In Vitro and in Vivo Magnetic Resonance Detection of Tumor Cells by Targeting Glutamine Transporters with Gd-Based Probes

Abstract

The glutamine transporting system is up-regulated in tumor cells because cell proliferation requires the uptake of large quantities of glutamine. It has been found that the paramagnetic magnetic resonance imaging (MRI) reporter Gd-DOTAMA-C6-Gln, where the glutamine residue is covalently bound to the Gd chelate through a C6 spacer, accumulates in tumor cells both "in vitro" and "in vivo" experiments. The observation that the relaxivity of cellular pellets does not increase with the increase in the amounts of entrapped Gd chelate is taken as an indication that the internalization has occurred through receptor mediated endocytosis. The iv administration of Gd-DOTAMA-C6-Gln allowed the MRI visualization of tumor masses in A/J mice grafted with the murine neuroblastoma cell line Neuro-2a and in Her-2/neu transgenic mice developing multiple mammary carcinoma, respectively.

Detection ofin situmammary cancer in a transgenic mouse model:in vitroandin vivoMRI studies demonstrate histopathologic correlation

“…If mice are to be used as successful models of human cancer biology, then imaging methods that detect in situ tumors are required to accurately assess preventive, diagnostic and therapeutic interventions. To date, however, there have been no reports of in vivo imaging of in situ or even nonpalpable invasive mammary gland cancers in mice (Abbey et al 2004, Artemov et al 2003, Bremer et al 2005, Galie et al 2004, Geninatti Crich et al 2006, Hsueh et al 2006, Jenkins et al 2005, Robinson et al 2003, Rodrigues et al 2004, 2006, Seemann et al 2006, Tian et al 2003). In fact, most imaging studies of mouse mammary cancer have focused on large tumors that are extremely advanced.…”

Synthesis and characterization of a cell-permeable bimodal contrast agent targeting β-galactosidase

“…In summary, we report the synthesis of a novel dual-labeled imaging probe Gd-DOTA-k(FR)-Gal-CPP, based on a galactose moiety with incorporated Gd-DOTA, FR and transduction (D-Tat [49][50][51][52][53][54][55][56][57] moieties. This contrast agent was produced using a multistep building block strategy.…”

“…In addition, the largely vesicular distribution of the probe in cells can cause so called relaxation quenching by restricting the number of water molecules which have access to the contrast agent. 48,49 Endosomal entrapment presumably reduced the extent of interactions between cytosolic enzyme and our conjugate. The detected higher accumulation of imaging reporters in C6/LacZ cells suggested, however, that a certain amount of conjugate could escape the vesicles and retained its intended functionality.…”

“…Thus, the unconverted CA should effectively efflux from cells in the absence of the target enzyme. To exploit the enzymatic cleavage reaction occurring at the anomeric center of the sugar unit, D-Tat [49][50][51][52][53][54][55][56][57] was incorporated at the C-1 position of galactose. The MRI imaging reporter was introduced at the C-6 position to maintain enzymatic activity.…”

Exploiting the Properties of Biomolecules for Brain Targeting of Nanoparticulate Systems

“…Another application of NPs is their use as contrast agents in magnetic resonance imaging (MRI) for detection of brain tumors. Gadolinium-based contrast agents are commonly used at present time [88], but they have a low targetspecifity, rapid exertion, and cause unwanted side effects in patients [89,90]. Superparamagnetic iron oxide nanoparticles (SPIONs), on the other hand, are highly sensitive and biocompatible but not tissue-specific.…”