Skip to main content
SpringerLink
Log in

Designing highly UV-emitting lanthanide nanoscintillators for in vivo X-ray-activated tumor therapy

高效X射线紫外发光稀土纳米闪烁体及其活体X射线激活肿瘤治疗应用

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

Abstract

X-ray nanoscintillator-based photoresponsive therapy is emerging as a promising strategy to treat in vivo tumors, necessitating the development of nanoscintillators with X-ray-excited luminescence in the ultraviolet region (UV-XEL) for the photoactivation of therapeutic precursors. However, it remains a challenge to achieve high-efficiency X-ray-activated tumor therapy due to the limited UV-XEL efficacy. Herein, we developed novel Gd3+/Ce3+-codoped LiLuF4 nanoscintillators with strong UV-XEL for in vivo tumor therapy. Significantly, through optimization of host materials, dopants, and energy transfer process, the developed nanoscintillators enabled effective enhancement of UV-XEL (up to 18-fold) as compared with the traditional Ce3+-doped counterparts. As a proof-of-concept study to evaluate the in vivo therapeutic applications of the nanoscintillators, we integrated them with nitric oxide (NO) precursors for controllably generating NO upon the X-ray exposure, achieving superior in vivo antitumor effect upon X-ray-induced synergetic NO therapy and radiotherapy. Moreover, X-ray-activated NO therapy can inhibit tumor metastasis into liver to suppress tumor regrowth and prolong mice survival. This work might motivate future development of X-ray nanoscintillators for treating diseases in deep tissue.

摘要

基于X射线纳米闪烁体的光响应疗法是一种新兴的有良好应用前景的活体肿瘤治疗策略, 迫切需要开发具有高效X射线激发紫外发光性能的纳米闪烁体. 然而, 由于当前纳米闪烁体的X射线紫外发光性能仍较弱, 实现高效的X射线激活肿瘤治疗仍然是一个巨大的挑战. 为此, 我们发展了一种新型的具有良好X射线紫外发光性能的Gd3+/Ce3+共掺杂的LiLuF 4 纳米闪烁体, 并将其应用于活体肿瘤治疗. 通过优化基质材料、 掺杂剂和能量传递设计合成的纳米闪烁体, 其X射线紫外发光强度比传统的Ce3+单掺杂材料增强了约18倍. 我们进一步将纳米闪烁体与一氧化氮(NO)前体结合以概念验证研究纳米闪烁体的应用. 在X射线照射下, 该纳米复合物能够可控地产生NO, 并在X射线诱导的NO和放射治疗协同作用下实现了优异的抗肿瘤效果. 此外, X射线激活的NO治疗可以抑制肿瘤向肝脏转移, 抑制肿瘤再生, 延长小鼠存活率. 这项工作有望推动纳米闪烁体的发展及其在活体深层组织疾病治疗中的应用.

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

Similar content being viewed by others

References

  1. McGregor DS. Materials for gamma-ray spectrometers: Inorganic scintillators. Annu Rev Mater Res, 2018, 48: 245–277

    CAS  Google Scholar 

  2. Ashworth C. Super scintillators. Nat Rev Mater, 2018, 3: 355

    Google Scholar 

  3. Zhou Y, Chen J, Bakr OM, et al. Metal halide perovskites for X-ray imaging scintillators and detectors. ACS Energy Lett, 2021, 6: 739–768

    CAS  Google Scholar 

  4. Li Z, Zhou F, Yao HH, et al. Halide perovskites for high-performance X-ray detector. Mater Today, 2021, 48: 155–175

    Google Scholar 

  5. Chen Q, Wu J, Ou X, et al. All-inorganic perovskite nanocrystal scintillators. Nature, 2018, 561: 88–93

    CAS  Google Scholar 

  6. Zhou Z, Song J, Nie L, et al. Reactive oxygen species generating systems meeting challenges of photodynamic cancer therapy. Chem Soc Rev, 2016, 45: 6597–6626

