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Cited by 196Hydrogen's biological and therapeutic effectsHydrogen Storage and MaterialsNanoplatforms for cancer theranostics

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Magnesium galvanic cells produce hydrogen and modulate the tumor microenvironment to inhibit cancer growth

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Yang, Nailin, Gong, Fei, Liu, Bo, Hao, Yu, Chao, Yu, Lei, Huali, Yang, Xiaoyuan, Gong, Yuehan, Wang, Xianwen, Liu, Zhuang, Cheng, Liang·2022·Nature Communications
DOI 10.1038/s41467-022-29938-6PMC PMC9051066
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Abstract

Abstract Hydrogen can be used as an anti-cancer treatment. However, the continuous generation of H2 molecules within the tumor is challenging. Magnesium (Mg) and its alloys have been extensively used in the clinic as implantable metals. Here we develop, by decorating platinum on the surface of Mg rods, a Mg-based galvanic cell (MgG), which allows the continuous generation of H2 in an aqueous environment due to galvanic-cell-accelerated water etching of Mg. By implanting MgG rods into a tumor, H2 molecules can be generated within the tumor, which induces mitochondrial dysfunction and intracellular redox homeostasis destruction. Meanwhile, the Mg(OH)2 residue can neutralize the acidic tumor microenvironment (TME). Such MgG rods with the micro-galvanic cell structure enable hydrogen therapy to inhibit the growth of tumors, including murine tumor models, patient-derived xenografts (PDX), as well as VX2 tumors in rabbits. Our research suggests that the galvanic cells for hydrogen therapy based on implantable metals may be a safe and effective cancer treatment.

