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. 2009 Dec 22;3(12):3917-26.
doi: 10.1021/nn900819y.

Conquering the dark side: colloidal iron oxide nanoparticles

Angana Senpan  1 , Shelton D Caruthers, Ilsu Rhee, Nicholas A Mauro, Dipanjan Pan, Grace Hu, Michael J Scott, Ralph W Fuhrhop, Patrick J Gaffney, Samuel A Wickline, Gregory M Lanza
Affiliations

Conquering the dark side: colloidal iron oxide nanoparticles

Angana Senpan et al. ACS Nano. .

Abstract

Nanomedicine approaches to atherosclerotic disease will have significant impact on the practice and outcomes of cardiovascular medicine. Iron oxide nanoparticles have been extensively used for nontargeted and targeted imaging applications based upon highly sensitive T2* imaging properties, which typically result in negative contrast effects that can only be imaged 24 or more hours after systemic administration due to persistent blood pool interference. Although recent advances involving MR pulse sequences have converted these dark contrast voxels into bright ones, the marked delays in imaging from persistent magnetic background interference and prominent dipole blooming effects of the magnetic susceptibility remain barriers to overcome. We report a T1-weighted (T1w) theranostic colloidal iron oxide nanoparticle platform, CION, which is achieved by entrapping oleate-coated magnetite particles within a cross-linked phospholipid nanoemulsion. Contrary to expectations, this formulation decreased T2 effects thus allowing positive T1w contrast detection down to low nanomolar concentrations. CION, a vascular constrained nanoplatform administered in vivo permitted T1w molecular imaging 1 h after treatment without blood pool interference, although some T2 shortening effects on blood, induced by the superparamagnetic particles, persisted. Moreover, CION was shown to encapsulate antiangiogenic drugs, like fumagillin, and retained them under prolonged dissolution, suggesting significant theranostic functionality. Overall, CION is a platform technology, developed with generally recognized as safe components, that overcomes the temporal and spatial imaging challenges associated with current iron oxide nanoparticle T2 imaging agents and which has theranostic potential in vascular diseases for detecting unstable ruptured plaque or treating atherosclerotic angiogenesis.

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Figures

Figure 1
Figure 1
(A) AFM of 0.5% ([Fe] w/v) CION Hav 114nm Dav 228nm, reflecting high compliance of the soft particle on the hard surface. (B) and (C) TEM of distribution of colloidal iron oxide nanoparticles demonstrating that the oleate-coated magnetite particles are incorporated into the oil core and the core is encapsulated with lipid layer (inset B). (D) Number-averaged hydrodynamic diameter distributions of Colloidal iron oxide nanoparticles.
Figure 2
Figure 2
(A) XRD analysis of magnetite (Fe3O4) and mixed-phase maghemite (Fe2O3-Fe3O4) iron oxide crystals used in for the CION nanoparticles in this study. (B) VSM magnetization (emu / liquid gram) result for mixed-phase maghemite (Fe2O3-Fe3O4) CION with (with XL) and without (No XL) cross-linking, which is 3× greater than magnetite (Fe3O4) presented in C. Note that surfactant cross-linking consistently decreases the magnetic susceptibility of both forms of iron oxides.
Figure 3
Figure 3
T1 relaxivity (r1) of CION particles: (Left) pure phase Fe3O4 (magnetite). (Right) Fe2O3-Fe3O4 (mixed phase maghemite). The r1 for the cross-linked, pure magnetite CION (Fe3O4) was 7.7 ([Fe]mM · s)-1 versus 1.3 ([Fe]Mm · s)-1 for Fe2O3-Fe3O4 (mixed phase maghemite) CION, a 6× improvement associated with the lower magnetic susceptibility iron crystals.
Figure 4
Figure 4
T1 relaxivity (r1) of 0.5% (left), 1.0% (middle), and 3.0% (right) (w/v) magnetite (Fe3O4) loaded CION. Improved relaxivity was observed with surfactant cross-linking (XL) and lower iron concentrations. X-axis varies due to inherent differences in [Fe].
Figure 5
Figure 5
(A) T1w images of CION with and without surfactant cross-linking at different loadings between 0.5% and 3.0%, (w/v) of magnetite in 96-well plastic dish in DI water in spaces surrounding the wells. (B) T1w-TSE image illustrates apparent, concentration dependent, contrast with 0.5% CION at low nM nanoparticle concentrations.
Figure 6
Figure 6
(A-D) Fibrin-rich clots in saline imaged at 1.5T. (A) Control untargeted clot is not well seen on high resolution T1w-TSE, whereas the clot with fibrin-targeted CION (B) enhances brightly. On lower resolution T1w gradient echo (FE) (C) the T1 effect is lessened and with T2 imaging (D) the typical signal dropout effects of superparamagnetic iron oxides are pronounced, almost completely obscuring the bright signal from saline within the test tube. (The very outer most fluid is copper sulfate-doped “phantom fluid”, which is bright on both T1 and T2). (E) Carotid endarterectomy samples targeted with CION and imaged at 3T with bright enhancement fibrin rich plaque on T1w-TSE; whereas gradient echo images of the same tissue (T1- and T2-weighted) displayed marked T2* effects (T1w image shown). (F-G) Dynamic T1 (F) and T2 (G) changes in blood following IV injection of CION in NZW rabbit which show T1 background contrast due to the persistence of CION in circulation reaches preinjection levels after 1 hour; whereas, the T2 background contrast level persists much longer as is expected of superparamagnetic agents imaged with T2 weighting.
Figure 7
Figure 7
Cartoon illustrating hypothesis of decreased T2* effects of CION to SPIO. (a) A typical iron oxide particle surrounded by water within a B0 field. The field dependent dipole moment created is shown. Protons pass deep within this magnetic flux field and experience strong dephasing T2 effects. (b) The encapsulation of CION iron crystals reduces the effective field experienced by the surrounding protons, such that the relative impact on T2* is greater than the changes of T1 relaxivity. (c) The encapsulation of CION iron crystals with surfactant cross-linking further reduces the effective field experienced by the surrounding protons, such that the impact on T2* is further increased relative to the changes of T1.
Scheme 1
Scheme 1
Preparation of CION nanoparticles
See this image and copyright information in PMC

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