Article

Successively activatable ultrasensitive probe for imaging tumour acidity and hypoxia

  • Nature Biomedical Engineering 1, Article number: 0057 (2017)
  • doi:10.1038/s41551-017-0057
  • Download Citation
Received:
Accepted:
Published online:

Abstract

Molecular imaging probes for biomarker-based diagnosis typically target, with limited sensitivity, a single molecular process or event in a complex biological system. Here, we show that the macromolecular near-infrared poly(ethylene glycol)-conjugated iridium (iii) complex can be designed to successively respond to tumour acidity and hypoxia while amplifying detection sensitivity via signal propagation. We used the probe to detect, by near-infrared imaging, primary tumours and metastatic tumour nodules as small as 1 mm in mice, and to measure the in vivo metabolic rate of cancer cells. We anticipate that probes for imaging coupled biological events with amplified detection sensitivity will offer opportunities for enhanced molecular diagnostics and image-guided biomedical applications.

  • Subscribe to Nature Biomedical Engineering for full access:

    $99

    Subscribe

  • Purchase article full text and PDF:

    $32

    Buy now

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    , , , & HER-2/neu protein expression in breast cancer evaluated by immunohistochemistry. A study of interlaboratory agreement. Am. J. Clin. Pathol. 113, 251–258 (2000).

  2. 2.

    , et al. An activity-based near-infrared glucuronide trapping probe for imaging β-glucuronidase expression in deep tissues. J. Am. Chem. Soc. 134, 3103–3110 (2012).

  3. 3.

    , , & Dysregulated pH: a perfect storm for cancer progression. Nat. Rev. Cancer. 11, 671–677 (2011).

  4. 4.

    et al. Multicolored pH-tunable and activatable fluorescence nanoplatform responsive to physiologic pH stimuli. J. Am. Chem. Soc. 134, 7803–7811 (2012).

  5. 5.

    & Oxygen, a source of life and stress. FEBS Lett. 581, 3582–3591 (2007).

  6. 6.

    et al. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3, 347–361 (2003).

  7. 7.

    et al. Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging. Proc. Natl Acad. Sci. USA 112, 6607–6612 (2015).

  8. 8.

    , , , & Comparison of cell uptake, bio-distribution and tumor retention of folate-coated and PEG-coated gadolinium nanoparticles in tumor-bearing mice. J. Control. Release 95, 613–626 (2004).

  9. 9.

    et al. Quantum dot/antibody conjugates for in vivo cytometric imaging in mice. Proc. Natl Acad. Sci. USA 112, 1350–1355 (2015).

  10. 10.

    , , & Tracking metastatic tumor cell extravasation with quantum dot nanocrystals and fluorescence emission-scanning microscopy. Nat. Med. 10, 993–998 (2004).

  11. 11.

    et al. Near-infrared optical imaging of epidermal growth factor receptor in breast cancer xenografts. Cancer Res. 63, 7870–7875 (2003).

  12. 12.

    et al. Real-time vital optical imaging of pre-cancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanoparticles. Cancer Res. 63, 1999–2004 (2003).

  13. 13.

    , & Recent progress in tumor pH targeting nanotechnology. J. Control. Release 132, 164–170 (2008).

  14. 14.

    et al. Ultra-pH-sensitive nanoprobe library with broad pH tunability and fluorescence emissions. J. Am. Chem. Soc. 136, 11085–11092 (2014).

  15. 15.

    , & Efficient wavelength shifting over the erbium amplifier bandwidth via cascaded second order processes in lithium niobate waveguides. Appl. Phys. Lett. 71, 1020–1022 (1997).

  16. 16.

    In vivo imaging of glucose uptake and metabolism in tumors. Nat. Med. 19, 1067–1072 (2013).

  17. 17.

    et al. Loss of PHD3 allows tumors to overcome hypoxic growth inhibition and sustain proliferation through EGFR. Nat. Commun. 5, 5582 (2014).

  18. 18.

    et al. Selective phosphorescence chemosensor for homocysteine based on an iridium (iii) complex. Inorg. Chem. 46, 11075−11081 (2007).

  19. 19.

    et al. A ratiometric fluorescent probe for cysteine and homocysteine displaying a large emission shift. Org. Lett. 10, 5577–5580 (2008).

  20. 20.

    Hypoxia, HIF1 and glucose metabolism in the solid tumor. Nat. Rev. Cancer 8, 705–713 (2008).

  21. 21.

    & Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat. Rev. Cancer 14, 709–721 (2014).

  22. 22.

    et al. A smart “sense-act-treat” system: combining a ratiometric pH sensor with a near infrared therapeutic gold nanocage. Adv. Mater. 26, 6635–6641 (2014).

  23. 23.

    et al. pH-responsive reversible PEGylation improves performance of antineoplastic agent. Adv. Healthc. Mater. 4, 844–855 (2015).