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Fig. 1 Schematic illustration to show the preparation of Mg galvanic cell (MgG) for tumor microenvironment modulation and enhanced cancer hydrogen therapy. MgG is developed by decorating platinum on the surface of Mg rods, which allows the continuous generation of H2 in an aqueous environment due to galvanic-cell-accelerated water etching of Mg. By implanting MgG rods into a tumor, H2 molecules can be generated within the tumor, which induces mitochondrial dysfunction and intracellular redox homeostasis destruction. Meanwhile, the Mg(OH)2 residue can neutralize the acidic tumor microenvironment (TME). Such MgG rods with the micro-galvanic cell structure enable hydrogen therapy to inhibit the growth of tumors.
Fig. 1 Schematic illustration to show the preparation of Mg galvanic cell (MgG) for tumor microenvironment modulation and enhanced cancer hydrogen therapy. MgG is developed by decorating platinum on the surface of Mg rods, which allows the continuous generation of H2 in an aqueous environment due to galvanic-cell-accelerated water etching of Mg. By implanting MgG rods into a tumor, H2 molecules can be generated within the tumor, which induces mitochondrial dysfunction and intracellular redox homeostasis destruction. Meanwhile, the Mg(OH)2 residue can neutralize the acidic tumor microenvironment (TME). Such MgG rods with the micro-galvanic cell structure enable hydrogen therapy to inhibit the growth of tumors.CC BY · PubMed Central
Fig. 2 Preparation and characterization of MgG rods. a Schematic illustration of the synthesis process of Mg galvanic cells and the H2 production mechanism. b The representative SEM image and EDS element mapping of MgG rods from three independent samples. c The XRD patterns of MgG rods. d Photograph showing H2 generation in PBS from Mg and MgG. e Schematic illustration of H2 generation detected by the MB probe. f Time-dependent absorption spectra of the MB solution (pH = 6.5) with MgG rods added. g Comparison of MB reduction by Mg rods and MgG rods. h Time-dependent H2 generation measured by gas chromatography from Mg or MgG rods in PBS (pH = 6.5, n = 3 biologically independent samples). i H2 generation profiles of MgG rods in PBS solutions with different pH values measured by gas chromatography. j The Tafel curve of Mg rods and MgG rods. k The corrosion potentials of Mg rods and MgG rods (n = 5 biologically independent samples). Data are presented as mean values ± SD.
Fig. 2 Preparation and characterization of MgG rods. a Schematic illustration of the synthesis process of Mg galvanic cells and the H2 production mechanism. b The representative SEM image and EDS element mapping of MgG rods from three independent samples. c The XRD patterns of MgG rods. d Photograph showing H2 generation in PBS from Mg and MgG. e Schematic illustration of H2 generation detected by the MB probe. f Time-dependent absorption spectra of the MB solution (pH = 6.5) with MgG rods added. g Comparison of MB reduction by Mg rods and MgG rods. h Time-dependent H2 generation measured by gas chromatography from Mg or MgG rods in PBS (pH = 6.5, n = 3 biologically independent samples). i H2 generation profiles of MgG rods in PBS solutions with different pH values measured by gas chromatography. j The Tafel curve of Mg rods and MgG rods. k The corrosion potentials of Mg rods and MgG rods (n = 5 biologically independent samples). Data are presented as mean values ± SD.CC BY · PubMed Central
Fig. 3 In vitro hydrogen therapy with MgG rods. a Schematic illustration showing the mechanims of hydrogen therapy with MgG for cancer cell killing. b Detection of mitochondria membrane potentials by confocal fluorescence images of 4T1 cells stained with JC-1 dye. c Time-dependent changes of intracellular ROS in 4T1 cells during different treatments (n = 5 biologically independent samples). d Flow cytometry data to show DCF-positive 4T1 cells after different treatments. e Time-dependent changes of intracellular ATP contents in 4T1 cells during different treatments (n = 5 biologically independent samples). f Relative viabilities of 4T1 and CT26 cells after various treatments (control, Mg, Pt, Mg(OH)2, and MgG, n = 5 biologically independent samples). g Flow cytometry analysis of 4T1 cells after various treatments using an Annexin V-FITC/PI kit. A representative image of three biologically independent samples from each group is shown in (b). Data are presented as mean values ± SD.
Fig. 3 In vitro hydrogen therapy with MgG rods. a Schematic illustration showing the mechanims of hydrogen therapy with MgG for cancer cell killing. b Detection of mitochondria membrane potentials by confocal fluorescence images of 4T1 cells stained with JC-1 dye. c Time-dependent changes of intracellular ROS in 4T1 cells during different treatments (n = 5 biologically independent samples). d Flow cytometry data to show DCF-positive 4T1 cells after different treatments. e Time-dependent changes of intracellular ATP contents in 4T1 cells during different treatments (n = 5 biologically independent samples). f Relative viabilities of 4T1 and CT26 cells after various treatments (control, Mg, Pt, Mg(OH)2, and MgG, n = 5 biologically independent samples). g Flow cytometry analysis of 4T1 cells after various treatments using an Annexin V-FITC/PI kit. A representative image of three biologically independent samples from each group is shown in (b). Data are presented as mean values ± SD.CC BY · PubMed Central
Fig. 4 In vivo hydrogen therapy with MgG rods. a In vivo time-dependent ultrasonic imaging of 4T1 tumor-bearing mice after intratumoral implantation with MgG rods. b Quantitative analysis of signal intensities based on ultrasonic imaging data. c Time-dependent pH value changes of tumors in mice post intratumoral implantation with Mg rods or MgG rods. d Ex vivo fluorescence images of tumors after implantation of MgG for different periods of time. e Tumor fluorescence (FL) signal ratios (480/440) based on ex vivo fluorescence imaging data in (C). f–h The quantification results of MDSCs (CD45+CD11b+Gr-1+, f), T cells (CD3+, g), CD8+ T cells (CD3+CD8+, h) by flow cytometry on day 6 post-MgG implantation. i The flow cytometric analysis results of CD8+ T cells (CD3+CD8+) within the tumors after different treatments. j The growth curves of tumors after various treatments. k Survival rates of tumor-bearing mice after various treatments. l Microscopy images of H&E and TUNEL stained tumor slices collected from mice post different treatment groups. m In vivo bioluminescence images of mice bearing subcutaneous 4T1 tumors expressing firefly luciferase (Luc-4T1) to display the therapeutic efficacy of mice after various treatments. n = 3 biologically independent animals in (b, c). n = 4 biologically independent animals in (e). n = 5 biologically independent animals in (f–h). n = 10 biologically independent animals in (j). A representative image of three biologically independent animals from each group is shown in (a, l). Data are presented as mean values ± SD. P values calculated by the two-tailed student’s t test are indicated in the Figures.
