Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review

Abstract

Superparamagnetic iron oxide nanoparticles have diverse diagnostic and potential therapeutic applications in the central nervous system (CNS). They are useful as magnetic resonance imaging (MRI) contrast agents to evaluate: areas of blood-brain barrier (BBB) dysfunction related to tumors and other neuroinflammatory pathologies, the cerebrovasculature using perfusion-weighted MRI sequences, and in vivo cellular tracking in CNS disease or injury. Novel, targeted, nanoparticle synthesis strategies will allow for a rapidly expanding range of applications in patients with brain tumors, cerebral ischemia or stroke, carotid atherosclerosis, multiple sclerosis, traumatic brain injury, and epilepsy. These strategies may ultimately improve disease detection, therapeutic monitoring, and treatment efficacy especially in the context of antiangiogenic chemotherapy and antiinflammatory medications. The purpose of this review is to outline the current status of superparamagnetic iron oxide nanoparticles in the context of biomedical nanotechnology as they apply to diagnostic MRI and potential therapeutic applications in neurooncology and other CNS inflammatory conditions.

Figures

Figure 1

(A) 1–8: Adapted with permission from Varallyay et al (2002). Patient with anaplastic oligodendroglioma. A.1–2: nonenhanced (A.1) and gadolinium-enhanced (A.2) SE T1-weighted images of a right temporal tumor. The gadolinium-enhanced image shows strong, lobulated peripheral enhancement with a central nonenhancing region. A.3: at 24 h after ferumoxtran-10 (Combidex) infusion, SE T1-weighted image shows high-signal intensity in a similar distribution, but with less peripheral lobulation, compared with the gadolinium-enhanced image. Also note that the nongadolinium-enhancing central zone became isointense to white matter, suggesting some ferumoxtran accumulation. A.4–6: fast SE T2-weighted image obtained before ferumoxtran-10 infusion (A.4) and fast SE T2-weighted (A.5) and GRE T2*-weighted (A.6) images obtained 24 h after ferumoxtran-10 infusion show a heterogeneous tumor mass with peripheral decreased signal intensity that is more prominent on the GRE T2*-weighted image. The distribution of low-signal intensity is similar to that of the high-signal intensity areas on the SE T1-weighted image (A.3). A.7–8: photomicrographs of pathologic specimens stained for iron (DAB-enhanced Perls stain). A.7: (original magnification—7.5 × ; bar indicates 1 mm), tumor (T) and reactive brain interface (RB) show intense staining for iron at the periphery of the tumor. A.8: (original magnification—100 × ; bar indicates 0.1 mm), cellular iron staining at the tumor-reactive brain interface shows iron uptake by parenchymal cells with fibrillar processes (arrows) rather than within the round tumor cells (T) themselves. (B) Adapted with permission from Muldoon et al (2005). Iron particle imaging of human small-cell lung cancer (LX-1 cell line) xenografts in a rodent model. B.1–8: T1 MRI scans (1.5 T) comparing ferumoxtran-10 (top), ferumoxytol (middle), and ferumoxides (bottom) 24 h after intravenous administration in nude rats with LX-1 intracerebral tumors. All animals were imaged at 9 days after tumor cell implantation except #3 and #4, which were imaged on day 6. B.9–10: iron histochemistry photomicrographs. Intense iron staining was found at the LX-1 tumor/reactive brain interface 24 h after administration of ferumoxtran-10 or ferumoxytol.

Figure 2

(A) MRI showing cerebral vasculature at 7 T. Minimum intensity projection (mIP) susceptibility-weighted images were obtained without contrast agent (A.1), with GBCA (gadoteridol, 0.1 mmol/kg, A.2), and immediately after USPIO injection (ferumoxytol 510 mg, A.3). The USPIO enhancement results in superior visualization of small intracerebral vessels. (B) 3D MPRAGE T1-weighted MRI in a patient at 3 T and 7 T without contrast (B.1 and B.4), with GBCA (B.2 and B.5), and with ferumoxytol (510 mg, 24 h after infusion—B.3 and B.6). GBCA associated T1-weighted signal intensity increases at higher magnetic field strength because of the increased nominal brain tissue T1 relaxation time constant, whereas ferumoxytol enhancement signal intensity is reduced because of increased T2* contributions at 7 T. (C) Adapted with permission from Neuwelt et al (2007). Time course of ferumoxytol enhancement in a patient with recurrent GBM. GBCA-enhanced T1-weighted (C.1), T2-weighted (C.2), and post-ferumoxytol T1-weighted (C.3–7) MRI scans were obtained using a 1.5 T MRI at five time points (C.3=4–6 h; C.4=6–20 h; C.5=24–28 h; C.6=48–52 h; C.7=∼72 h). Peak intensity is observed at the 24 to 28 h time point; much later than that observed with GBCA (not shown), which enhances maximally 3.5 to 25 mins after injection. The figure shows comparison of ferumoxytol-enhancement intensity curves at 1.5 T and 3 T MRI. Maximum ferumoxytol T1 enhancement is greater at 1.5 T than on 3 T.