    CAS  Google Scholar 

  7. Liang H, Hong Z, Li S, et al. An activatable X-ray scintillating luminescent nanoprobe for early diagnosis and progression monitoring of thrombosis in live rat. Adv Funct Mater, 2021, 31: 2006353

    CAS  Google Scholar 

  8. Sun W, Zhou Z, Pratx G, et al. Nanoscintillator-mediated X-ray induced photodynamic therapy for deep-seated tumors: From concept to biomedical applications. Theranostics, 2020, 10: 1296–1318

    Google Scholar 

  9. He L, Yu X, Li W. Recent progress and trends in X-ray-induced photodynamic therapy with low radiation doses. ACS Nano, 2022, 16: 19691–19721

    CAS  Google Scholar 

  10. Lu L, Sun M, Lu Q, et al. High energy X-ray radiation sensitive scintillating materials for medical imaging, cancer diagnosis and therapy. Nano Energy, 2021, 79: 105437

    CAS  Google Scholar 

  11. Fan W, Tang W, Lau J, et al. Breaking the depth dependence by nanotechnology-enhanced X-ray-excited deep cancer theranostics. Adv Mater, 2019, 31: 1806381

    Google Scholar 

  12. Fan W, Yung BC, Chen X. Stimuli-responsive NO release for on-demand gas-sensitized synergistic cancer therapy. Angew Chem Int Ed, 2018, 57: 8383–8394

    CAS  Google Scholar 

  13. Xie Z, Fan T, An J, et al. Emerging combination strategies with phototherapy in cancer nanomedicine. Chem Soc Rev, 2020, 49: 8065–8087

    CAS  Google Scholar 

  14. Zhou S, Li D, Lee C, et al. Nanoparticle phototherapy in the era of cancer immunotherapy. Trends Chem, 2020, 2: 1082–1095

    CAS  Google Scholar 

  15. Chen Q, Chen M, Liu Z. Local biomaterials-assisted cancer immunotherapy to trigger systemic antitumor responses. Chem Soc Rev, 2019, 48: 5506–5526

    CAS  Google Scholar 

  16. Zheng L, Zhu R, Chen L, et al. X-ray sensitive high-Z metal nanocrystals for cancer imaging and therapy. Nano Res, 2021, 14: 3744–3755

    CAS  Google Scholar 

  17. Zhang Y, Xu C, Yang X, et al. Photoactivatable protherapeutic nanomedicine for cancer. Adv Mater, 2020, 32: 2002661

    CAS  Google Scholar 

  18. Du Z, Zhang X, Guo Z, et al. X-ray-controlled generation of peroxynitrite based on nanosized LiLuF4:Ce3+ scintillators and their applications for radiosensitization. Adv Mater, 2018, 30: 1804046

    Google Scholar 

  19. Grajcarek J, Monlong J, Nishinaka-Arai Y, et al. Genome-wide microhomologies enable precise template-free editing of biologically relevant deletion mutations. Nat Commun, 2019, 10: 4856

    Google Scholar 

  20. Wang C, Cheng L, Liu Z. Upconversion nanoparticles for photodynamic therapy and other cancer therapeutics. Theranostics, 2013, 3: 317–330

    Google Scholar 

  21. Li J, Duan H, Pu K. Nanotransducers for near-infrared photoregulation in biomedicine. Adv Mater, 2019, 31: 1901607

    Google Scholar 

  22. Chen X, Song J, Chen X, et al. X-ray-activated nanosystems for theranostic applications. Chem Soc Rev, 2019, 48: 3073–3101

    CAS  Google Scholar 

  23. Ding B, Sheng J, Zheng P, et al. Biodegradable upconversion nanoparticles induce pyroptosis for cancer immunotherapy. Nano Lett, 2021, 21: 8281–8289

