Development And Evaluation Of Magnetic Resonance Contrast Agents

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Abstract

Various MRI contrast agents have been developed for cellular MR imaging over the past few years. In general most contrast agents used for cell labeling are superparamagnetic iron oxide nanoparticles (SPIO) that result in T2 and T2 shortening of the surrounding tissues and hypointense regions on T2 weighted MRI. Gadolinium or manganese based agents can be used to enhance signal from regions on T1weighted images. Gadolinium based nanoparticles combined with single wall carbon nanotubes can be used as MRI contrast agent. We investigated the physiochemical properties of gadolinium (Gd) catalyzed single-walled carbon nanotubes (Gd-SWCNTs). Gd-SWCNTs are paramagnetic with an effective magnetic moment of 7.29B. Gd-SWCNT solutions show high r1 and r2 relaxivities at very low (0.01 MHz) to clinically relevant (61 MHz) magnetic fields (r1 &#8805; 130 mM-1s-1, r2 &#8805; 160 mM-1s-1). T1 weighted MRI signal intensity of Gd-SWCNT phantom solution is 14 times greater than the Gd chelate-based clinical MRI contrast agent. Additionally, these nanotubes exhibit near infrared fluorescence with distinct transitions consistent with several semiconducting SWCNTs. These results demonstrate that Gd-SWCNTs have potential as a novel, highly efficacious, multimodal MRI-NIR optical imaging contrast agent. We also evaluated manganese (Mn) G8 dendrimers targeted to oxidation-specific epitopes (OSE) allow for in vivo detection of atherosclerotic lesions. OSE have been identified as key factors in atherosclerotic plaque progression and destabilization. Mn offers a potentially clinically translatable alternative to gadolinium-based agents when bioretention and potential toxicity of gadolinium is anticipated. However, to be effective, high payloads of Mn must accumulate intracellularly in macrophages. We used G8 dendrimers targeted to OSE may allow delivery of high Mn payloads, thereby enabling in vivo detection of macrophage-rich plaques. G8 dendrimers were modified to allow conjugation with MnDTPA (758 Mn ion) and the antibody MDA2 that is targeted to malondialdehyde (MDA)-lysine epitopes. Both the untargeted and targeted G8 dendrimers were characterized and their in vivo efficacy evaluated in apoE-/- mice over a 96-hour time period after bolus administration of a 0.05 mmol Mn/kg dose using a clinical MR system (3T). Significant enhancement of atherosclerotic lesions was observed within a 72-hour time period following administration of the targeted dendrimers. The presence of Mn within atherosclerotic lesions was confirmed using spectroscopic methods. Limited signal attenuation (<18%) and Mn deposition was observed in the arterial wall following injection of the untargeted material. This study demonstrates that manganese-labeled dendrimers, allowing a high Mn payload, targeted to OSE may allow in vivo image of atherosclerotic lesions.