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Cited by 41Nanoplatforms for cancer theranosticsPhotodynamic Therapy Research StudiesUltrasound and Hyperthermia Applications

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Mitochondria-Targeted Mesoporous Titanium Dioxide Nanoplatform for Synergistic Nitric Oxide Gas-Sonodynamic Therapy of Breast Cancer

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Zuo, Shuting, Zhang, Yan, Wang, Zhenyu, Wang, Jing·2022·International Journal of Nanomedicine
DOI 10.2147/ijn.s348618PMC PMC8906874
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Abstract

Background: Sonodynamic therapy (SDT) has rapidly advanced as a promising alternative to conventional photodynamic therapy owing to its preferable therapeutic depth. However, single-modal SDT exhibits limited efficacy due to the long-term hypoxia in tumors. Method and Results: To address these issues, we proposed a synergistic SDT strategy that integrates mitochondrial targeting with nitric oxide (NO) gas therapy by using multifunctional nanoplatforms. The nanoplatform, which was named as T-mTNPs@L-Arg, was composed of mesoporous titanium dioxide loaded with the NO donor precursor L-arginine (L-Arg) and modified with triphenyl phosphonium (TPP), a mitochondria-targeting ligand. Therefore, T-mTNPs@L-Arg could efficiently concentrate into mitochondria and release NO gas as well as generate reactive oxygen species (ROS) with ultrasound stimulus. Importantly, the released NO gas exerted multiple synergies with SDT, including inducing NO poisoning, generating more lethal reactive nitrogen species (RNS) by reaction with ROS, and alleviating hypoxia through NO-mediated mitochondrial respiration inhibition. On account of the synergistic effects, T-mTNPs@L-Arg showed an outstanding SDT efficacy and a reduced side effect. Conclusion: This work designed a nanoplatform to integrate mitochondria targeting, SDT and NO gas therapy, providing a new strategy for highly efficient breast cancer therapy.