    CAS  Google Scholar 

  24. Bünzli JCG. Lanthanide-doped nanoscintillators. Light Sci Appl, 2022, 11: 285

    Google Scholar 

  25. Jiang M, Deng Z, Zeng S, et al. Recent progress on lanthanide scintillators for soft X-ray-triggered bioimaging and deep-tissue theranostics. VIEW, 2021, 2: 20200122

    CAS  Google Scholar 

  26. Ou X, Qin X, Huang B, et al. High-resolution X-ray luminescence extension imaging. Nature, 2021, 590: 410–415

    CAS  Google Scholar 

  27. Matsubara T, Yanagida T, Kawaguchi N, et al. Remote control of neural function by X-ray-induced scintillation. Nat Commun, 2021, 12: 4487

    Google Scholar 

  28. Ning Y, Zhu M, Zhang JL. Near-infrared (NIR) lanthanide molecular probes for bioimaging and biosensing. Coord Chem Rev, 2019, 399: 213028

    CAS  Google Scholar 

  29. Squillante MR, Jüstel T, Anderson RR, et al. Fabrication and characterization of UV-emitting nanoparticles as novel radiation sensitizers targeting hypoxic tumor cells. Optical Mater, 2018, 80: 197–202

    CAS  Google Scholar 

  30. Nakamura F, Kato T, Okada G, et al. Scintillation, dosimeter and optical properties of MgF2 transparent ceramics doped with Gd3+. Mater Res Bull, 2018, 98: 83–88

    CAS  Google Scholar 

  31. Bulin A, Broekgaarden M, Chaput F, et al. Radiation dose-enhancement is a potent radiotherapeutic effect of rare-earth composite nanoscintillators in preclinical models of glioblastoma. Adv Sci, 2020, 7: 2001675

    CAS  Google Scholar 

  32. Bartley AF, Fischer M, Bagley ME, et al. Feasibility of cerium-doped LSO particles as a scintillator for X-ray induced optogenetics. J Neural Eng, 2021, 18: 046036

    Google Scholar 

  33. Wang H, Lv B, Tang Z, et al. Scintillator-based nanohybrids with sacrificial electron prodrug for enhanced X-ray-induced photodynamic therapy. Nano Lett, 2018, 18: 5768–5774

    CAS  Google Scholar 

  34. Liu S, Fang L, Ding H, et al. Alternative strategy to optimize cerium oxide for enhanced X-ray-induced photodynamic therapy. ACS Nano, 2022, 16: 20805–20819

    CAS  Google Scholar 

  35. Liu S, Li W, Zhang Y, et al. Tailoring silica-based nanoscintillators for peroxynitrite-potentiated nitrosative stress in postoperative radiotherapy of colon cancer. Nano Lett, 2022, 22: 6409–6417

    CAS  Google Scholar 

  36. Du Z, Wang X, Zhang X, et al. X-ray-triggered carbon monoxide and manganese dioxide generation based on scintillating nanoparticles for cascade cancer radiosensitization. Angew Chem Int Ed, 2023, 62: e202302525

    CAS  Google Scholar 

  37. Steeg PS. Tumor metastasis: Mechanistic insights and clinical challenges. Nat Med, 2006, 12: 895–904

    CAS  Google Scholar 

  38. Bakir B, Chiarella AM, Pitarresi JR, et al. EMT, MET, plasticity, and tumor metastasis. Trends Cell Biol, 2020, 30: 764–776

    Google Scholar 

  39. Zhang Z, Wang H, Tan T, et al. Rational design of nanoparticles with deep tumor penetration for effective treatment of tumor metastasis. Adv Funct Mater, 2018, 28: 1801840

    Google Scholar 

  40. Kong X, Cheng R, Wang J, et al. Nanomedicines inhibiting tumor metastasis and recurrence and their clinical applications. Nano Today, 2021, 36: 101004

    CAS  Google Scholar 

  41. Pokorný M, Babin V, Beitlerová A, et al. Gd-admixed (Lu,Gd)AlO3 single crystals: Breakthrough in heavy perovskite scintillators. NPG Asia Mater, 2021, 13: 66

