Editors' ChoiceCancer

Imaging tumor pH-ysiology with smart contrast agents

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Science Translational Medicine  15 Jun 2016:
Vol. 8, Issue 343, pp. 343ec94
DOI: 10.1126/scitranslmed.aag1873

Magnetic resonance imaging (MRI) is an established diagnostic modality for cancer, with excellent spatial resolution but inherently low sensitivity. MRI contrast agents (CAs) help address such limitations, but they still under-detect micrometastases and inadequately measure key tumor parameters such as hypoxia. Tumor hypoxia (associated with pH levels of 6.5 to 6.8) can promote angiogenesis, metastases, and therapeutic resistance; robust in vivo detection and tracking of hypoxia remains an unmet need. Nanomedicine affords opportunities to develop nanometer-range CAs small enough to traverse membranes and bind biological molecules, yet still large enough to remain customizable. Mi et al. developed manganese (Mn2+) doped nanoparticle CAs that greatly amplify the MRI signal within hypoxic regions. In the presence of low pH, stably confined paramagnetic Mn2+ ions are released from nanoparticles composed of calcium phosphate (CaP) cores and polyethylene glycol (PEG) shells. The released Mn2+ ions are then available to interact with surrounding proteins, resulting in sharp contrast enhancement. In mouse models, Mn2+ CAs produced 50% better tumor/normal tissue signal enhancement lasting for several hours, compared with the rapid signal reduction after 30 min seen with a clinically used gadolinium-based contrast agent. Mn2+ CAs also offered better performance in a model of liver micrometastases.

These elegantly designed smart CAs are not the first described pH-sensitive CAs, but they demonstrate highly convincing MRI results in a cancer context. Beyond their reported application for deep-tissue MRI imaging, these CAs could potentially function as theranostic agents. For example, one could incorporate cytotoxic drugs into the CaP-PEG matrix such that they would be selectively released when the CA reaches hypoxic tumor areas. Moreover, hypoxia readouts could be used to inform the application of other treatments thought to work better in hypoxic environments (for example, antiangiogenic agents and radiation). Acute and long-term toxicities are the biggest concern in the current iteration of this technology. Mn2+ is a known human toxin that can exert neurological insults. Thus, extensive toxicology studies would be needed before transitioning to broader clinical testing. The translational reach of the platform and contrast enhancement could be extended through safer iron-oxide nanoparticles, gadolinium-based probes, or other ions beyond Mn2+.

P. Mi et al., A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy. Nat. Nanotechnol. 10.1038/nnano.2016.72 (2016). [Abstract]

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