TMIC-03. IMAGING BRAIN TUMOR-ASSOCIATED NEUROINFLAMMATION IN ANIMAL MODELS USING FERUMOXYTOL

Abstract

In the brain tumor microenvironment, non-neoplastic cells with inflammatory function such as tumor-associated macrophages can influence the survival, proliferation and infiltrative activity of cancer cells. The ultrasmall superparamagnetic iron oxide nanoparticle, ferumoxytol, can be used as a contrast agent for magnetic resonance imaging (MRI) of brain vasculature, intracerebral tumors and neurological lesions. Although ferumoxytol is a blood pool agent immediately after infusion, we have shown that by 24h ferumoxytol leaks across the damaged blood-brain barrier in a rat model of acute neuroinflammation, where MRI signal changes correlated with nanoparticle uptake by macrophages, microglia and activated astrocytes. The purpose of this study was to test the hypothesis that delayed MRI would demonstrate uptake of ferumoxytol by inflammatory cells in and around the tumor in rat models of intracerebral metastasis. Immune-compromised nude rats received intracerebral implantation of human metastatic cancer cells including H460 non-small cell lung carcinoma and HCC1954 breast carcinoma. When brain tumors were >10mm3 volume, rats underwent baseline T1, T2, and T2* scans on the 11.75T Bruker MRI scanner, then received ferumoxytol 25 mg/kg IV. MRI scans were repeated 24h after ferumoxytol, and rat brains were immediately harvested for immunohistochemical analysis. Post-ferumoxytol T1-weighted scans showed pockets of hypointensity dispersed throughout the tumor and, occasionally, a distinct rim of signal dropout at the tumor border, combined with hyperintensity extending 1-2 mm around the tumor mass. Post-ferumoxytol T2-weighted scans showed mottled signal dropout throughout the tumor, while T2* scans showed intense hypointensity throughout the tumor mass extending into surrounding brain. Immunohistochemistry for the ferumoxytol coating showed intense staining in macrophages within necrotic areas of the tumor and dispersed staining in cells of astroglial morphology in peritumoral brain, but little to no staining within tumor cells. We conclude that delayed ferumoxytol MRI provides a biomarker of the inflammatory component of intracerebral tumors.