    Google Scholar 

  42. Sun B, Xie Y, Zhao Y, et al. A highly robust Ce3+-doped and Gd3+-mixed KLaF4 nano-glass composite scintillator. J Mater Chem C, 2021, 9: 17504–17510

    CAS  Google Scholar 

  43. Lei L, Wang Y, Xu W, et al. Manipulation of time-dependent multicolour evolution of X-ray excited afterglow in lanthanide-doped fluoride nanoparticles. Nat Commun, 2022, 13: 5739

    CAS  Google Scholar 

  44. Thoma RE, Insley H, Hebert GM. The sodium fluoride-lanthanide trifluoride systems. Inorg Chem, 1966, 5: 1222–1229

    CAS  Google Scholar 

  45. Richard C, Viana B. Persistent X-ray-activated phosphors: Mechanisms and applications. Light Sci Appl, 2022, 11: 123

    CAS  Google Scholar 

  46. Naccache R, Yu Q, Capobianco JA. The fluoride host: Nucleation, growth, and upconversion of lanthanide-doped nanoparticles. Adv Opt Mater, 2015, 3: 482–509

    CAS  Google Scholar 

  47. Huang P, Zheng W, Tu D, et al. Unraveling the electronic structures of neodymium in LiLuF4 nanocrystals for ratiometric temperature sensing. Adv Sci, 2019, 6: 1802282

    Google Scholar 

  48. Maurizio SL, Mandl GA, Long MD, et al. Investigating the fundamental material properties that influence the radioluminescence of lanthanide-doped nanoparticles. Chem Mater, 2022, 34: 10123–10132

    CAS  Google Scholar 

  49. Shalapska T, Stryganyuk G, Demchenko P, et al. Luminescence properties of Ce3+-doped LiGdP4O12 upon vacuum-ultraviolet and X-ray excitation. J Phys-Condens Matter, 2009, 21: 445901

    CAS  Google Scholar 

  50. Demchenko P, Gektin A, Krasnikov A, et al. Energy migration and Gd3+ ↔ Ce3+ transfer in Ce3+-doped GdP3O9 metaphosphate. J Phys D-Appl Phys, 2013, 46: 235103

    Google Scholar 

  51. Kucera M, Rathaiah M, Beitlerova A, et al. Scintillation properties and energy transfer in (GdY)AlO3Ce3+ perovskites with high Gd content. IEEE Trans Nucl Sci, 2020, 67: 1049–1054

    CAS  Google Scholar 

  52. Bartosiewicz K, Babin V, Kamada K, et al. Energy migration processes in undoped and Ce-doped multicomponent garnet single crystal scintillators. J Lumin, 2015, 166: 117–122

    CAS  Google Scholar 

  53. Rathaiah M, Kucera M, Pejchal J, et al. Epitaxial growth, photoluminescence and scintillation properties of Gd3+ co-doped YAlO3:Ce3+ films. Radiat Measurements, 2019, 121: 86–90

    CAS  Google Scholar 

  54. Xu Y, Liu J, Liu Z, et al. Blockade of platelets using tumor-specific NO-releasing nanoparticles prevents tumor metastasis and reverses tumor immunosuppression. ACS Nano, 2020, 14: 9780–9795

    CAS  Google Scholar 

  55. Li S, Li L, Lin X, et al. Targeted inhibition of tumor inflammation and tumor-platelet crosstalk by nanoparticle-mediated drug delivery mitigates cancer metastasis. ACS Nano, 2021, 16: 50–67

    CAS  Google Scholar 

  56. Shi M, Zhang J, Wang Y, et al. Tumor-specific nitric oxide generator to amplify peroxynitrite based on highly penetrable nanoparticles for metastasis inhibition and enhanced cancer therapy. Biomaterials, 2022, 283: 121448