Fig. 4 In vivo hydrogen therapy with MgG rods. a In vivo time-dependent ultrasonic imaging of 4T1 tumor-bearing mice after intratumoral implantation with MgG rods. b Quantitative analysis of signal intensities based on ultrasonic imaging data. c Time-dependent pH value changes of tumors in mice post intratumoral implantation with Mg rods or MgG rods. d Ex vivo fluorescence images of tumors after implantation of MgG for different periods of time. e Tumor fluorescence (FL) signal ratios (480/440) based on ex vivo fluorescence imaging data in (C). f–h The quantification results of MDSCs (CD45+CD11b+Gr-1+, f), T cells (CD3+, g), CD8+ T cells (CD3+CD8+, h) by flow cytometry on day 6 post-MgG implantation. i The flow cytometric analysis results of CD8+ T cells (CD3+CD8+) within the tumors after different treatments. j The growth curves of tumors after various treatments. k Survival rates of tumor-bearing mice after various treatments. l Microscopy images of H&E and TUNEL stained tumor slices collected from mice post different treatment groups. m In vivo bioluminescence images of mice bearing subcutaneous 4T1 tumors expressing firefly luciferase (Luc-4T1) to display the therapeutic efficacy of mice after various treatments. n = 3 biologically independent animals in (b, c). n = 4 biologically independent animals in (e). n = 5 biologically independent animals in (f–h). n = 10 biologically independent animals in (j). A representative image of three biologically independent animals from each group is shown in (a, l). Data are presented as mean values ± SD. P values calculated by the two-tailed student’s t test are indicated in the Figures.CC BY · PubMed Central
Fig. 5 In vivo hydrogen therapy of different tumor models vith MgG rods. a Scheme of the subcutaneous CT26 mouse tumor model for MgG-based hydrogen therapy. b, c Tumor growth curves (b) and survival rates (c) of CT26 tumor-bearing mice after different treatments as indicated. d Microscopy images of H&E and TUNEL stained CT26 tumor slices collected from different groups. e Scheme of the PDX tumor model in mice for MgG-based hydrogen therapy. f, g Tumor growth curves (f) and survival rates (g) of nude mice after different treatments. h Microscopy images of H&E and TUNEL stained PDX tumor slices collected from different groups. i Scheme of the VX2 liver rabbit tumor model for MgG-based hydrogen therapy. j, k Tumor growth curves (j) and survival rates (k) of rabbits after different treatments. l Microscopy images of H&E and TUNEL stained VX2 tumor slices collected from different groups. n = 10 biologically independent animals in (b). n = 7 biologically independent animals in (f). n = 6 biologically independent animals in (j). A representative image of three biologically independent animals from each group is shown in (d, h, l). Data are presented as mean values ± SD.
Fig. 5 In vivo hydrogen therapy of different tumor models vith MgG rods. a Scheme of the subcutaneous CT26 mouse tumor model for MgG-based hydrogen therapy. b, c Tumor growth curves (b) and survival rates (c) of CT26 tumor-bearing mice after different treatments as indicated. d Microscopy images of H&E and TUNEL stained CT26 tumor slices collected from different groups. e Scheme of the PDX tumor model in mice for MgG-based hydrogen therapy. f, g Tumor growth curves (f) and survival rates (g) of nude mice after different treatments. h Microscopy images of H&E and TUNEL stained PDX tumor slices collected from different groups. i Scheme of the VX2 liver rabbit tumor model for MgG-based hydrogen therapy. j, k Tumor growth curves (j) and survival rates (k) of rabbits after different treatments. l Microscopy images of H&E and TUNEL stained VX2 tumor slices collected from different groups. n = 10 biologically independent animals in (b). n = 7 biologically independent animals in (f). n = 6 biologically independent animals in (j). A representative image of three biologically independent animals from each group is shown in (d, h, l). Data are presented as mean values ± SD.CC BY · PubMed Central
Fig. 6 In vivo safety and biodegradation behaviors of MgG rods. a The Mg levels in tumors of mice after being implanted with MgG rods for different periods of time. b The Mg levels in major organs and blood of mice after being implanted with MgG rods for different periods of time. The Mg contents were measured by ICP-OES. No notable variation of Mg levels was found in the blood or organs of implanted mice compared to the control. c The Pt levels in tumors of mice after being implanted with MgG rods for different periods of time (1, 2, 3, 7, and 15 D). d The Pt levels in major organs of mice after being implanted with MgG rods for different periods of time (1, 2, 3, 7, and 15 D). e Hematoxylin and eosin (H&E) staining of mouse major organs (liver, spleen, kidney, heart, and lung) to examine the histological changes after implantation of MgG rods in mice. f Blood biochemistry data of Balb/c mice after being implanted with MgG rods for different periods of time (0, 6 h, 24 h, 48 h, 72 h, 7 days, and 15 days). The measured indexes included alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and blood urea. g Blood pH value variation of Balb/c mice after being implanted with MgG rods for different periods of time (0, 4 h, 12 h, 24 h, 72 h, and 7 days). n = 4 biologically independent animals in (a, c–d). n = 3 biologically independent animals in (g). A representative image of three biologically independent animals from each group is shown in (e). Data are presented as mean values ± SD.
Fig. 6 In vivo safety and biodegradation behaviors of MgG rods. a The Mg levels in tumors of mice after being implanted with MgG rods for different periods of time. b The Mg levels in major organs and blood of mice after being implanted with MgG rods for different periods of time. The Mg contents were measured by ICP-OES. No notable variation of Mg levels was found in the blood or organs of implanted mice compared to the control. c The Pt levels in tumors of mice after being implanted with MgG rods for different periods of time (1, 2, 3, 7, and 15 D). d The Pt levels in major organs of mice after being implanted with MgG rods for different periods of time (1, 2, 3, 7, and 15 D). e Hematoxylin and eosin (H&E) staining of mouse major organs (liver, spleen, kidney, heart, and lung) to examine the histological changes after implantation of MgG rods in mice. f Blood biochemistry data of Balb/c mice after being implanted with MgG rods for different periods of time (0, 6 h, 24 h, 48 h, 72 h, 7 days, and 15 days). The measured indexes included alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and blood urea. g Blood pH value variation of Balb/c mice after being implanted with MgG rods for different periods of time (0, 4 h, 12 h, 24 h, 72 h, and 7 days). n = 4 biologically independent animals in (a, c–d). n = 3 biologically independent animals in (g). A representative image of three biologically independent animals from each group is shown in (e). Data are presented as mean values ± SD.CC BY · PubMed Central

