Biologically-compatible gadolinium(at)(carbon nanostructures) as advanced contrast agents for magnetic resonance imaging

[摘要] Paramagnetic gadolinium-based carbon nanostructures are introduced as a new paradigm in high-performance magnetic resonance imaging (MRI) contrast agent (CA) design. Two Gd C60-based nanomaterials, Gd C60 [C(COOH)2]10 and Gd C60(OH)x are shown to have MRI efficacies (relaxivities) 5 to 20 times larger than any current Gd3+-based CA in clinical use. The first detailed and systematic physicochemical characterization was performed on these materials using the same experimental techniques usually applied to traditional Gd 3+-based CAs. Water-proton relaxivities were measured for the first time on these materials, as a function of magnetic field (5 x 10-4--9.4 T) to elucidate the different interaction mechanisms and dynamic processes influencing the relaxation behavior. These studies attribute the observed enhanced relaxivities completely to the ;;outer sphere;; proton relaxation mechanism. These ;;outer sphere;; relaxation effects are the largest reported for any Gd3+-based agent without inner-sphere water molecules. The proton relaxivities displayed a remarkable pH-dependency, increasing dramatically with decreasing pH (pH: 3--12). The increase in relaxivity resulted mainly from aggregation and subsequent three-order-of-magnitude increase in tauR, the rotational correlation time. Water-soluble fullerene materials (such as the neuroprotective fullerene drug, C3) readily cross cell membranes, suggesting an application for these gadofullerenes as the first intracellular, as well as pH-responsive MRI CAs. Studies performed at 60 MHz in the presence of phosphate-buffered saline (PBS, mice serum pH: 7.4) to mimic physiological conditions demonstrated that the aggregates can be disrupted by addition of salts, leading to a decrease in relaxivity. Biological fluids present a high salt concentration and should strongly modify the behavior of any fullerenes/metallofullerene-based drug in vivo. Gd C60[C(COOH)2]10 also showed enhanced relaxivity (23% increase) in the presence of the blood protein, human serum albumin (HSA). This result suggests a strong non-covalent interaction between Gd C60[C(COOH)2]10 and HSA leading to slower rotation and a subsequent increase in relaxivity. This also suggests Gd C 60[C(COOH)2]10 as a promising candidate for non-invasive MR angiographic applications to image the ;;blood pool.;; Finally, the various important factors or parameters discussed in this work provide valuable insight that can, in general, be used not only for the development of other carbon nanostructure-based MRI contrast agents, but also for any fullerene-based biomedical application.

[发布机构] Rice University

[效力级别] Materials science