    CAS  Google Scholar 

  57. Salvati A, Åberg C, dos Santos T, et al. Experimental and theoretical comparison of intracellular import of polymeric nanoparticles and small molecules: Toward models of uptake kinetics. Nanomed-Nanotechnol Biol Med, 2011, 7: 818–826

    CAS  Google Scholar 

  58. Song X, Li S, Guo H, et al. Graphene-oxide-modified lanthanide nanoprobes for tumor-targeted visible/NIR-II luminescence imaging. Angew Chem Intl Edit, 2019, 58: 18981–18986

    CAS  Google Scholar 

  59. Song L, Li PP, Yang W, et al. Low-dose X-ray activation of W(VI)-doped persistent luminescence nanoparticles for deep-tissue photodynamic therapy. Adv Funct Mater, 2018, 28: 1707496

    Google Scholar 

  60. Cheng S, Liu L, Yang Q, et al. In vivo optical bioimaging by using Nd-doped LaF3 luminescent nanorods in the second near-infrared window. J Rare Earths, 2019, 37: 931–936

    CAS  Google Scholar 

  61. Li S, Wei J, Yao Q, et al. Emerging ultrasmall luminescent nanoprobes for in vivo bioimaging. Chem Soc Rev, 2023, 52: 1672–1696

    CAS  Google Scholar 

  62. Fan C, Wang Q, van der Zon G, et al. OVOL1 inhibits breast cancer cell invasion by enhancing the degradation of TGF-β type I receptor. Sig Transduct Target Ther, 2022, 7: 126

    CAS  Google Scholar 

  63. Yu L, Hu P, Chen Y. Gas-generating nanoplatforms: Material chemistry, multifunctionality, and gas therapy. Adv Mater, 2018, 30: 1801964

    Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (22027805 and 22274024), the Major Project of Science and Technology of Fujian Province (2020HZ06006), the Young Elite Scientist Sponsorship Program by CAST (YESS20200110), and China Postdoctoral Science Foundation (2022M720737 and 2021T140117)

Author information

Authors and Affiliations

  1. MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou, 350108, China

    Kaidong Yang  (杨凯栋), Yating Yang  (杨雅婷), Dongquan Sun  (孙东泉), Shihua Li  (李诗华), Xiaorong Song  (宋晓荣) & Huanghao Yang  (杨黄浩)

  2. Fujian Science & Technology Innovation Laboratory for Optoelectronic Information of China, Fuzhou, 350108, China

    Xiaorong Song  (宋晓荣) & Huanghao Yang  (杨黄浩)

Authors
  1. Kaidong Yang  (杨凯栋)
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yating Yang  (杨雅婷)
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dongquan Sun  (孙东泉)
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shihua Li  (李诗华)
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaorong Song  (宋晓荣)
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Huanghao Yang  (杨黄浩)
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Author contributions Song X conceived the idea and supervised this work. Yang K, Yang Y, and Sun D conducted the experiments, analyzed the data, and prepared the manuscript. Li S, Song X, and Yang H revised the manuscript. All authors contributed to the general discussion.

Corresponding author

Correspondence to Xiaorong Song  (宋晓荣).

Ethics declarations

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

Additional information

Kaidong Yang is a Master candidate at Fuzhou University. His current research focuses on the lanthanide-doped nanoscintillators.

Xiaorong Song is an associate professor at the college of chemistry, Fuzhou University. He received his PhD degree in 2017 from Fuzhou University, and continued his visiting scholar study at the National University of Singapore (NUS) and postdoctoral research at Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences (China). His research interests focus on the luminescent nanomaterials and bioapplications.

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

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, K., Yang, Y., Sun, D. et al. Designing highly UV-emitting lanthanide nanoscintillators for in vivo X-ray-activated tumor therapy. Sci. China Mater. 66, 4090–4099 (2023). https://doi.org/10.1007/s40843-023-2548-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40843-023-2548-8

Keywords

Search

Navigation