Superparamagnetic iron oxide nanoparticles: promises for diagnosis and treatment of multiple sclerosis

Abstract

Smart superparamagnetic iron oxide nanoparticles (SPIONs) are the most promising candidate for theragnosis (i.e., diagnosis and treatment) of multiple sclerosis. A deep understanding of the dynamics of the in vivo neuropathology of multiple sclerosis can be achieved by improving the efficiency of various medical techniques (e.g., positron emission tomography and magnetic resonance imaging) using multimodal SPIONs. In this Review, recent advances and challenges in the development of smart SPIONs for theragnostic applications are comprehensively described. In addition, critical outlines of emerging developments are provided from the points of view of both clinicians and nanotechnologists.

Keywords: Superparamagnetic iron oxide nanoparticles; multimodality; multiple sclerosis; neuropathology; theragnosis.

Figure 1

Most prominent classification, synthesis routes, and application of nanomaterials.

Figure 2

Effect of the USPIONs on the MR contrast in inflamed muscle. Typical T₂-weighted images before (top) and 3 h after (bottom) the administration of USPIO-PEGsLeX. The control muscle is located on the left, the inflamed muscle on the right. The white circles indicate the regions of interest in the inflamed muscles with an obvious signal decrease after administration of USPIO-PEG-sLeX. Reproduced with permission from ref (149). Copyright 2000 Elsevier.

Figure 3

Axial GE MR images of healthy (A, B) and Con A-treated (C, D) mice 65 min after the injection of 30 mmol Fe/kg USPIONs (B, D) or USPIO-g-sLex (A, C). Color scale used for MR images shows signal intensity mapping with the Osiris software (E). Reproduced with permission from ref (150). Copyright 2004 Elsevier.

Figure 4

Development of a contrast agent for molecular diagnosis of atherosclerotic plaques (pre-clinical studies conducted on mice ApoE-/-); unpublished work by authors.

Figure 5

Evans rats received intravenous Fe-Pro complex, ferumoxytol (20 mg/kg)-Pro (2 mg/kg), or Pro alone. Whole blood, plasma, and mononuclear leukocytes were isolated after 2 h and transferred to a 96-well microtiter plate in 0.25% agarose. The presence of iron is indicated by a T₂ shortening effect (signal loss). Iron particles can be identified in the well containing isolated leukocytes after in vivo iron labeling with Fe-Pro complex but not after ferumoxtyol-Pro injection. Reproduced with permission from ref (116). Copyright 1998 Informa Healthcare.

Figure 6

3D data sets of T₂*-weighted images taken (A, C, and E) and 3D reconstructions of the accumulation of contrast agent (B, D, and F) reveal that glycol nanoparticles conjugated with sLe(x) enable clear detection of lesions in clinically relevant models of MS (C and D) and stroke (E and F) in contrast to unfunctionalized control nanoparticles (A and B). In addition, use of a gadolinium-based contrast agent in spin−echo T₁-weighted images to assess BBB permeability (G) and regional cerebral blood volume (H) failed to detect the presence of pathology. Views are from the front depicting left brain on the right-hand side. Reproduced with permission from ref (166). Copyright 2009 American Roentgen Ray Society.

Figure 7

MRI brain scans of EAE animals during acute phase, i.e., 11, 12 dpi (first row), remitting phase 18, 19 dpi (second row), and first relapse 24, 25 dpi (third row). Left column: USPIONs enhancement. Tissue infiltrated by labeled macrophages appears hypointense in T₂-weighted images. Middle column: MTR maps. There are no large changes visible in the images. Right column: Enhancement of Gd-DOTA in brain tissue as a marker for BBB damage. Areas of Gd-DOTA extravasation in the medulla appear blue on the Enh maps. Enhancement of Gd-DOTA in the medulla is more diffuse as compared with USPIONs enhancement. Reproduced with permission from ref (173). Copyright 2010 Informa Healthcare.

Figure 8

Mismatch of contrast agent uptake in a USPIONs-enhanced acute MS plaque. MR imaging 1 T₂-weighted image (A) and T₁-weighted postgadolinium image (B) show a large MS lesion that was not enhanced by gadolinium. MR imaging 2 shows the USPIONs uptake at the periphery of the lesion (arrows), seen as a decreased signal intensity on T₂-weighted images (C) and a high signal intensity on T₁-weighted images (D). Reproduced with permission from ref (179). Copyright 2005 Wiley-Liss, Inc.

Figure 9

Cross-sectional patterns of lesion enhancement: pre-Gd T2SE images showing multiple periventricular MS lesions (A and E), pre-Gd T₁-weighted images showing hypointensity of some of the MS lesions (B and F), post-Gd T₁-weighted images showing several MS lesions enhanced with Gd in focal and ringlike patterns (C and G), post-USPIONs T₁-weighted images showing different patterns of USPIONs enhancement. Arrowhead upper row: focal USPIONs-enhancement. Arrows upper row: ringlike USPIONs-enhancement. Arrow bottom row: change to isointensity of a previously hypointense lesion as seen on precontrast T₁-weighted images (see B and F). Arrowhead bottom row: hypointense lesion that remains hypointense on post-USPIONs images (D and H). Pre-Gd T2SE images showing MS lesions (I), pre-Gd T₁-weighted images showing hypointensity of some of the MS lesions (J), some lesions are Gd-DTPA-positive (K), post-USPIONs images showing a Gd-DTPA-positive, USPIONs ring-enhancing lesion (arrow) and a Gd-DTPA-negative, focally USPIONs-positive lesion (arrowhead) (L). Reproduced with permission from ref (184). Copyright 1999 Springer.

Figure 10

Cartoons of the loading/release function of future smart SPIONs for MS therapy, illustrating drug interaction with polymer brushes (A), trapping of drug using responsive behavior of polymer (B), and preservation and release of drug in the normal (C) and inflamed (D) sites due to the pH-responsive capability of polymer.