In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide

Abstract

Multiple sclerosis (MS) is a disease of the central nervous system that is associated with leukocyte recruitment and subsequent inflammation, demyelination and axonal loss. Endothelial vascular cell adhesion molecule-1 (VCAM-1) and its ligand, α 4 β 1 integrin, are key mediators of leukocyte recruitment and new selective inhibitors that bind to the α 4 subunit of α 4 β 1 substantially reduce clinical relapse in MS. Urgently needed is a molecular imaging technique to accelerate diagnosis, quantify disease activity and guide specific therapy.We report in vivo detection of VCAM-1 in acute brain inflammation, using MRI in a mouse model, at a time when pathology is otherwise undetectable. Antibody-conjugated microparticles carrying a high payload of iron oxide provided potent, quantifiable contrast effects that delineated the architecture of activated cerebral blood vessels. Rapid clearance from blood resulted in minimal background contrast. This technology is adaptable to monitor expression of endovascular molecules in vivo in a range of pathologies.Multiple sclerosis (MS) is a disease of the central nervous system characterized by multifocal white matter lesions 1 . Current diagnostic criteria for MS, incorporating both clinical and magnetic resonance imaging (MRI) characteristics, require the demonstration of lesion dissemination in both time and space 2 , 3 T2-weighted and gadolinium-enhanced T1-weighted MRI detect some, but not all, lesions while advanced MRI techniques such as diffusion imaging 4 , magnetization transfer 5 and MR spectroscopy 6 may provide additional insights. However, these approaches are limited in two key respects: (1) they image downstream injury, reflecting relatively advanced pathology and (2) while providing an indication of severity, current imaging techniques can not accurately assess disease activity 7 .

Molecular MRI enables early and sensitive detection of brain metastases

“…The low background or nonspecific MPIO binding in the control groups indicates both the high specificity of the VCAM-MPIO for VCAM-1 expression, as previously shown (19), and the lack of constitutive VCAM-1 expression in normal cerebral vasculature. This latter finding is in accord with our previous findings and suggests that up-regulation of VCAM-1 is a consequence rather than an initiating event for the development of brain metastases.…”

“…This property has previously been used to track MPIO-labeled tumor cells in mouse models, thus enabling visualization of early metastasis distribution in the brain with sensitivity down to a single metastatic cell loaded with ∼50 pg iron at an imaging field strength of 1.5 T (17). Alternatively, conjugation of MPIO with targeting ligands enables their accumulation at sites where specific molecules are expressed (18)(19)(20)(21)(22)(23)(24)(25). Importantly, the targeted MPIO are not taken up by endothelial cells and do not enter the brain, thus providing an endovascular biomarker for pathology within the brain.…”

“…Importantly, the targeted MPIO are not taken up by endothelial cells and do not enter the brain, thus providing an endovascular biomarker for pathology within the brain. In particular, we have shown that, by conjugating anti-VCAM-1 antibodies to MPIO, we are able to detect VCAM-1 up-regulation on the cerebral endothelium with high sensitivity in vivo (19). Our objectives, therefore, were to determine whether endothelial VCAM-1 is up-regulated in association with brain metastases, and if so, whether our VCAM-1-targeted MRI contrast agent could enable early detection of these tumors.…”

“…VCAM-MPIO or control IgG-MPIO were synthesized as described previously (19). On the day of imaging, 4T1-injected mice were anesthetized with 2-3% (vol/vol) isoflurane in 70% N 2 O:30% O 2 (vol/vol) and injected i.v.…”

Systemic Inflammatory Response Reactivates Immune-Mediated Lesions in Rat Brain

“…Areas of hypointensity resulting from ultrasmall superparamagnetic iron oxide particles (USPIO) accumulation on ex vivo 3D high-resolution imaging were quantified by drawing around the regions of T 2 * hypointensity in the injected hemisphere on a slice-by- slice basis. 3D reconstruction maps of USPIO accumulation were generated using Image Pro software (version 4.5.1; Media Cybernetic) as described previously (McAteer et al, 2007).…”