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MRI-detectable pH nanosensors incorporated into hydrogels for in vivo sensing of transplanted-cell viability

Abstract

Biocompatible nanomaterials and hydrogels have become an important tool for improving cell-based therapies by promoting cell survival and protecting cell transplants from immune rejection. Although their potential benefit has been widely evaluated, at present it is not possible to determine, in vivo, if and how long cells remain viable following their administration without the use of a reporter gene. Here, we report a pH-nanosensor-based magnetic resonance imaging (MRI) technique that can monitor cell death in vivo non-invasively. We demonstrate that specific MRI parameters that change on cell death of microencapsulated hepatocytes are associated with the measured bioluminescence imaging radiance. Moreover, the readout from this pH-sensitive nanosensor can be directly co-registered with high-resolution anatomical images. All of the components of these nanosensors are clinical grade and hence this approach should be a translatable and universal modification of hydrogels.

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Figure 1: Schematic showing the principles of in vivo detection of cell viability using LipoCEST microcapsules as pH nanosensors.
Figure 2: Cartoon outlining the structures of the CEST probes and procedure for preparation of LipoCEST microcapsules.
Figure 3: MRI data determining the CEST contrast and stability for LipoCEST microcapsules as a function of formulation.
Figure 4: MRI data showing the sensitivity of the LipoCEST capsule contrast to local pH.
Figure 5: In vitro data verifying that LipoCEST capsules can report on apoptosis through MRI contrast.
Figure 6: In vivo CEST and BLI imaging of LipoCEST capsules containing hepatocytes.

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Acknowledgements

The authors sincerely thank S. Bernard and S.C. Galpoththawela for technical assistance, A. Kim for helping with the image processing of the permeability study, and C. Thompson and P. Murakami for assistance in the statistical analysis. The study was supported by NIH R01 EB012590, EB015031, EB015032 and EB007825.

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K.W.Y.C., M.T.M. and J.W.M.B. were responsible for the study concepts, design of experiments and analysis and interpretation of data. K.W.Y.C., D.R.A. and T.Y. were involved in the capsule preparation and characterization. K.W.Y.C., G.L., X.S. and H.K. carried out the in vivo experiments and MRI studies. K.W.Y.C. and G.L. processed the MRI data. A.A.G. designed the cell transduction. J.H. directed the permeability study, which was performed on instruments in his laboratory. P.W. directed the histological and immunosuppression studies. P.C.M.V.Z. directed the CEST imaging protocols. K.W.Y.C. and M.T.M. drafted the manuscript, and all authors commented on and edited the manuscript.

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Correspondence to Michael T. McMahon.

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Chan, K., Liu, G., Song, X. et al. MRI-detectable pH nanosensors incorporated into hydrogels for in vivo sensing of transplanted-cell viability. Nature Mater 12, 268–275 (2013). https://doi.org/10.1038/nmat3525

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