Skip to main content
SpringerLink
Log in

Autophagy inhibitor-loaded mesoporous AgNPs@SiO2 nanoplatform for synergistically enhanced glioma radiotherapy

装载自噬抑制剂的纳米银核介孔硅协同增强胶质瘤放疗

  • Articles
  • Published:
Science China Materials Aims and scope Submit manuscript

Abstract

Our previous studies demonstrated that silver nanoparticles (AgNPs) could be used as a potential radio-sensitizer for glioma radiotherapy enhancement, which, however, is restricted by autophagy elicitation. As one of the most promising drug-delivery carriers, mesoporous silica nanospheres (MSNs) have made great contributions to the developments of biomedicine due to their excellent drug loading performance, inherent biocompatibility, and tunable pore size. Herein, we designed autophagy inhibitor (3-methyladenine)-loaded AgNPs-cored MSNs, which exhibited excellent synergistic anticancer efficacy in vitro and in vivo. Besides, it was also confirmed that by inhibition of autophagy, the outcome of radiotherapy can be further enhanced. Moreover, we also explored the enhancing mechanisms from the perspective of the nuclear transcription factor Nrf2, including autophagy inhibition-related enhancement of radiation induced oxidative stress injury and the interaction of Nrf2 with autophagy. This study provided a vision of utilizing AgNPs as a potential radiosensitizer in combination with autophagy inhibitor and proposed a feasible strategy for its translation into the clinic.

摘要

先前研究表明, 银纳米颗粒可作为潜在的胶质瘤放疗的增敏剂, 但这一作用受到自噬的限制. 作为最有前途的药物递送载体之一, 介孔二氧化硅纳米球由于其优异的药物负载性能、 固有的生物相容性和可调节的孔径, 对生物医学的发展做出了巨大贡献. 在此, 我们设计了一种负载自噬抑制剂3-甲基腺嘌呤的纳米银核介孔二氧化硅纳米球, 其在体外和体内均表现出优异的协同抗癌作用. 并且证实了抑制自噬可以进一步改善胶质瘤放疗的效果. 此外, 还从与氧化应激相关的核转录因子Nrf2的角度探讨了可能的机制, 包括自噬抑制增强辐射诱导的氧化应激损伤以及Nrf2与自噬的相互作用. 这项研究为将纳米银作为与自噬抑制剂结合用于胶质瘤放射增敏提供了一个愿景, 并为其临床转化提供了一种可行的策略.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Björkblom B, Wibom C, Eriksson M, et al. Distinct metabolic hallmarks of WHO classified adult glioma subtypes. Neuro-Oncology, 2022, 24: 1454–1468

    Google Scholar 

  2. Ostrom QT, Cote DJ, Ascha M, et al. Adult glioma incidence and survival by race or ethnicity in the united states from 2000 to 2014. JAMA Oncol, 2018, 4: 1254

    Google Scholar 

  3. Fleischmann DF, Schön R, Corradini S, et al. Multifocal high-grade glioma radiotherapy safety and efficacy. Radiat Oncol, 2021, 16: 165

    Google Scholar 

  4. Griveau A, Seano G, Shelton SJ, et al. A glial signature and Wnt7 signaling regulate glioma-vascular interactions and tumor microenvironment. Cancer Cell, 2018, 33: 874–889.e7

    CAS  Google Scholar 

  5. Wang Z, Zhan M, Hu X. Pulsed laser excited photoacoustic effect for disease diagnosis and therapy. Chem Eur J, 2022, 28

  6. Zhao J, Liu P, Ma J, et al. Enhancement of radiosensitization by silver nanoparticles functionalized with polyethylene glycol and aptamer As1411 for glioma irradiation therapy. IJN, 2019, Volume 14: 9483–9496

    CAS  Google Scholar 

  7. Yang X, Gao L, Guo Q, et al. Nanomaterials for radiotherapeutics-based multimodal synergistic cancer therapy. Nano Res, 2020, 13: 2579–2594

    CAS  Google Scholar 

  8. Chaloupka K, Malam Y, Seifalian AM. Nanosilver as a new generation of nanoproduct in biomedical applications. Trends Biotechnol, 2010, 28: 580–588

