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A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals

Nature Materials volume 13, pages 204–212 (2014)Cite this article

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Abstract

Stimuli-responsive nanomaterials are increasingly important in a variety of applications such as biosensing, molecular imaging, drug delivery and tissue engineering. For cancer detection, a paramount challenge still exists in the search for methods that can illuminate tumours universally regardless of their genotypes and phenotypes. Here we capitalized on the acidic, angiogenic tumour microenvironment to achieve the detection of tumour tissues in a wide variety of mouse cancer models. This was accomplished using ultra pH-sensitive fluorescent nanoprobes that have tunable, exponential fluorescence activation on encountering subtle, physiologically relevant pH transitions. These nanoprobes were silent in the circulation, and then strongly activated (>300-fold) in response to the neovasculature or to the low extracellular pH in tumours. Thus, we have established non-toxic, fluorescent nanoreporters that can nonlinearly amplify tumour microenvironmental signals, permitting the identification of tumour tissue independently of histological type or driver mutation, and detection of acute treatment responses much more rapidly than conventional imaging approaches.

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Figure 1: A schematic of imaging the tumour microenvironment using UPS nanoprobes.
Figure 2: Synthesis and characterization of UPS nanoprobes.
Figure 3: UPSe nanoprobes can specifically image acidic tumour pHe.
Figure 4: cRGD- UPSi nanoprobes can specifically image angiogenic tumour vasculature.
Figure 5: iUPS nanoprobes target both acidic pHe and tumour vasculature with broad tumour specificity.

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Acknowledgements

This work is supported by the NIH (R01EB013149 and R01CA129011) and Cancer Prevention and Research Institute of Texas (RP120094). Animal imaging work is supported by the UT Southwestern Small Animal Imaging Resource Grant (U24 CA126608) and Simmons Cancer Center Support Grant (P30 CA142543). We thank H. Zhou for help with the Maestro imaging, X. Luo for assistance with animal handling, and J. T. Hsieh and L. Gandee for help with histology.

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Authors and Affiliations

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

    Yiguang Wang, Kejin Zhou, Gang Huang, Xiaonan Huang, Xinpeng Ma, Tian Zhao & Jinming Gao

  2. Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA

    Christopher Hensley & Ralph J. DeBerardinis

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

    Baran D. Sumer

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  1. Yiguang Wang
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Contributions

Y.W. and J.G. are responsible for all phases of the research; K.Z., G.H., X.H., X.M. and T.Z. helped with synthesis of different dye-conjugated polymers and characterization of UPS nanoprobes; C.H. and R.J.D. designed metabolic inhibition experiments and performed in vitro cell studies; R.J.D. supplied the transgenic MMTV-PyMT breast tumour model; B.D.S. guided the preclinical development of the experiments. Y.W. and G.H. wrote the initial draft. R.J.D., B.D.S. and J.G. revised the final draft.

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Correspondence to Jinming Gao.

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Wang, Y., Zhou, K., Huang, G. et al. A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals. Nature Mater 13, 204–212 (2014). https://doi.org/10.1038/nmat3819

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