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PET imaging of occult tumours by temporal integration of tumour-acidosis signals from pH-sensitive 64Cu-labelled polymers

Nature Biomedical Engineering volume 4, pages 314–324 (2020)Cite this article

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Abstract

Owing to the diversity of cancer types and the spatiotemporal heterogeneity of tumour signals, high-resolution imaging of occult malignancy is challenging. 18F-fluorodeoxyglucose positron emission tomography allows for near-universal cancer detection, yet in many clinical scenarios it is hampered by false positives. Here, we report a method for the amplification of imaging contrast in tumours via the temporal integration of the imaging signals triggered by tumour acidosis. This method exploits the catastrophic disassembly, at the acidic pH of the tumour milieu, of pH-sensitive positron-emitting neutral copolymer micelles into polycationic polymers, which are then internalized and retained by the cancer cells. Positron emission tomography imaging of the 64Cu-labelled polymers detected small occult tumours (10–20 mm3) in the brain, head, neck and breast of mice at much higher contrast than 18F-fluorodeoxyglucose, 11C-methionine and pH-insensitive 64Cu-labelled nanoparticles. We also show that the pH-sensitive probes reduce false positive detection rates in a mouse model of non-cancerous lipopolysaccharide-induced inflammation. This macromolecular strategy for integrating tumour acidosis should enable improved cancer detection, surveillance and staging.

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Fig. 1: Synthesis and characterization of 64Cu-UPS6.9 nanoprobes.
Fig. 2: All-or-nothing proton distribution of UPS6.9 nanoprobes.
Fig. 3: Irreversible capture of UPS nanoprobes by serum protein binding and cancer cell uptake after pH activation.
Fig. 4: 64Cu-UPS6.9 reduced false positive PET signals from LPS-induced inflammation compared with FDG.
Fig. 5: The ‘capture and integration’ strategy allowed binary detection of a brain tumour at both macroscopic (animal) and microscopic (subcellular) levels.
Fig. 6: Non-invasive digitization of tumour acidotic signals by PET.
Fig. 7: Schematic of the capture and integration algorithm.

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Data availability

The authors declare that the main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are available for research purposes from the corresponding authors on reasonable request.

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Acknowledgements

We thank R. Bachoo for the original 73C cancer cells, Y. Li and Q. Feng for helpful discussions. This work is supported by the National Institutes of Health (R01CA192221 and R01CA211930) and Cancer Prevention and Research Institute of Texas (RP180343). The animal imaging work was supported by a University of Texas Southwestern Small Animal Imaging Resource Grant (U24 CA126608), and radiochemistry and PET imaging were supported by a Simmons Cancer Center Support Grant (P30 CA142543) and CPRIT Grant (RP110771) to X.S.

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Authors and Affiliations

  1. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Gang Huang, Tian Zhao, Chensu Wang & Jinming Gao

  2. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Kien Nham, Yahong Xiong, Guiyang Hao & Xiankai Sun

  3. Children’s Research Institute, Departments of Pediatrics, Neuroscience, and Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Xiaofei Gao, Yihui Wang & Woo-Ping Ge

  4. Department of Otolaryngology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Baran D. Sumer & Jinming Gao

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Contributions

G.Huang, B.D.S. and J.G. are responsible for all of the phases of the research. G.Huang performed all of the experiments and analyses. T.Z. assisted the polymer synthesis and FDG-PET imaging. C.W. performed the confocal imaging on cell uptake of nanoprobes. K.N. ran the PET/CT scan and imaging analysis. Y.X. performed the initial radiolabelling experiments. X.G. and Y.W. prepared the 73C brain tumour model. G.Hao helped with 64Cu coupling with UPS nanoprobes. W.-P.G. assisted with the analysis of the 73C brain tumour study. X.S. helped design the FDG and 64Cu PET experiments.

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 and scientific advisors of OncoNano Medicine, Inc. G.Huang is a scientific advisor for OncoNano Medicine, Inc. T.Z. is currently an employee of OncoNano Medicine, Inc.

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Supplementary information

Supplementary Information

Supplementary figures, tables and video captions.

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Supplementary Video 1

3D rotation of the PET/CT imaging of HN5 tumour-bearing mice 24 h post-injection of 64Cu-UPS6.9.

Supplementary Video 2

3D rotation of the PET/CT imaging of HN5 tumour-bearing mice 1 h post-injection of FDG.

Supplementary Video 3

3D rotation of the PET/CT imaging of HN5 tumour-bearing mice 24 h post-injection of 64Cu-PEG-PLA.

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Huang, G., Zhao, T., Wang, C. et al. PET imaging of occult tumours by temporal integration of tumour-acidosis signals from pH-sensitive 64Cu-labelled polymers. Nat Biomed Eng 4, 314–324 (2020). https://doi.org/10.1038/s41551-019-0416-1

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