    CAS  Google Scholar 

  9. Chen X, Schluesener HJ. Nanosilver: A nanoproduct in medical application. Toxicol Lett, 2008, 176: 1–12

    CAS  Google Scholar 

  10. Liu PD, Jin H, Guo Z, et al. Silver nanoparticles outperform gold nanoparticles in radiosensitizing U251 cells in vitro and in an intracranial mouse model of glioma. IJN, 2016, Volume 11: 5003–5014

    CAS  Google Scholar 

  11. Hsin YH, Chen CF, Huang S, et al. The apoptotic effect of nanosilver is mediated by a ROS- and JNK-dependent mechanism involving the mitochondrial pathway in NIH3T3 cells. Toxicol Lett, 2008, 179: 130–139

    CAS  Google Scholar 

  12. Soumya RS, Hela PG. Nano silver based targeted drug delivery for treatment of cancer. Der Pharm Lettre, 2013, 5: 189–197

    CAS  Google Scholar 

  13. Rubinsztein DC, Mariño G, Kroemer G. Autophagy and aging. Cell, 2011, 146: 682–695

    CAS  Google Scholar 

  14. Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer, 2017, 17: 528–542

    CAS  Google Scholar 

  15. Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer, 2007, 7: 961–967

    CAS  Google Scholar 

  16. Liu P, Huang Z, Chen Z, et al. Silver nanoparticles: A novel radiation sensitizer for glioma? Nanoscale, 2013, 5: 11829–11836

    CAS  Google Scholar 

  17. Wu H, Lin J, Liu P, et al. Is the autophagy a friend or foe in the silver nanoparticles associated radiotherapy for glioma? Biomaterials, 2015, 62: 47–57

    CAS  Google Scholar 

  18. Wu H, Lin J, Liu P, et al. Reactive oxygen species acts as executor in radiation enhancement and autophagy inducing by AgNPs. Biomaterials, 2016, 101: 1–9

    CAS  Google Scholar 

  19. Lin J, Huang Z, Wu H, et al. Inhibition of autophagy enhances the anticancer activity of silver nanoparticles. Autophagy, 2014, 10: 2006–2020

    Google Scholar 

  20. Lin J, Liu Y, Wu H, et al. Key role of TFEB nucleus translocation for silver nanoparticle-induced cytoprotective autophagy. Small, 2018, 14: 1703711

    Google Scholar 

  21. Zhu L, Guo D, Sun L, et al. Activation ofautophagy by elevated reactive oxygen species rather than released silver ions promotes cytotoxicity of polyvinylpyrrolidone-coated silver nanoparticles in hematopoietic cells. Nanoscale, 2017, 9: 5489–5498

    CAS  Google Scholar 

  22. Pan L, He Q, Liu J, et al. Nuclear-targeted drug delivery of TAT pep-tide-conjugated monodisperse mesoporous silica nanoparticles. J Am Chem Soc, 2012, 134: 5722–5725

    CAS  Google Scholar 

  23. Wan X, Liu T, Hu J, et al. Photo-degradable, protein-polyelectrolyte complex-coated, mesoporous silica nanoparticles for controlled co-release of protein and model drugs. Macromol Rapid Commun, 2013, 34: 341–347

    CAS  Google Scholar 

  24. Wu T, Ge Z, Liu S. Fabrication of thermoresponsive cross-linked poly-(N-isopropylacrylamide) nanocapsules and silver nanoparticle-embedded hybrid capsules with controlled shell thickness. Chem Mater, 2011, 23: 2370–2380

    CAS  Google Scholar 

  25. Tarn D, Ashley CE, Xue M, et al. Mesoporous silica nanoparticle nanocarriers: Biofunctionality and biocompatibility. Acc Chem Res, 2013, 46: 792–801

    CAS  Google Scholar 

  26. Li Z, Barnes JC, Bosoy A, et al. Mesoporous silica nanoparticles in biomedical applications. Chem Soc Rev, 2012, 41: 2590–2605