  24. 24.

    et al. A nanoparticle-based strategy for the imaging of a broad range of tumors by nonlinear amplification of microenvironment signals. Nat. Mater. 13, 204–212 (2014).

  25. 25.

    et al. Overhauser enhanced magnetic resonance imaging for tumor oximetry: coregistration of tumor anatomy and tissue oxygen concentration. Proc. Natl Acad. Sci. USA 99, 2216–2221 (2002).

  26. 26.

    , , & Phosphorescent complexes of porphyrin ketones: optical properties and application to oxygen sensing. Anal. Chem. 67, 4112–4117 (1995).

  27. 27.

    Methods in optical oxygen sensing: protocols and critical analyses. Methods Enzymol. 381, 715–735 (2004).

  28. 28.

    et al. Hypoxia-specific ultrasensitive detection of tumors and cancer cells in vivo. Nat. Commun. 6, 5834 (2015).

  29. 29.

    , , , & Image-guided cancer surgery using near-infrared fluorescence. Nat. Rev. Clin. Oncol. 10, 507–518 (2013).

  30. 30.

    et al. The FLARE intraoperative near-infrared fluorescence imaging system: a first-in-human clinical trial in breast cancer sentinel lymph node mapping. Ann. Surg. Oncol. 16, 2943–2952 (2009).

  31. 31.

    et al. Patient-derived tumour xenografts as models for oncology drug development. Nat. Rev. Clin. Oncol. 9, 338–350 (2012).

  32. 32.

    et al. In vivo imaging of tumor metabolism and acidosis by combining PET and MRI-CEST pH imaging. Cancer Res. 76, 6463–6470 (2016).

  33. 33.

    . et al. Tumor imaging by means of proteolytic activation of cell-penetrating peptides. Proc. Natl Acad. Sci. USA. 101, 17867–17872 (2004).

  34. 34.

    et al. Real-time in vivo molecular detection of primary tumors and metastases with ratiometric activatable cell-penetrating peptides. Cancer Res. 73, 855–864 (2013).

  35. 35.

    et al. Selective molecular imaging of viable cancer cells with pH-activatable fluorescence probes. Nat. Med. 15, 104–109 (2009).

  36. 36.

    et al. Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature 453, 940–944 (2008).

  37. 37.

    Oxygen sensing, homeostasis, and disease. N. Engl. J. Med. 365, 537–547 (2011).

  38. 38.

    , & Highly sensitive DNA detection using cascade amplification strategy based on hybridization chain reaction and enzyme-induced metallization. Biosens. Bioelectron. 66, 520–526 (2015).

  39. 39.

    et al. Sensitive and convenient detection of microRNAs based on cascade amplification by catalytic DNAzymes. Chem. Eur. J. 19, 92–95 (2013).

  40. 40.

    et al. Ultra-small, highly stable, and sensitive dual nanosensors for imaging intracellular oxygen and pH in cytosol. J. Am. Chem. Soc. 134, 17011–17014 (2012).

  41. 41.

    , , , & Real-time imaging of oxidative and nitrosative stress in the liver of live animals for drug-toxicity testing. Nat. Biotechnol. 32, 373–380 (2014).

  42. 42.

    et al. Spatiotemporal targeting of a dual-ligand nanoparticle to cancer metastasis. ACS Nano 9, 8012–8021 (2015).

  43. 43.

    et al. Dataset for ‘Successively activatable ultrasensitive probe for imaging tumour acidity and hypoxia’ figshare (2017).

Download references

Acknowledgements

This work was supported by the Natural Science Foundation of China (grant nos. 51690153, 21474045 and 51422303), the Specialized Research Fund for the Doctoral Program of Higher Education, and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT), Ministry of Education of China.

Author information

Affiliations

  1. MOE Key Laboratory of High Performance Polymer Materials and Technology, and Department of Polymer Science and Engineering, College of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China.

    • Xianchuang Zheng
    • , Wei Wu
    •  & Xiqun Jiang
  2. Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30329, USA.

    • Hui Mao
  3. Institute of Materials Engineering, College of Engineering and Applied Sciences, Nanjing University, Nanjing 210093, China.

    • Da Huo
  4. Department of Oncology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210093, China.

    • Baorui Liu

Authors

  1. Search for Xianchuang Zheng in:

  2. Search for Hui Mao in:

  3. Search for Da Huo in:

  4. Search for Wei Wu in:

  5. Search for Baorui Liu in:

  6. Search for Xiqun Jiang in:

Contributions

X.Z., H.M. and X.J. conceived and designed the research. X.Z., D.H. and W.W. performed the experiments. X.Z., H.M., X.J. and B.L. analysed the data and wrote the manuscript. X.J. supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Xiqun Jiang.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary figures, tables, methods and references.