Medulloblastoma, the primary brain tumor in children, is difficult to detect early and to reassess post-surgery with respect to recurrence and metastasis. This project will test a biological tool for non-invasive quantitation of gene expression in cells expressing the JC virus oncoprotein, T-antigen, which has been associated with medulloblastoma. The tool, a nanoconjugate, will have a core of superparamagnetic iron oxide for detection by MRI and, as proof of concept, will target T-antigen in T-antigen transformed cancer cells. An antibody fragment which recognizes JC virus T-antigen will be used to recognize cell-surface antigens appearing on tumor cells for targeting. MR imaging will be used to track the nanoconjugate in vivo. Studies will be done to characterize and quantify the uptake by tumor cells in vitro and in an animal model. Histopathology and radionuclide studies will be used to correlate the nanoconjugate trafficking to cells with the MR images. This platform will be used as a proof of concept to rapidly and effectively demonstrate that the nanoconjugate is able to selectively home to T-antigen expressing tumor cells but not normal cells. This project will allow us to optimize composition of the nanoparticle, determine specificity of the nanoparticle for T-antigen, quantitate particle uptake per cell, and optimize MRI parameters in vitro and in vivo. This strategy will enable determination of which tumors express T-antigen, quantitative analysis of the level of T-antigen expression, and monitoring of response to therapeutic treatment non-invasively through MRI and image post-process analysis. This technology may then be modified for other highly expressed intracellular or viral molecular targets of cancer. Furthermore the comprehensive methodology used and developed in this proposal from synthesis of the target-specific contrast agent to imaging and image analysis techniques may be used for translation into clinical imaging of human tumors and potentially into a vehicle for targeted therapy.
STATEMENT: The current proposal seeks to develop a novel molecular based contrast agent which will specifically target medulloblastoma tumor cells. This agent would improve diagnosis of brain tumors and provide novel methods to non-invasively monitor response to brain tumor treatment.
| Knight, Linda C; Romano, Jan E; Krynska, Barbara et al. (2010) Binding and Internalization of Iron Oxide Nanoparticles Targeted to Nuclear Oncoprotein. J Mol Biomark Diagn 1: |