    CAS  Google Scholar 

  27. Manzano M, Vallet-Regí M. Mesoporous silica nanoparticles for drug delivery. Adv Funct Mater, 2020, 30: 1902634

    CAS  Google Scholar 

  28. Han L, Wei H, Tu B, et al. A facile one-pot synthesis of uniform core-shell silver nanoparticle@mesoporous silica nanospheres. Chem Commun, 2011, 47: 8536–8538

    CAS  Google Scholar 

  29. Wang Y, Ding X, Chen Y, et al. Antibiotic-loaded, silver core-embedded mesoporous silica nanovehicles as a synergistic antibacterial agent for the treatment of drug-resistant infections. Biomaterials, 2016, 101: 207–216

    CAS  Google Scholar 

  30. Zheng N, Liu P. Amine facilitates the synthesis of silica-supported ultrasmall bimetallic nanoparticles. Sci China Mater, 2018, 61: 1129–1131

    CAS  Google Scholar 

  31. Che S, Liu Z, Ohsuna T, et al. Synthesis and characterization of chiral mesoporous silica. Nature, 2004, 429: 281–284

    CAS  Google Scholar 

  32. Thomassen LCJ, Aerts A, Rabolli V, et al. Synthesis and characterization of stable monodisperse silica nanoparticle sols for in vitro cyto-toxicity testing. Langmuir, 2010, 26: 328–335

    CAS  Google Scholar 

  33. Jing M, Li Y, Wang M, et al. Photoresponsive PAMAM-assembled nanocarrier loaded with autophagy inhibitor for synergistic cancer therapy. Small, 2021, 17: 2102295

    CAS  Google Scholar 

  34. Zhang Y, Zhi Z, Jiang T, et al. Spherical mesoporous silica nano-particles for loading and release of the poorly water-soluble drug telmisartan. J Control Release, 2010, 145: 257–263

    CAS  Google Scholar 

  35. Huang S, Ma P’, Wei Y, et al. Controllable synthesis of hollow porous silica nanotubes/CuS nanoplatform for targeted chemo-photothermal therapy. Sci China Mater, 2020, 63: 864–875

    CAS  Google Scholar 

  36. El Yamani N, Mariussen E, Gromelski M, et al. Hazard identification of nanomaterials: In silico unraveling of descriptors for cytotoxicity and genotoxicity. Nano Today, 2022, 46: 101581

    CAS  Google Scholar 

  37. Chen X, Zhang M, Gan H, et al. A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma. Nat Commun, 2018, 9: 2949

    Google Scholar 

  38. Yang Y, Wang Q, Song L, et al. Uptake of magnetic nanoparticles for adipose-derived stem cells with multiple passage numbers. Sci China Mater, 2017, 60: 892–902

    CAS  Google Scholar 

  39. Wang G, Song W, Shen N, et al. Curcumin-encapsulated polymeric nanoparticles for metastatic osteosarcoma cells treatment. Sci China Mater, 2017, 60: 995–1007

    CAS  Google Scholar 

  40. Liu C, Sun S, Feng Q, et al. Arsenene nanodots with selective killing effects and their low-dose combination with β-elemene for cancer therapy. Adv Mater, 2021, 33: 2102054

    CAS  Google Scholar 

  41. Wang X, Zhong X, Li J, et al. Inorganic nanomaterials with rapid clearance for biomedical applications. Chem Soc Rev, 2021, 50: 8669–8742

    CAS  Google Scholar 

  42. Mukha A, Kahya U, Dubrovska A. Targeting glutamine metabolism and autophagy: The combination for prostate cancer radiosensitization. Autophagy, 2021, 17: 3879–3881

    CAS  Google Scholar 

  43. Vera-Ramirez L, Vodnala SK, Nini R, et al. Autophagy promotes the survival of dormant breast cancer cells and metastatic tumour recurrence. Nat Commun, 2018, 9: 1–2

    CAS  Google Scholar 

  44. Chen Q, He S, Zhang F, et al. A versatile Pt-Ce6 nanoplatform as catalase nanozyme and NIR-II photothermal agent for enhanced PDT/PTT tumor therapy. Sci China Mater, 2021, 64: 510–530

