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Nano Research 2024, 17(6): 5435-5451 https://doi.org/10.1007/s12274-024-6455-2
Research Article | Issue | Published: 01 February 2024

Inhalable iron redox cycling powered nanoreactor for amplified ferroptosis-apoptosis synergetic therapy of lung cancer

Show Author's Information Linjing Wu1,§,  Wenhao Wang2,§,  Mengqin Guo1,§,  Fangqin Fu1,  Wenhua Wang2,  Tszching Sung1,  Meihong Zhang1,  Ziqiao Zhong1,  Chuanbin Wu1,  Xin Pan2,  Zhengwei Huang1( )
College of Pharmacy, Jinan University, Guangzhou 511436, China
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China

§ Linjing Wu, Wenhao Wang, and Mengqin Guo contributed equally to this work.

Keywords:
lung cancer, ferroptosis, pulmonary delivery, metallic polyphenol network
Topics:
Drug therapy
Cite this article:
Wu L, Wang W, Guo M, et al. Inhalable iron redox cycling powered nanoreactor for amplified ferroptosis-apoptosis synergetic therapy of lung cancer. Nano Research, 2024, 17(6): 5435-5451. https://doi.org/10.1007/s12274-024-6455-2
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Abstract Full text Electronic supplementary material About this article

Fenton reaction centered ferroptosis-apoptosis synergetic therapy has emerged as a promising tumor elimination strategy. However, the low intracellular Fenton level and accumulation of therapeutics at the lesion site greatly limit the efficacy of ferroptosis therapy. To overcome these two bottlenecks, an inhalable metal polyphenol network (MPN)-hybrid liposome, encoded as LDG, was proposed for enhancing the intracellular Fenton reaction level by co-delivering the ferroptosis inducer dihydroartemisinin (DHA) and the ferrous ion (Fe2+) donor MPN. The synthesized LDG had excellent nebulization performance which significantly improved the accumulation in the lungs, about 8.2 times of intravenous injection. In terms of anticancer mechanisms, MPN raised the intracellular level of Fe2+ by constructing iron cycling in the weakly acidic environment of tumors. Triggered by Fe2+, DHA with peroxide-bridge structure underwent a high level of Fenton-like reaction, promoted the production of intracellular reactive oxygen species (ROS) and induced strong ferroptosis while cooperating with apoptosis. LDG exhibited extraordinary antitumor ability in an orthotopic lung tumor model, whose tumor inhibition efficiency was 1.53 (P = 0.0014) and 1.32 (P = 0.0183) times of the LG group (liposomes coated with gallic acid (GA)-Fe MPN) and LD group (liposomes loaded with DHA), respectively, showing the strongest anticancer effect. In conclusion, the constructed MPN-hybrid liposomes could be a potent custom nanoplatform for pulmonary delivery and underscored the great potential of ferroptosis-apoptosis synergetic therapy.


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Abstract
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Electronic supplementary material
About this article

Inhalable iron redox cycling powered nanoreactor for amplified ferroptosis-apoptosis synergetic therapy of lung cancer

Show Author's information Linjing Wu1,§, Wenhao Wang2,§, Mengqin Guo1,§, Fangqin Fu1, Wenhua Wang2, Tszching Sung1, Meihong Zhang1, Ziqiao Zhong1, Chuanbin Wu1, Xin Pan2, Zhengwei Huang1( )
College of Pharmacy, Jinan University, Guangzhou 511436, China
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China

§ Linjing Wu, Wenhao Wang, and Mengqin Guo contributed equally to this work.

Abstract

Fenton reaction centered ferroptosis-apoptosis synergetic therapy has emerged as a promising tumor elimination strategy. However, the low intracellular Fenton level and accumulation of therapeutics at the lesion site greatly limit the efficacy of ferroptosis therapy. To overcome these two bottlenecks, an inhalable metal polyphenol network (MPN)-hybrid liposome, encoded as LDG, was proposed for enhancing the intracellular Fenton reaction level by co-delivering the ferroptosis inducer dihydroartemisinin (DHA) and the ferrous ion (Fe2+) donor MPN. The synthesized LDG had excellent nebulization performance which significantly improved the accumulation in the lungs, about 8.2 times of intravenous injection. In terms of anticancer mechanisms, MPN raised the intracellular level of Fe2+ by constructing iron cycling in the weakly acidic environment of tumors. Triggered by Fe2+, DHA with peroxide-bridge structure underwent a high level of Fenton-like reaction, promoted the production of intracellular reactive oxygen species (ROS) and induced strong ferroptosis while cooperating with apoptosis. LDG exhibited extraordinary antitumor ability in an orthotopic lung tumor model, whose tumor inhibition efficiency was 1.53 (P = 0.0014) and 1.32 (P = 0.0183) times of the LG group (liposomes coated with gallic acid (GA)-Fe MPN) and LD group (liposomes loaded with DHA), respectively, showing the strongest anticancer effect. In conclusion, the constructed MPN-hybrid liposomes could be a potent custom nanoplatform for pulmonary delivery and underscored the great potential of ferroptosis-apoptosis synergetic therapy.

Keywords: lung cancer, ferroptosis, pulmonary delivery, metallic polyphenol network

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Publication history
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Acknowledgements

Publication history

Received: 01 December 2023
Revised: 27 December 2023
Accepted: 28 December 2023
Published: 01 February 2024
Issue date: June 2024

Copyright

© Tsinghua University Press 2024

Acknowledgements

Acknowledgements

We appreciated the grants from the National Natural Science Foundation of China (Nos. 82104070 and 82373800), Guangdong Universities Keynote Regions Special Funded Project (No. 2022ZDZX2002), and General Project of Traditional Chinese Medicine Bureau of Guangdong Province (No. 20241071).

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