| Glioblastoma multiforme (GBM) is an aggressive, diffuse, and lethal disease, marked by infiltration of cancerous cells into the surrounding normal brain. On average, GBM patients only survive approximately 14.6 months following diagnosis, despite the combination of surgical resection, chemotherapy, and radiation treatment. The dire outcome of GBM patients stems from ineffective treatment regimens, as well as from the limitations of current neuroimaging methods. Notably, early cancer detection methodologies are lacking, and aggressive, metastatic tumor cells remain unidentified when using conventional imaging techniques. We have developed cellular and molecular MRI approaches for GBM detection, taking advantage of the unique characteristics of the tumor environment for specific targeting and visualization.;The first technique to detect GBM employs the specific tumor tropism of mesenchymal stem cells (MSCs). Studies have shown that glioblastoma cells produce and secrete chemoattractants that stimulate stem and immune cell migration. To enable specific MRI of MSCs, these cells are labeled with micron-sized iron oxide particles (MPIOs). Here, we show for the first time that MPIO labeled MSCs exhibit specific and significant chemotactic migration towards glioma conditioned medium in vitro. In addition, MPIOs were internalized and did not impact these and other important cell processes of MSCs. Furthermore, MPIO labeled MSCs appeared as single distinct, dark spots on T2* weighted MRI, allowing for the robust detection and quantification of single cells using image processing techniques. The potential for detecting single MPIO labeled MSCs provides rationale for in vivo extension of this methodology to visualize GBM in animal models.;The second method takes advantage of inorganic manganese-based particles. While the dark contrast from iron oxide is robust, it is always in an "on" state regardless of the environment, and can also be confounding with endogenous stores of iron in the liver, spleen, bone marrow, and in areas of hemorrhage. Inorganic manganese-based particles are becoming attractive for molecular and cellular imaging, due to their ability to provide switchable, bright contrast on MRI. Using a single emulsion technique, we have successfully fabricated pH sensitive, poly(lactic-co-glycolic acid) (PLGA) encapsulated manganese oxide (MnO) nanocrystals. Two classes of particles were fabricated at ∼ 140 nm and 1.7 μm, each of which incorporated 15 to 20 nm MnO nanocrystals with high encapsulation efficiencies. Intact particles at physiological pH caused little contrast on MRI; however, exposure to a low pH environment resulted in significant particle erosion to dissolve MnO into Mn2+ , generating positive contrast on T1 weighted MRI. The magnitude of the change in MRI properties is as high as 35-fold, making it the most dynamic 'smart' MRI contrast agent yet reported. Through their pH sensing ability, our MnO particles can be applied to selectively visualize GBM and other tumors, which produce large amounts of lactic acid through glycolysis, and thus have a low pH within their extracellular space. Targeting ligands can readily be added to the particle surface to achieve specific delivery to tumor cells. |
