance chemosensitivity, but quench GSH antioxidability to elevate the accruement of intracellular reactive oxygen species (ROS), leading to an explosion of oxidative stress induced cell injury. Particularly, in vivo studies show that GPS selectively accumulates in tumor tissues, effectively inhibits tumor growth, exhibits minimal systemic adverse effects, and consequently prolongs the survival time of tumor-bearing mice. Therefore, GPS is a unique stimuli-responsive treatment with programmed and on-demand drug delivery, as well as explosive therapeutic efficacy, and provides an intelligent anticancer treatment.


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Abstract
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Electronic supplementary material
About this article

A glutathione-triggered precision explosive system for improving tumor chemosensitivity

Show Author's information Yuanyuan Nie§, Yurui Xu§( ), Ya Gao§, Jielei He, Lei Sun, Jianmei Chen, Yushuang Cui( ), Haixiong Ge( ), Xinghai Ning( )
National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing 210093, China

§ Yuanyuan Nie, Yurui Xu, and Ya Gao contributed equally to this work.

Abstract

Stimuli-responsive delivery systems hold promise in cancer treatments. However, their application potential has been limited due to undesirable drug leaking during blood circulation and inefficient therapeutic efficacy in tumors, resulting in undesirable therapeutic outcomes. Herein, we have developed a novel redox-sensitive pegylated phospholipid, termed as DOPE-SS-PEG, which can form a glutathione (GSH)-triggered precision explosive system (GPS) for simultaneously improving circulation stability, tumor specificity, and chemosensitivity, leading to explosive anticancer effects. GPS is constructed of liposomal doxorubicin (DOX) functionalized with DOPE-SS-PEG and MnO2 nanoparticles, which can protect liposome structure in the presence of serum GSH (20 μM), whereas converts to cationic liposome in response to intracellular GSH (10 mM), thereby enhancing circulation stability, tumor specificity, endosomal escape, and cytoplasmic delivery. Importantly, GPS can not only generate oxygen to relieve hypoxia and consequently enhance chemosensitivity, but quench GSH antioxidability to elevate the accruement of intracellular reactive oxygen species (ROS), leading to an explosion of oxidative stress induced cell injury. Particularly, in vivo studies show that GPS selectively accumulates in tumor tissues, effectively inhibits tumor growth, exhibits minimal systemic adverse effects, and consequently prolongs the survival time of tumor-bearing mice. Therefore, GPS is a unique stimuli-responsive treatment with programmed and on-demand drug delivery, as well as explosive therapeutic efficacy, and provides an intelligent anticancer treatment.

Keywords: synergistic effects, glutathione-responsive, serum stability, selective intracellular release, explosive reactive oxygen species (ROS) production, enhanced anticancer effects

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Publication history
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Acknowledgements

Publication history

Received: 23 August 2020
Revised: 07 November 2020
Accepted: 14 November 2020
Published: 05 July 2021
Issue date: July 2021

Copyright

© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020

Acknowledgements

This work were supported by the National Key Research and Development Program of China (No. 2019YFA0802800), the National Key Research and Development Program of China (No. 2018YFB1105400), the National Natural Science Foundation of China (No. 21472090), the Natural Science Foundation of Jiangsu Province (No. BK20180334), the Fundamental Research Funds for Central Universities Nanjing University, the Scientific Research Foundation of Graduate School of Nanjing University (No. 2018CL12), and The Key Research and Development Program of Jiangsu Provincial Department of Science and Technology of China (No. BE2019002).

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