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A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle

Abstract

The difficulty in delineating brain tumor margins is a major obstacle in the path toward better outcomes for patients with brain tumors. Current imaging methods are often limited by inadequate sensitivity, specificity and spatial resolution. Here we show that a unique triple-modality magnetic resonance imaging–photoacoustic imaging–Raman imaging nanoparticle (termed here MPR nanoparticle) can accurately help delineate the margins of brain tumors in living mice both preoperatively and intraoperatively. The MPRs were detected by all three modalities with at least a picomolar sensitivity both in vitro and in living mice. Intravenous injection of MPRs into glioblastoma-bearing mice led to MPR accumulation and retention by the tumors, with no MPR accumulation in the surrounding healthy tissue, allowing for a noninvasive tumor delineation using all three modalities through the intact skull. Raman imaging allowed for guidance of intraoperative tumor resection, and a histological correlation validated that Raman imaging was accurately delineating the brain tumor margins. This new triple-modality–nanoparticle approach has promise for enabling more accurate brain tumor imaging and resection.

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Figure 1: Triple-modality MPR concept.
Figure 2: Characterization of the MPRs.
Figure 3: Triple-modality detection of brain tumors in living mice with MPRs.
Figure 4: Histological validation.
Figure 5: Raman-guided intraoperative surgery using MPRs.

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Acknowledgements

We thank M. Gozin for help with ICP-AES, L. Pisani for assistance with quantifying and acquiring magnetic resonance data, S.M. Korn and S. Bodapati for assistance in conducting the photoacoustic experiments, J. Rosenberg for assistance with the statistical analysis and the Memorial Sloan-Kettering Cancer Center Animal Imaging Core Facility (J. Koutcher and C.C. Le) for technical assistance. M.F.K. would like to thank R. Herfkens and the Stanford Department of Radiology for providing academic time to perform the study. We would like to acknowledge the following funding sources: National Cancer Institute grants CCNE U54 CA119367 (S.S.G.), CCNE U54 U54CA151459 (S.S.G.) and ICMIC P50 CA114747 (S.S.G.); The Ben and Catherine Ivy Foundation (S.S.G.); the Canary Foundation (S.S.G.); the Sir Peter Michael Foundation (S.S.G.); the Bio-X Graduate Student Fellowship (A.d.l.Z.); the Department of Defense Breast Cancer Research Program—Pre-doctoral Traineeship Award BC083014 (A.d.l.Z.) and the National Cancer Institute SMIS R25T Fellowship 5R25CA118681 (J.V.J.). The authors would also like to thank T.F. Massoud, D. Akin, H.E. Daldrup-Link, S. Bohndiek, S. Harmsen and J. Samii for critical review of the manuscript and B.T. Khuri-Yakub, S. Vaithilingam, O. Oralkan, E.E. Graves and H. Fan-Minogue for helpful discussions.

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Authors and Affiliations

Authors

Contributions

M.F.K. co-initiated the project, designed the research, synthesized and characterized MPR nanoparticles, performed MRI, Raman, photoacoustic and histology experiments, analyzed data and wrote the manuscript. A.d.l.Z. modified the photoacoustic system, designed and performed photoacoustic experiments, analyzed data and wrote the manuscript. J.V.J. synthesized and characterized MPR nanoparticles. C.L.Z. designed, performed and analyzed Raman experiments and edited the paper. P.J.K. and R.S. performed and analyzed the electron microscopy experiments. K.P. performed immunohistochemistry. F.H. helped create three-dimensional renderings. E.M., M.F.K., K.P., R.H., C.C., C.W.B., I.K.M. and E.C.H. provided mouse models. S.S.G. co-initiated the project, designed the research, analyzed data, supervised and coordinated all investigators for the project and wrote the manuscript.

Corresponding author

Correspondence to Sanjiv S Gambhir.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–14, Supplementary Discussion and Supplementary Methods (PDF 5246 kb)

Supplementary Video 1

Three-dimensional STEM rendering of MPR nanoparticles in U87MG tumor (AVI 9619 kb)

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Kircher, M., de la Zerda, A., Jokerst, J. et al. A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle. Nat Med 18, 829–834 (2012). https://doi.org/10.1038/nm.2721

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