    CAS  Google Scholar 

  45. Xia H, Green DR, Zou W. Autophagy in tumour immunity and therapy. Nat Rev Cancer, 2021, 21: 281–297

    CAS  Google Scholar 

  46. Bourdenx M, Martín-Segura A, Scrivo A, et al. Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome. Cell, 2021, 184: 2696–2714.e25

    CAS  Google Scholar 

  47. Shi J, Wang D, Ma Y, et al. Photoactivated self-disassembly of multifunctional DNA nanoflower enables amplified autophagy suppression for low-dose photodynamic therapy. Small, 2021, 17: 2104722

    CAS  Google Scholar 

  48. Clement S, Campbell JM, Deng W, et al. Mechanisms for tuning engineered nanomaterials to enhance radiation therapy of cancer. Adv Sci, 2020, 7: 2003584

    CAS  Google Scholar 

  49. Maremonti E, Eide DM, Rossbach LM, et al. In vivo assessment of reactive oxygen species production and oxidative stress effects induced by chronic exposure to gamma radiation in Caenorhabditis elegans. Free Radical Biol Med, 2020, 152: 583–596

    CAS  Google Scholar 

  50. Pisoschi AM, Pop A, Iordache F, et al. Oxidative stress mitigation by antioxidants—An overview on their chemistry and influences on health status. Eur J Medicinal Chem, 2021, 209: 112891

    CAS  Google Scholar 

  51. Liu Z, Tan H, Zhang X, et al. Enhancement of radiotherapy efficacy by silver nanoparticles in hypoxic glioma cells. Artif Cells Nanomed Bio-technol, 2018, 46: 922–930

    CAS  Google Scholar 

  52. Li Y, Yan D, Fu F, et al. Composite core-shell microparticles from microfluidics for synergistic drug delivery. Sci China Mater, 2017, 60: 543–553

    CAS  Google Scholar 

  53. Toulany M. Targeting DNA double-strand break repair pathways to improve radiotherapy response. Genes, 2019, 10: 25

    Google Scholar 

  54. Li H, Yang Y, Hong W, et al. Applications of genome editing technology in the targeted therapy of human diseases: Mechanisms, advances and prospects. Sig Transduct Target Ther, 2020, 5: 1–27

    Google Scholar 

  55. Singh I, Ozturk N, Cordero J, et al. High mobility group proteinmediated transcription requires DNA damage marker γ-H2AX. Cell Res, 2015, 25: 837–850

    CAS  Google Scholar 

  56. Goutas A, Syrrou C, Papathanasiou I, et al. The autophagic response to oxidative stress in osteoarthritic chondrocytes is deregulated. Free Radical Biol Med, 2018, 126: 122–132

    CAS  Google Scholar 

  57. Rojo de la Vega M, Chapman E, Zhang DD. Nrf2 and the hallmarks of cancer. Cancer Cell, 2018, 34: 21–43

    CAS  Google Scholar 

  58. Tonelli C, Chio IIC, Tuveson DA. Transcriptional regulation by Nrf2. Antioxid Redox Signal, 2018, 29: 1727–1745

    CAS  Google Scholar 

  59. Lu J, Wang R, Shen L, et al. Enabling topical and long-term anti-radical properties for percutaneous coronary intervention-related complications by incorporating TEMPOL into electrospun nanofibers. Sci China Mater, 2021, 64: 769–782

    CAS  Google Scholar 

  60. McDonald JT, Kim K, Norris AJ, et al. Ionizing radiation activates the Nrf2 antioxidant response. Cancer Res, 2010, 70: 8886–8895

    CAS  Google Scholar 

  61. Sun X, Yang Y, Shi J, et al. NOX4- and Nrf2-mediated oxidative stress induced by silver nanoparticles in vascular endothelial cells. J Appl Toxicol, 2017, 37: 1428–1437

    CAS  Google Scholar 

  62. Ichimura Y, Waguri S, Sou Y, et al. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell, 2013, 51: 618–631

    CAS  Google Scholar 

  63. Walker A, Singh A, Tully E, et al. Nrf2 signaling and autophagy are complementary in protecting breast cancer cells during glucose deprivation. Free Radical Biol Med, 2018, 120: 407–413

