A new class of gel-based DO3A-ethylamine-derived targeted contrast agents for MR and optical imaging

Anurag Mishra, Josef Pfeuffer, Ritu Mishra, Jörn Engelmann, Anil K. Mishra, Kamil Ugurbil, Nikos K. Logothetis

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63 Scopus citations

Abstract

Synthetic bifunctional probes based on [4,7-bis-carboxymethyl-10-(2- aminoethyl)-1,4,7,10-tetraaza-cyclododecl-yl]-acetic acid (DO3A-ethylamine) preloaded with gadolinium were prepared for applications in targeted magnetic resonance imaging (MRI) and optical imaging. A convenient route of synthesis is reported, which allowed conjugation of this probe with biomolecules for the preparation of model MR contrast agents for targeted imaging. The conjugated probes have the following interesting properties: (1) GdDO3A-ethylamido-biotin (Gd-9) can be used for targeted imaging using an avidin-biotin system. (2) The fluorescent probe GdDO3A-ethylthioureafluorescein (Gd-12) is a bimodal compound, which can be used for both MR and optical imaging. The precursors, DO3A-ethylamidopropyl-maleimide (11) and DO3A-ethyl-isothiocyanate (13) contain a highly reactive moiety, which can interact with free SH-terminals and N-terminals of biological molecules, respectively. In vitro MR relaxivity studies were performed at 300 MHz using different concentrations and chemical environments. MR relaxivity for ligand Gd-9 at pH 7.4, r1 was (3.32 ± 0.03) s-1 mM-1 and r2 was (5.02 ± 0.14) s-1 mM-1. For the mixture of Gd-9 with avidin, at pH 7.4, relaxivity increased linearly with the avidin concentration. A relaxivity enhancement of 45% for r1 and more than 400% for r 2 with respect to the unbound biotinylated Gd3+ complex was found at a ratio of 4:1. MR relaxivity for ligand Gd-12, r1 was (5.36 ± 0.05) s-1 mM-1 at pH 7.4. Fluorescence microscopy and spectroscopy of Gd-12-labeled 3T3 mouse fibroblasts showed a concentration-dependent intracellular uptake, accompanied by a slight dose-dependent increase in toxicity up to 150 μM. MR studies on labeled cells indicated a contrast enhancement in both T1- and T 2-weighted images by the internalized compound, with the effect being more pronounced in T2-weighted images. Our results indicate that DO3A-ethylamine is a multipurpose precursor, from which various targeted contrast agents can be synthesized after a single-step conjugation with organic/bioorganic molecules.

Original languageEnglish (US)
Pages (from-to)773-780
Number of pages8
JournalBioconjugate Chemistry
Volume17
Issue number3
DOIs
StatePublished - May 1 2006

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    Mishra, A., Pfeuffer, J., Mishra, R., Engelmann, J., Mishra, A. K., Ugurbil, K., & Logothetis, N. K. (2006). A new class of gel-based DO3A-ethylamine-derived targeted contrast agents for MR and optical imaging. Bioconjugate Chemistry, 17(3), 773-780. https://doi.org/10.1021/bc050295b