CION v2.0: a better way to T1 enhancement with iron oxides

Introduction and purpose

Molecular imaging and nanomedicine approaches to the diagnosis, monitoring and treatment of cardiovascular diseases, e.g. atherosclerosis, could have significant consequence on medical practice and outcomes. Due to the exquisite sensitivity of MR to magnetic field disturbances of iron oxides (IO), a variety of IO-based agents have been utilized. However, despite many elegant new imaging techniques, the highly-sensitive detection and visualization of IO still depends on the disruption of the local magnetic field. Contrary to typical IO agents, we have presented a novel colloidal iron oxide nanoparticle (CION) that encapsulates multiple magnetite nanocrystals suspended in oil, encased in a lipid membrane thereby reducing T2* effects such that T1 effects can be detected. The purpose of this work was to develop a CION with improved longitudinal relaxivity (r1) and the ability to carry drugs.

Methods

To evaluate the role of IO concentration within the oil core, CION were created with [IO] of 7.5%, 15% and 45% (w/v) Fe₃O₄, both with and without cross-linking the outer lipid membrane. To compare the effect of iron phase, CION was made with mixed-phase maghemite (Fe₂O₃-Fe₃O₄) at 7.5% (w/v). CION were characterized using dynamic light scattering, vibrating sample magnetometer, atomic force microscopy (AFM) and transmission electron microscopy (TEM). The r1 was calculated at 1.5 T using the Look-Locker technique to measure T1 of serial dilutions of CION. To demonstrate drug-carrying capability, fumagillin was incorporated into the outer surfactant. A dissolution study was performed over 3 d.

Results

Hydrodynamic diameter and zeta potential of the CIONs ranged from 110-300 nm and 23 to 40 mV, respectively, depending on composition. AFM revealed an asymmetric (deformable) particle size of 114 ± 22 nm (height) by 228 ± 69 nm (diameter). TEM confirmed that the iron nanocrystals were retained in the oil core. In all cases, r1 ([Fe]mMs^-1) of the cross-linked CION was 2-3× greater than the non-cross-linked version. Decreasing magnetite loading (45%, 15%, 7.5%) increased r1 from 1.8, 4.5, to 7.7, respectively. Comparing CION comprising magnetite vs. mixed-phased maghemite nanocrystals gave an r1 of 7.7 vs. 1.3, respectively, the lower susceptibility pure phase performing better. T1-weighted imaging confirmed r1 relationships (see Figure 1). For loading fumagillin into CION, 98% efficiency was achieved with less than 1% released over 3 d.

Figure 1

T1w images of various CION formulations. Cross-linking (top row) the outer lipid membrane dearly increases the T1 effects compared to without cross-linking (bottom row) as soes reducing the overall IO concentraion within the oily core of the CION (columns). At the highest iron concentration within the CION (45% w/v), the T2* effects overwhelm the T1 effects (bottom right).

Conclusion

Targeted CION is a positive-contrast T1 agent wherein pure magnetite, low Fe concentration, and cross-linking each augment overall r1 relaxivity. Additionally, CION offers a good potential platform for targeted drug delivery exhibiting excellent drug retention in dissolution.