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A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy

Abstract

Engineered nanoparticles that respond to pathophysiological parameters, such as pH or redox potential, have been developed as contrast agents for the magnetic resonance imaging (MRI) of tumours. However, beyond anatomic assessment, contrast agents that can sense these pathological parameters and rapidly amplify their magnetic resonance signals are desirable because they could potentially be used to monitor the biological processes of tumours and improve cancer diagnosis. Here, we report an MRI contrast agent that rapidly amplifies magnetic resonance signals in response to pH. We confined Mn2+ within pH-sensitive calcium phosphate (CaP) nanoparticles comprising a poly(ethylene glycol) shell. At a low pH, such as in solid tumours, the CaP disintegrates and releases Mn2+ ions. Binding to proteins increases the relaxivity of Mn2+ and enhances the contrast. We show that these nanoparticles could rapidly and selectively brighten solid tumours, identify hypoxic regions within the tumour mass and detect invisible millimetre-sized metastatic tumours in the liver.

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Figure 1: Preparation and characterization of PEGMnCaP.
Figure 2: PEGMnCaP could specifically enhance the contrast of solid tumours for cancer diagnosis.
Figure 3: PEGMnCaP could specifically indicate hypoxic regions in tumours through a higher contrast.
Figure 4: PEGMnCaP could specifically enhance the contrast of small metastatic tumours in the liver.

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Acknowledgements

This research was financially supported by the Center of Innovation Program stream from the Japan Science and Technology Agency and the Funding Program for World-Leading Innovative R&D on Science and Technology from the Japan Society for the Promotion of Science to K.K. The TEM characterization at the Research Hub for Advanced Nano Characterization, The University of Tokyo, was supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan. The μ-SR-XRF characterization was supported by the Nanotechnology Support Program of the Japan Synchrotron Radiation Research Institute. We thank S. Shibata, N. Nitta, Y. Ozawa, S. Murayama and A. Sekita for assistance with MRI experiments.

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Contributions

P.M. designed and performed the experiments. D.K. and I.A. performed MRI measurements. H.C. and Y.T. helped in the μ-SR-XRF measurement. H.W. performed immunostaining. P.M., D.K., H.C., I.A., N.N., T.S. and K.K. discussed and analysed the data. P.M. wrote and revised the manuscript. H.C., I.A., N.N. and K.K. commented and revised the manuscript. H.C. N.N., T.S., I.A. and K.K. led or supervised this project.

Corresponding authors

Correspondence to Ichio Aoki, Nobuhiro Nishiyama or Kazunori Kataoka.

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The authors declare no competing financial interests.

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Mi, P., Kokuryo, D., Cabral, H. et al. A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy. Nature Nanotech 11, 724–730 (2016). https://doi.org/10.1038/nnano.2016.72

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