In vivo MR tracking of therapeutic microglia to a human glioma model

• Published in: NMR in biomedicine 2011-12, Vol.24 (10), p.1361-1368
• Main Authors: Ribot, Emeline J., Miraux, Sylvain, Konsman, Jan P., Bouchaud, Véronique, Pourtau, Line, Delville, Marie-Hélène, Franconi, Jean-Michel, Thiaudière, Eric, Voisin, Pierre J.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cell Movement; cell tracking; Cell Tracking - methods; Chemical Sciences; Contrast Media - chemistry; Disease Models, Animal; Endocytosis; Fluorescence; Gadolinium DTPA - chemistry; gene therapy; Genes, Reporter - genetics; Genes, Transgenic, Suicide; glioma; Glioma - therapy; Green Fluorescent Proteins - metabolism; Humans; Magnetic Resonance Imaging - methods; Material chemistry; Mice; Mice, Nude; microglia; Microglia - metabolism; Microglia - pathology; MRI; Nanoparticles - chemistry; Silicon Dioxide - chemistry; Survival Analysis; Thymidine Kinase - genetics; Xenograft Model Antitumor Assays
• ISSN: 0952-3480; 1099-1492
• DOI: 10.1002/nbm.1699

A knowledge of the spatial localization of cell vehicles used in gene therapy against glioma is necessary before launching therapy. For this purpose, MRI cell tracking is performed by labeling the cell vehicles with contrast agents. In this context, the goal of this study was to follow noninvasively the chemoattraction of therapeutic microglial cells to a human glioma model before triggering therapy. Silica nanoparticles grafted with gadolinium were used to label microglia. These vehicles, expressing constitutively the thymidine kinase suicide gene fused to the green fluorescent protein gene, were injected intravenously into human glioma‐bearing nude mice. MRI was performed at 4.7 T to track noninvasively microglial accumulation in the tumor. This was followed by microscopy on brain slices to assess the presence in the glioma of the contrast agents, microglia and fusion gene through the detection of silica nanoparticles grafted with tetramethyl rhodamine iso‐thiocyanate, 3,3′‐dioctadecyloxacarbocyanine perchlorate and green fluorescent protein fluorescence, respectively. Finally, gancyclovir was administered systemically to mice. Human microglia were detectable in living mice, with strong negative contrast on T2*‐weighted MR images, at the periphery of the glioma only 24 h after systemic injection. The location of the dark dots was identical in MR microscopy images of the extracted brains at 9.4 T. Fluorescence microscopy confirmed the presence of the contrast agents, exogenous microglia and suicide gene in the intracranial tumor. In addition, gancyclovir treatment allowed an increase in mice survival time. This study validates the MR tracking of microglia to a glioma after systemic injection and their use in a therapeutic strategy against glioma. Copyright © 2011 John Wiley & Sons, Ltd. Microglia can be used as a therapeutic vehicle to transport the thymidine kinase gene and gadolinium‐based silica nanoparticles into brain tumors. In vivo MRI shows that, as soon as 24 h after systemic injection, contrast agent‐labeled microglia are efficiently chemoattracted to human glioma implanted in the brains of nude mice. Systemic injection of a thymidine kinase substrate induces a significantly prolonged survival time of the mice.