    CAS  Google Scholar 

  64. Towers CG, Fitzwalter BE, Regan D, et al. Cancer cells upregulate Nrf2 signaling to adapt to autophagy inhibition. Dev Cell, 2019, 50: 690–703.e6

    CAS  Google Scholar 

  65. Lv H, Yang H, Wang Z, et al. Nrf2 signaling and autophagy are complementary in protecting lipopolysaccharide/d-galactosamine-induced acute liver injury by licochalcone A. Cell Death Dis, 2019, 10: 313

    Google Scholar 

  66. Tao S, Zhang H, Xue L, et al. Vitamin D protects against particles-caused lung injury through induction of autophagy in an Nrf2-dependent manner. Environ Toxicol, 2019, 34: 594–609

    CAS  Google Scholar 

  67. Tao S, Wang S, Moghaddam SJ, et al. Oncogenic KRAS confers chemoresistance by upregulating Nrf2. Cancer Res, 2014, 74: 7430–7441

    CAS  Google Scholar 

  68. Guan L, Zhang L, Gong Z, et al. FoxO3 inactivation promotes human cholangiocarcinoma tumorigenesis and chemoresistance through Keap1-Nrf2 signaling. Hepatology, 2016, 63: 1914–1927

    CAS  Google Scholar 

Download references

Acknowledgements

We highly appreciate financial supports from the National Key Research and Development Program of China (2019YFA0210103 and 2017YFA0104302), the National Natural Science Foundation of China (81901873, 51832001, and 81971701), the National Key Laboratory of Science and Technology on Strong Electromagnetic Environment Simulation and Protection (6142205190402), the Natural Science Foundation of Jiangsu Province (BK20201352), and the Program of Jiangsu Specially Appointed Professor.

Author information

Authors and Affiliations

  1. School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, 211166, China

    Hao Wu  (吴昊), Yuehui Yuan  (袁月辉), Shixiong Kang  (康世雄), Gaoxin Zhou  (周高信), Yue Gu  (谷越), Xingyi Yuan  (袁星怡), Jiajie Li  (李嘉婕) & Ning Gu  (顾宁)

  2. Medical School, Nanjing University, Nanjing, 210093, China

    Ning Gu  (顾宁)

Authors
  1. Hao Wu  (吴昊)
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuehui Yuan  (袁月辉)
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shixiong Kang  (康世雄)
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gaoxin Zhou  (周高信)
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yue Gu  (谷越)
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xingyi Yuan  (袁星怡)
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jiajie Li  (李嘉婕)
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ning Gu  (顾宁)
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Author contributions Wu H designed and performed the experiments and wrote the paper; Gu N proposed the concept and supervised this study. All authors contributed to the general discussion and revision of the manuscript.

Corresponding author

Correspondence to Ning Gu  (顾宁).

Ethics declarations

Conflict of interest The authors declare that they have no conflict of interest.

Additional information

Supplementary information Supporting data are available in the online version of the paper.

Hao Wu received his PhD degree from Southeast University in 2016. He is now a lecturer at the School of Biomedical Engineering and Informatics, Nanjing Medical University. His research focuses on biological effects of nanomaterials and electromagnetic fields.

Ning Gu was born in 1964. He received his PhD degree in biomedical engineering from the Department of Biomedical Engineering, Southeast University, Nanjing, China, in 1996. Currently he is an academician of the Chinese Academy of Sciences, Changjiang Scholar Professor and NSFC Outstanding Young Investigator Fund Winner at the School of Medical, Nanjing University. His research interests include biomaterials, nanobiology, medical imaging, and advanced instrument development.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, H., Yuan, Y., Kang, S. et al. Autophagy inhibitor-loaded mesoporous AgNPs@SiO2 nanoplatform for synergistically enhanced glioma radiotherapy. Sci. China Mater. 66, 2902–2912 (2023). https://doi.org/10.1007/s40843-022-2395-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40843-022-2395-y

Keywords

Search

Navigation