Figure 3

(A) Cartoon depiction of cerebral blood volume (CBV) and mean transit time (MTT) calculation using DSC first-pass MRI. The first-pass effect of a contrast agent bolus in brain tissue is monitored using a series of T2*-weighted MR images from the same brain region, which is scanned repeatedly. The susceptibility effect of a paramagnetic (GBCA), or superparamagnetic (USPIO), contrast agent causes decreased signal intensity that can be converted into a contrast agent concentration. This concentration can then be converted into quantitative measurements of CBV proportional to the area under the curve (hatched area) assuming that the longitudinal relaxation time T1 of bulk tissue remains constant during bolus passage. This assumption holds true if the contrast agent is confined to the vascular space and the vascular volume fraction is so small that its contribution to the overall signal intensity may be neglected. (B) Comparison of gadodiamide versus ferumoxytol perfusion imaging in a highly vascular and permeable human glioma (U87 MG cell line) xenograft at 12 T. The curves depicted (B.1 and B.4) show the signal intensity—time course using standard rapid T2*-weighted gradient echo MR sequences during gadodiamide (B.1) and ferumoxytol (B.4) first-pass boli. Regions of interest were defined on the T2-weighted anatomical images (B.2 and B.5) in the tumor (red) and normal-appearing brain tissue (blue). Because of extravasation of the smaller molecular weight gadodiamide from the vasculature, CBV calculations (area under the curve proportional to area of DSC dip) will be inappropriately low. The CBV parametric maps (B.3 and B.6) show the discrepancy between CBV calculations using these two agents; ferumoxytol-based perfusion imaging correctly delineates elevated CBV in this aggressive tumor model. Adapted with permission from Neuwelt et al (2007) and Varallyay et al (2009).

Figure 4

(A) Discordance of rCBV calculated using ferumoxytol versus GBCA enhancement suggestive of pseudoprogression. At the middle of radiation time point (middle row), rCBV with ferumoxytol clearly shows increased blood flow (yellow/green area on rCBV with Fe parametric map marked with small red arrow) in a second posterior frontal lobe lesion (this lesion was not initially radiated after the patient's first resection of a left frontal GBM). After completion of radiation (bottom row), the area of GBCA enhancement is increased; however, DSC-MRI with ferumoxytol (third column) shows decreased rCBV compared with surrounding normal brain. (B) A 19-year-old man with GBM imaged pre- and postoperatively, after standard radiochemotherapy (RCT) and at multiple time points after treatment with bevacizumab. B.1: GBCA-enhanced, T1-weighted MRI before surgery shows a large ring enhancing lesion in the right parietooccipital lobe with mass effect and midline shift; B.2: postoperative image, before initiating RCT. B.3: MRI 1 month after completion of RCT revealed increased area of GBCA enhancement on T1-weighted images (see white arrow) with predominantly low blood volume except for a thin area of high blood volume at the periphery of the Gd- and Fe-rCBV parametric maps (B.4 and B.5). Note that the peripheral rCBV is more prominent (intense green/yellow circle marked by white arrow in image 5; the red area in image 4 is likely artifact) using ferumoxytol versus gadoteridol. Adjuvant temozolomide treatment was continued and bevacizumab treatment was then initiated. B.6–7: GBCA-enhanced, T1-weighted MRIs—after first and second courses of treatment with bevacizumab show significant improvements in mass effect and diminished contrast enhancement. B.8–10: after six treatments with bevacizumab and temozolomide, there is a slight increase in GBCA enhancement, but decreased rCBV on both gadoteridol and ferumoxytol perfusion imaging.

Figure 5

(A) Reprinted with permission from Saleh et al (2007). The USPIO-enhanced MRI of a 54-year-old man with infarction involving the left middle cerebral artery distribution reveals the differential development of USPIO-related signal changes over time. Compared with the nonenhanced, T1-weighted image 5 days after stroke (A.1), T1-weighted images 24 h (A.2), and 48 h (A.3) after USPIO infusion show increasing hyperintense signal enhancement in the periphery of the infarcted parenchyma. Nonenhanced, T2*-weighted image (A.4) displays hyperintense demarcation of the infarcted territory. T2*-weighted images 24 h (A.5) and 48 h (A.6) after USPIO infusion show signal change from hyperintense to hypointense attributable to USPIO perfusion. (B) Ferumoxytol MR angiography at 3 T of the supraaortic arteries in a kidney transplant patient with a glomerular filtration rate (GFR) <60 mL/mins/1.73 m2. Large plaque causes significant luminal narrowing at the origin of the innominate artery (red arrows). A significant stenosis was also observed at the origin of the left subclavian artery (not shown). Carotid bulb shows moderate stenosis on both sides (white arrows). Note the difference in diameter between the left and right carotid as well as the vertebral arteries. The color reproduction of this figure is available on the html full text version of the manuscript.

Figure 6

Adapted with permission from Manninger et al (2005). Patient with ADEM. Axial, T1-weighted images without (1), and with (2) gadolinium (inset, coronal) show faint, subtle enhancement in multiple brain stem lesions. Six days later, significant and more prominent enhancement can be seen at the same sites (3) using ferumoxtran-10 (inset, coronal). Three months later, the lesions no longer enhance on T1-weighted images with gadolinium (4).

Figure 7

(A) Pre- and postferumoxtyol (15 mins, middle row; 24 h, bottom row) enhanced 12 T MRIs after controlled cortical injury in a rat model of traumatic brain injury. At 72 h after injury, there is marked signal loss visualized on T2* (Fe 24 h images); (B) Phagocytic inflammatory cells, seen on H&E (B.1) and stained with CD68 (B.2) and fibronectin (B.3). (C) The inflammatory cells are at least in part derived from peripheral circulating monocytes as illustrated in panels (C.1) and (C.2), which show quantum dot (Invitrogen, Carlsbad, CA)-labeled peripheral mononuclear cells infiltrating around the cortical injury (#1; 800 × magnification) or within blood vessels on the uninjured side (C.2; 800 × magnification).