Nanoparticle MR Imaging of BBB Inflammation at High Tesla in CNS Tumors

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In this proposal we will test the overall hypothesis that high Tesla magnetic resonance (MR) imaging with magnetic iron oxide nanoparticles will add quantitative perfusion data and cell specific imaging of the neurovascular unit to classic anatomic MR of central nervous system (CMS)metastases and glioblastoma. We propose to test three major hypotheses: A) The nanoparticle ferumoxytol will supplement nonspecific gadolinium (Gd) MRI of brain tumors by targeting phagocytic cells rather than tumor cells; B) Dynamic contrast imaging of perfusion, permeability and angiography with ferumoxytol will improve visualization of vascular injury at the blood-brain barrier (BBS) compared to Gd, due to minimal vascular leak at early time points; C) Labeling white blood cells with a different iron oxide nanoparticle, ferumoxides, in combination with protamine will allow tracking of this "cellular contrast agent" into CNS tumors, initially in animal models, and if feasible in humans later in the funding period. Specific Aim 1 will compare dynamic and conventional MR imaging with histological imaging of vascular changes and inflammation at the BBB, using state-of-the-art high Tesla MR scanners. Vascular changes due to cancer therapies or steroids will be evaluated in animal models of glioblastoma and CNS metastasis. In Specific Aim 2, in vivo labeling of peripheral inflammatory cells with ferumoxides/protamine will be optimized in animal studies. We will characterize the use of this cellular contrast agent in imaging the BBB and intracerebral tumors with both MR and histological correlation. Specific Aim 3 will assess vascular and inflammatory changes at the BBB in neoplastic CNS lesions in a clinical trial comparing ferumoxytol magnetic nanoparticles and Gd at both 3T and 7T. Dynamic imaging, MR angiography and MRI will be performed in four subject groups: glioblastoma or metastatic CNS malignacy stratified by prior chemotherapy and/or radiation therapy. In Specific Aim 4, we propose to develop a Phase I clinical trial of the safety of ferumoxides/protamine and the potential to label circulating dendritic cells, to assess transvascular migration in tumor at both 3T and 7T. We hypothesize that state-of- the-art high Tesla MR imaging of nanoparticle perfusion and delivery in both animal brain tumor models and clinical trials may identify tumor responses before tumor shrinkage can be detected on conventional imaging. This proposal is responsive to PAS-03-165.