A glutathione-triggered precision explosive system for improving tumor chemosensitivity

Yuanyuan Nie; Yurui Xu; Ya Gao; Jielei He; Lei Sun; Jianmei Chen; Yushuang Cui; Haixiong Ge; Xinghai Ning

doi:10.1007/s12274-020-3238-2

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Research Article

A glutathione-triggered precision explosive system for improving tumor chemosensitivity

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.

Show Author Information

Graphical Abstract

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

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

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12274_2020_3238_MOESM1_ESM.pdf (3 MB)

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Nano Research

Volume 14 Issue 7,
July 2021

Pages 2372-2382

DOI: 10.1007/s12274-020-3238-2

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

Topics:

Cardiovascular system Cell proliferation Controlled drug delivery Mammals Manganese oxide Oxygen Peptides Targeted drug delivery

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Received: 23 August 2020

Revised: 07 November 2020

Accepted: 14 November 2020

Published: 05 July 2021