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A transistor-like pH nanoprobe for tumour detection and image-guided surgery

Nature Biomedical Engineering volume 1, Article number: 0006 (2017) Cite this article

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Abstract

It is challenging to detect a broad range of malignant tumours at high resolution, because of profound genetic and histological differences in cancerous tissue. Here, we report the design and performance of a fluorescent nanoprobe with transistor-like responses (transition pH = 6.9) for the detection of deregulated pH, which drives many of the invasive properties of cancer. The nanoprobe amplifies the fluorescence signal in the tumour over that in the surrounding normal tissues, resulting in a discretized, binary output signal with a spatial resolution smaller than 1 mm. The nanoprobe allowed us to image a broad range of tumours in mouse models using a variety of clinical cameras. We were able to perform real-time tumour-acidosis-guided detection and surgery of occult nodules (<1 mm3) in mice bearing head and neck or breast tumours, significantly lengthening mice survivability. We also show that the pH nanoprobe can be used as a reporter in a fast, quantitative assay to screen for tumour-acidosis inhibitors. The binary delineation of pH achieved by the nanoprobe promises to improve the accuracy of cancer detection, surveillance and therapy.

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Figure 1: pH transistor nanoprobes achieve broad tumour detection specificity.
Figure 2: Comparison between PINS and other commercial NIR probes.
Figure 3: PINS improves cancer detection compared with FDG–PET.
Figure 4: TAGS in mice bearing orthotopic head and neck tumours.
Figure 5: Tumour-acidosis-guided surgery in mice bearing small occult breast tumour nodules.
Figure 6: PINS evaluation of small molecular inhibitors targeting different tumour acidosis pathways.

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Acknowledgements

This work was supported by the National Institutes of Health (R01EB013149 and R01CA192221, to J.G.) and Cancer Prevention and Research Institute of Texas (RP140140, to B.D.S. and J.G.). Animal imaging work was supported by the UT Southwestern Small Animal Imaging Resource Grant (U24 CA126608) and Simmons Cancer Center Support Grant (P30 CA142543). We thank J. Sun for animal imaging, L.C. Su for histology analysis, D. Zhao for preparation of the U87 brain tumour model, A. Pavia-Jimenez and J. Brugarolas for the renal PDX model and G. Balch for the peritoneal metastatis model.

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  1. Tian Zhao

    Present address: †Present address: OncoNano Medicine Inc., 5323 Harry Hines Boulevard Y.3224, Dallas, Texas 57390, USA.,

Authors and Affiliations

  1. Department of Pharmacology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, OncoNano Medicine Inc., 5323 Harry Hines Boulevard, Y3.224, Dallas, 75390, Texas, USA

    Tian Zhao, Gang Huang, Yang Li, Shunchun Yang, Zhiqiang Lin, Yiguang Wang, Xinpeng Ma, Zhiqun Zeng, Min Luo & Jinming Gao

  2. Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390, Texas, USA

    Saleh Ramezani & Xiankai Sun

  3. Department of Surgery, University Medical Center Groningen, Hanzeplein 1, Groningen, 9713 GZ, Netherlands

    Esther de Boer

  4. Department of Clinical Science, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390, Texas, USA

    Xian-Jin Xie

  5. Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390, Texas, USA

    Joel Thibodeaux

  6. Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390, Texas, USA

    Rolf A. Brekken

  7. Department of Otolaryngology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390, Texas, USA

    Baran D. Sumer

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Contributions

T.Z., B.D.S and J.G. are responsible for all phases of the research. G.H., S.Y., M.L. and Z.Z. assisted animal surgery, tumour-margin analysis and safety evaluation. Y.L. helped develop the transistor concept and performed TEM analysis. S.R. and X.K.S. designed the FDG–PET experiment and performed image analysis. Z.Q.L. performed the imaging comparison of PINS with other commercial probes. Y.G.W. and E.B. helped with fluorescence imaging and X.P.M. assisted with the design and synthesis of the PEPA polymer. B.D.S. and T.Z. performed the survival surgery in mice bearing head and neck cancer, and breast cancer, respectively. X.J.X. performed the statistical analysis. J.T. interpreted the histology slides. R.A.B. helped establish genetic pancreatic models and histology interpretations.

Corresponding authors

Correspondence to Baran D. Sumer or Jinming Gao.

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Competing interests

B.D.S. and J.G. are scientific co-founders of OncoNano Medicine, Inc.

Supplementary information

Supplementary Information

Supplementary methods, figures and tables, and video captions. (PDF 3212 kb)

Video 1

Real-time tumour acidosis guided surgery (TAGS) of a HN5 head/neck tumour-bearing mouse using the SPY Elite camera. (MOV 16223 kb)

Video 2

Real-time TAGS of an orthotopic 4T1 breast tumour-bearing mouse using the SPY Elite. (MOV 9731 kb)

Video 3

Real-time TAGS of a small occult breast tumour-bearing mouse using the SPY Elite camera. (MOV 10775 kb)

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Zhao, T., Huang, G., Li, Y. et al. A transistor-like pH nanoprobe for tumour detection and image-guided surgery. Nat Biomed Eng 1, 0006 (2017). https://doi.org/10.1038/s41551-016-0006

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