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  1. Vetter, K. J. Electrochemical kinetics: theoretical aspects. (Elsevier, 2013).
  2. Zoski, C. G. Handbook of electrochemistry. (Elsevier, 2006).

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Metadata

Authors
Yang, N., Gong, F., Liu, B., Hao, Y., Chao, Y., Lei, H., Yang, X., Gong, Y., Wang, X., Liu, Z., & Cheng, L.
Affiliations
Soochow University (CN)
Corresponding author
  • Liu, Zhuang
  • Cheng, Liang
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-04-28
Volume
13
Issue
1
Pages
2336-2336
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-29938-6
PMC
PMC9051066
OpenAlex
W4225002645
Cited by
196
References
52
Citations by year
2026: 32 · 2025: 70 · 2024: 62 · 2023: 23 · 2022: 9
FWCI
39.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (U20A20254, 52072253)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Hydrogen's biological and therapeutic effects
  • Physical Sciences › Materials Science › Materials Chemistry › Hydrogen Storage and Materials
  • Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
Keywords
hydrogen treatment, tumor microenvironment, mitochondrial dysfunction, redox homeostasis, magnesium hydroxide, cancer growth inhibition, patient-derived xenografts
MeSH terms
Alloys, Animals, Humans, Hydrogen, Magnesium, Neoplasms, Rabbits, Mice, Tumor Microenvironment

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