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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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.
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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