For this review study, using the keywords ‘MRI, Ferumoxytol, brain, macrophage-targeted’, ferumoxytol based macrophage–targeted MRI-CA primary research studies on human and animal brain tumor diagnosis and brain arteriovenous malformation s(bAVM) were searched for publications dating between 2005 and 2018 in the Web of Science database, described and listed in Figures 4&5.
Macrophages(M), the circulating white blood cells, are involved in the detection and elimination of microorganisms, nanoparticles, dead cells and abnormal tissue [12,13] (Figure 1). The duality of macrophage-associated response, which is essential for immunity (M1 phenotype) and tissue repair (M2 phenotype), involves both inflammatory and therapeutic mechanisms. The extent of macrophage-mediated inflammatory response in diseases such as atherosclerosis, cancers and damaged vasculature in the CNS can be used to monitor presence and status of inflammation. Using Ferumoxytol phagocytosis by macrophages, the malignant tumors, progression of brain arteriovenous malformation (bAVM) and the risk of rupture can be monitored [14-16].
The vascular leakage of ferumoxytol to cancerous tissue is manifested as the greater accumulation of molecules in tumor tissue than in normal tissues, due to Enhanced Permeability and Retention (EPR) effect (Figure 2) [17]. With the growth of tumor cells, angiogenesis (vascularization) is stimulated by various growth factors to nourish and oxygenate the tumor cells. Angiogenesis may thus produce vessels with wide fenestrations and poor lymphatic drainage, muscular layer and innervation. The blood vessel structure may lead to enhanced vascular permeability caused by molecules and factors, compounded with lack of lymphatics and thus retention of macromolecules and lipids in solid tumors [17].
The vascular leakage of ferumoxytol into the cancerous tissue enables the MRI of malignant CNS lymphomas using USPIO nanoparticles [18,19], especially when malignant tumors cannot be distinguished from benign via contrast-enhanced MRI. Ferumoxytol enhanced MRI (FeMRI) has thus been shown to differentiate metastatic disease from meningiomas using the differences in tumor vasculature [20,21]. Histopathological studies have shown compartmentalization of ferumoxytol NPs in macrophages associated with cancerous tissue within 24 hours of injection. In animal models and in human trials, the negative (dark) tumor enhancement on T2-weighted MRI and a decreased T1-signal effect, are indicative of intracellular compartmentalization of ferumoxytol by the metabolically active, proliferating M1 and M2 macrophages [7,13].
Progression of brain arteriovenous malformation (bAVM) and the risk of rupture may also be indicated by macrophage-targeted ferumoxytol use in MRN of CNS inflammation, such as cerebral aneurysms, CNS arteriovenous malformations and inflammatory diseases [12,15-16,22-23]. Intracranial aneurysm formation may involve factors such as hemodynamic stress, endothelial dysfunction, and inflammation due to oncotic or microorganismal infiltration, resultin in higher levels of immunologic elements in the aneurysm wall than in normal vessels [24]. Aneurysm formation and rupture have been shown to involve immunological pathways and mediators leading to prolonged inflammatory changes and thus continued wall remodeling, low-density lipoprotein accumulation, atherosclerotic and fibrotic changes culminating in the infiltration of polymorphonuclear cells [24,25]. Cerebral aneurysm progress is indicated by the M1 cells, and an increased M1/M2 ratio. Inflammatory cytokines from M1 cells initiate the pathological changes of aneurysmal walls. Sustained inflammatory response may lead to apoptosis and to aneurysm rupture [26], indicated by presence of increasing number of macrophages within several hours after injection, forming a peak at 24 hours and lasting for minimum 3 days [8,27,28]. High numbers of macrophages weaken the aneurysm wall by secreting extracellular matrix proteolytic enzymes and reactive oxygen species, where early in vivo ferumoxytol internalization within 24-hrs is indicative of aneurysmal instability and rupture within 6 months [24].
Fe-MRI, used to detect delayed development assessment of Ferumoxytol phagocytosis by macrophages, has been shown to visualize CNS tumors at all field forces using MRI within 24-28 hours after administration [29,30,31]. Fe-MRI can potentially be used as a biomarker to research lesional macrophage infiltration, time based progression and prevalence of inflammation and to assess therapeutic progress [32,33].
Limitations of Fe-MRI arise from subtraction of pre- and post-injection images to eliminate hemoglobin signals. The 2D-Gradient echo MR images acquire macrophage images with re time gap. Subtraction of MRI T2* images may be complicated with the MRI resolution and the aneurysm wall thickness in a clinical setting. The SNR correlates inversely with the dose, making the use of high doses difficult [1,8,34].