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Scheme 1 Schematic illustration of mitochondria-targeted mesoporous titanium dioxide nanoparticles with L-arginine loading for synergistic nitric oxide gas-sonodynamic therapy.
Scheme 1 Schematic illustration of mitochondria-targeted mesoporous titanium dioxide nanoparticles with L-arginine loading for synergistic nitric oxide gas-sonodynamic therapy.CC BY-NC · PubMed Central
Figure 1 Characterization of T-mTNPs: (A) TEM images of mTNPs, scale bar=30 nm, (B) DLS analysis of mTNPs, (C) N2 adsorption/desorption isotherms of mTNPs, (D) Pore size distribution of mTNPs, (E) UV−vis absorption spectra, (F) L-Arg release profiles of T-mTNPs@L-Arg under different pH value, (G) Cumulative NO generation at different pH at the presence or absence of H2O2, (H) ROS generation detected by DPBF probe, (I) fluorescence spectrum of ONOO− detected by DHR probe.
Figure 1 Characterization of T-mTNPs: (A) TEM images of mTNPs, scale bar=30 nm, (B) DLS analysis of mTNPs, (C) N2 adsorption/desorption isotherms of mTNPs, (D) Pore size distribution of mTNPs, (E) UV−vis absorption spectra, (F) L-Arg release profiles of T-mTNPs@L-Arg under different pH value, (G) Cumulative NO generation at different pH at the presence or absence of H2O2, (H) ROS generation detected by DPBF probe, (I) fluorescence spectrum of ONOO− detected by DHR probe.CC BY-NC · PubMed Central
Figure 2 Mitochondria targeting and hypoxia relief: (A) Confocal microscope images of MCF-7 cells after incubated with FITC-labeled T-mTNPs@L-Arg and mTNPs@L-Arg and stained with Hoechst 33258 and MitoTracker, scale bar=10 nm (B) FITC fluorescence intensity of isolated mitochondria from MCF-7 cells after incubated with FITC-labeled T-mTNPs@L-Arg and mTNPs@L-Arg. The data are presented as the mean ± S.D. (n = 4). *p < 0.05 versus the mTNPs@L-Arg (C) Activity of Cco after various treatments. The data are presented as the mean ± S.D. (n = 4). *p < 0.05 versus the control groups, #p < 0.05 versus mTNPs@L-Arg. (D) Relative dissolved oxygen content in the cell medium of various groups. (E) Hypoxic status of MCF-7 cells detected by hypoxia red detection reagent l, scale bar=10 nm.
Figure 2 Mitochondria targeting and hypoxia relief: (A) Confocal microscope images of MCF-7 cells after incubated with FITC-labeled T-mTNPs@L-Arg and mTNPs@L-Arg and stained with Hoechst 33258 and MitoTracker, scale bar=10 nm (B) FITC fluorescence intensity of isolated mitochondria from MCF-7 cells after incubated with FITC-labeled T-mTNPs@L-Arg and mTNPs@L-Arg. The data are presented as the mean ± S.D. (n = 4). *p < 0.05 versus the mTNPs@L-Arg (C) Activity of Cco after various treatments. The data are presented as the mean ± S.D. (n = 4). *p < 0.05 versus the control groups, #p < 0.05 versus mTNPs@L-Arg. (D) Relative dissolved oxygen content in the cell medium of various groups. (E) Hypoxic status of MCF-7 cells detected by hypoxia red detection reagent l, scale bar=10 nm.CC BY-NC · PubMed Central
Figure 3 In Vitro SDT efficacy of T-mTNPs@L-Arg. (A) The destruction of mitochondria in MCF-7 cells after various treatments detected by CLSM, scale bar=10 nm. Cytotoxicity of different nanoparticles towards MCF-7 cells in the absence (B) or presence (C) of US stimulus. (D) Cell viability of hypoxic MCF-7 cells after treated with different nanoparticles in the presence of US. (E) CLSM images of MCF-7 cells stained with DCFH-DA in various groups, scale bar=10 nm. (F) ROS generation in various groups detected by FACS (“H” represents hypoxia). The data are presented as the mean ± S.D. (n = 4).
Figure 3 In Vitro SDT efficacy of T-mTNPs@L-Arg. (A) The destruction of mitochondria in MCF-7 cells after various treatments detected by CLSM, scale bar=10 nm. Cytotoxicity of different nanoparticles towards MCF-7 cells in the absence (B) or presence (C) of US stimulus. (D) Cell viability of hypoxic MCF-7 cells after treated with different nanoparticles in the presence of US. (E) CLSM images of MCF-7 cells stained with DCFH-DA in various groups, scale bar=10 nm. (F) ROS generation in various groups detected by FACS (“H” represents hypoxia). The data are presented as the mean ± S.D. (n = 4).CC BY-NC · PubMed Central
Figure 4 In Vivo SDT efficacy of T-mTNPs@L-Arg. (A) Biodistribution of T-mTNPs@L-Arg in MCF-7 tumor-bearing mice after intravenous injection at different time points. (B) Immunofluorescence images of tumors in various treatments on day 6. Tumor hypoxia was detected by Pimonidazole binding of HIF-1α antibody staining, scale bar=50 nm. (C) FACS assay of hypoxic area in tumor tissues. *p < 0.05 versus the control groups, #p < 0.05 versus mTNPs@L-Arg. (D) Tumor photographs. (E) Tumor volume. *p < 0.05 versus mTNPs@L-Arg. (F) Tumor weight. *p < 0.05 versus the control groups, #p < 0.05 versus mTNPs@L-Arg. All the data are presented as the mean ± S.D. (n = 4).
Figure 4 In Vivo SDT efficacy of T-mTNPs@L-Arg. (A) Biodistribution of T-mTNPs@L-Arg in MCF-7 tumor-bearing mice after intravenous injection at different time points. (B) Immunofluorescence images of tumors in various treatments on day 6. Tumor hypoxia was detected by Pimonidazole binding of HIF-1α antibody staining, scale bar=50 nm. (C) FACS assay of hypoxic area in tumor tissues. *p < 0.05 versus the control groups, #p < 0.05 versus mTNPs@L-Arg. (D) Tumor photographs. (E) Tumor volume. *p < 0.05 versus mTNPs@L-Arg. (F) Tumor weight. *p < 0.05 versus the control groups, #p < 0.05 versus mTNPs@L-Arg. All the data are presented as the mean ± S.D. (n = 4).CC BY-NC · PubMed Central
Figure 5 Evaluation of the systemic toxicity: (A) body weight. (B–E) blood biochemistry indicators include (B) alanine aminotransferase (ALT), (C) aspartate aminotransferase (AST), (D) blood urea nitrogen (BUN), and (E) creatinine (CRE). Data are presented as the mean ± S.D. (n = 4).
Figure 5 Evaluation of the systemic toxicity: (A) body weight. (B–E) blood biochemistry indicators include (B) alanine aminotransferase (ALT), (C) aspartate aminotransferase (AST), (D) blood urea nitrogen (BUN), and (E) creatinine (CRE). Data are presented as the mean ± S.D. (n = 4).CC BY-NC · PubMed Central
Figure 6 H&E staining images of the heart, liver, spleen, lung, and kidney from mice in various treatments, scale bar=100 nm.
Figure 6 H&E staining images of the heart, liver, spleen, lung, and kidney from mice in various treatments, scale bar=100 nm.CC BY-NC · PubMed Central

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Metadata

Authors
Zuo, S., Zhang, Y., Wang, Z., & Wang, J.
Affiliations
Jilin University (CN)
Corresponding author
Wang, Jing
ORCID
Zhang, Yan
Venue
International Journal of Nanomedicine
Publisher
Informa UK Limited
Published
2022-03
Volume
Volume 17
Pages
989-1002
ISSN
  • 1176-9114 (ISSN-L)
  • 1178-2013
DOI
10.2147/ijn.s348618
PMC
PMC8906874
OpenAlex
W4214871068
Cited by
41
References
0
Citations by year
2026: 5 · 2025: 9 · 2024: 6 · 2023: 14 · 2022: 7
FWCI
2.62
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Nanomedicine (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
Funders
People's Government of Jilin Province
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Photodynamic Therapy Research Studies
  • Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
Keywords
sonodynamic therapy, breast cancer, mitochondrial targeting, mesoporous TiO2, L-arginine, tumor hypoxia, reactive oxygen species, reactive nitrogen species, mitochondrial respiration inhibition, ultrasound-triggered drug release, synergistic cancer therapy
MeSH terms
Humans, Mitochondria, Neoplasms, Nitric Oxide, Titanium

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