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In recent years, numerous Gd(3+)-based contrast agents have been developed to enable target-specific MR imaging of in vivo processes at the molecular level. The combination of powerful contrast agents and amplification strategies, aimed at increasing the contrast agent dose at the target site, is an often-used strategy to improve the sensitivity of biomarker detection. One such amplification mechanism is to target a disease-specific cell membrane receptor that can undergo multiple rounds of internalization following ligand binding and thus shuttle a sizeable amount of contrast agent into the target cell. An example of such a membrane receptor is the alpha(nu)beta(3) integrin. The goal of this study was to investigate the consequences of this amplification approach for the T(1)- and T(2)-shortening efficacy of a paramagnetic contrast agent. Cultured endothelial cells were incubated with paramagnetic liposomes that were conjugated with a cyclic RGD-peptide to enable internalization by means of the alpha(nu)beta(3) integrin receptor. Non-targeted liposomes served as a control. This study showed that alpha(nu)beta(3) targeting dramatically increased the uptake of paramagnetic liposomes. This targeting strategy, however, strongly influenced both the longitudinal and transverse relaxivity of the internalized paramagnetic liposomes., ((c) 2009 Wiley-Liss, Inc.)

The goal of this work was to elaborate a model describing the effective longitudinal relaxation rate constant R(1) for (1)H(2)O in three cellular compartments experiencing possible equilibrium water exchange, and to apply this model to explain the effective R(1) dependence on the overall concentration of a cell-internalized Gd(3+)-based contrast agent (CA). The model voxel comprises three compartments representing extracellular, cytoplasmic, and vesicular (e.g., endosomal, lysosomal) subcellular spaces. Relaxation parameters were simulated using a modified Bloch-McConnell equation including magnetization exchange between the three compartments. With the model, several possible scenarios for internalized CA distribution were evaluated. Relaxation parameters were calculated for contrast agent restricted to the cytoplasmic or vesicular compartments. The size or the number of CA-loaded vesicles was varied. The simulated data were then separately fitted with empirical mono- and biexponential inversion recovery expressions. The voxel CA-concentration dependencies of R(1) can be used to qualitatively and quantitatively understand a number of different experimental observations reported in the literature. Most important, the simulations reproduced the relaxivity "quenching" for cell-internalized contrast agent that has been observed., ((c) 2009 Wiley-Liss, Inc.)