Current in vivo imaging modalities can detect tumors of 1 mm3 size, or 107 cells. The ability to detect very small tumors, 2-3 orders of magnitude smaller than currently possible (104 - 105 cells;0.001 - 0.01 mm3), would have a profound impact on cancer treatment as early detection of cancer is critical both for increasing survival chances of the patient, as well as for also detecting more and smaller metastases in patients with existing cancer. The typical molecular imaging approach to detecting cancer is to use a chemical probe targeted against some phenotypic property, such as an overexpressed surface antigen, or enhanced vascular permeability. The angiogenic switch, the phenomenon by which the tumor grows large enough to induce local angiogenesis, and hence increases the permeability of the local vasculature, occurs at tumor size ~ 1-2 mm3. As such, current targeted molecular imaging approaches inherently detect tumors larger than 1 mm3, after the angiogenic switch has been activated. Our unique and innovative approach for detection of cancer is to use MRI to track the infiltration of monocytes and mesenchymal stem cells (MSCs) into very small tumors. Indeed, tumorigenesis, in its earliest stages, is marked by monocyte and MSC infiltration. MRI-based cell tracking has proven useful for visualizing the infiltration of cells ito numerous injury and disease models, in vivo. In short, cells can be labeled in vitro or directly in vivo with magnetic particles, enabling their detection by locally modulating the physics behind image generation in MRI. We have pioneered the use of clinically viable, biodegradable micron sized particles of iron oxide (MPIOs) for cellular MRI. Due to the loading efficiency of MPIOs, cells can be labeled with very high iron levels, allowing the detection of single cells in vivo in animals. Hence, we expect to develop a protocol for using MRI to sensitively and specifically detect low numbers of infiltrating cells, identifying very small tumors. Early detection of cancer is critical for increasing survival of the patient, as well as for also detecting more and smaller metastases in patients with existing cancer. If indeed magnetically labeled monocytes and MSCs can target small tumors behind the intact BBB, then there would be a high likelihood that the same cells can infiltrate tumors in other areas of the body. Thus, while we are studying glioma in this proposal, the protocol could be broadened to investigate different cancer types. The most original aspect of the proposed work is our fundamentally different approach to tumor detection. Rather than using targeted chemical agents, we are relying on the known and demonstrated trophic behaviors of 2 different cell types, to detect very small tumors. In essence, the cells do the hard work for you, in penetrating the brain and migrating to the correct locations Coupled with our in vivo single cell detection capabilities, we expect to beat the detection limit f 107 cells, or 1 mm3 tumors by 2-3 orders of magnitude. MRI-based cell tracking in humans is gaining acceptance, and if successful, the MRI protocols we propose here for early tumor detection in rats have potential in humans.
The ability to detect very small tumors (104 - 105 cells;0.001 - 0.01 mm3), 2-3 orders of magnitude smaller than currently possible, would have a profound impact on cancer treatment. Our unique and innovative approach for detection of cancer is to use MRI to track the infiltration of magnetically labeled monocytes and mesenchymal stem cells into very small tumors. While this proposal focuses on glioma, successful completion of this project opens up the possibility using this methodology for detection of multiple cancer types in other anatomical locations.