Lanthanide(III) Complexes of Rhodamine–DO3A Conjugates as Agents for Dual-Modal Imaging

Abstract

Two novel dual-modal MRI/optical probes based on a rhodamine–DO3A conjugate have been prepared. The bis(aqua)gadolinium(III) complex Gd.L1 and mono(aqua)gadolinium(III) complex Gd.L2 behave as dual-modal imaging probes (r1 = 8.5 and 3.8 mM–1 s–1 for Gd.L1 and Gd.L2, respectively; λex = 560 nm and λem = 580 nm for both complexes). The rhodamine fragment is pH-sensitive, and upon lowering of the pH, an increase in fluorescence intensity is observed as the spirolactam ring opens to give the highly fluorescent form of the molecule. The ligands are bimodal when coordinated to Tb(III) ions, inducing fluorescence from both the lanthanide center and the rhodamine fluorophore, on two independent time frames. Confocal imaging experiments were carried out to establish the localization of Gd.L2 in HEK293 cells and primary mouse islet cells (∼70% insulin-containing β cells). Colocalization with MitoTracker Green demonstrated Gd.L2’s ability to distinguish between tumor and healthy cells, with compartmentalization believed to be in the mitochondria. Gd.L2 was also evaluated as an MRI probe for imaging of tumors in BALB/c nude mice bearing M21 xenografts. A 36.5% decrease in T1 within the tumor was observed 30 min post injection, showing that Gd.L2 is preferentially up taken in the tumor. Gd.L2 is the first small-molecule MR/fluorescent dual-modal imaging agent to display an off–on pH switch upon its preferential uptake within the more acidic microenvironment of tumor cells.

Magnetic resonance imaging, gadolinium neutron capture therapy, and tumor cell detection using ultrasmall Gd2O3 nanoparticles coated with polyacrylic acid-rhodamine B as a multifunctional tumor theragnostic agent

“…Lastly, pH-sensitive uorescent tumor cell detection of ultrasmall Gd 2 O 3 nanoparticle colloids was explored in this study. To this end, Rho was conjugated to surface-coating PAA through amide bond because Rho shows pH-dependent uorescent intensity in the visible region (l em ¼ 582 nm), which is useful for its use as a pH-sensitive tumor cell detection probe, [38][39][40] as well as for use as an FI agent. 40,41 Rho tints red in acidic conditions but has no color in basic conditions, and thus exhibits a stronger uorescent intensity at more acidic conditions.…”

Tuning the pKa of Fluorescent Rhodamine pH Probes through Substituent Effects

“…Recent examples include RSLs for the single‐wavelength monitoring of pH fluctuations in lysosomes and other biological environments, an RSL‐fluorescein construct for wide range pH monitoring, and RSL‐containing dyads for ratiometric pH measurements . Acid‐responsive RSLs have also been incorporated into macromolecular systems for pH sensing, tumor imaging, and anticancer drug release . The p K a values of RSLs vary with the spirolactam R group, with many rhodamine B‐derived probes intended for acidic pH monitoring falling in the pH 4–5 range.…”

A multimeric MR-optical contrast agent for multimodal imaging

“…12,13 However, the intrinsic variability of nanoparticles can be an obstacle for some applications. In order to address this issue, researchers have developed small molecule MR-optical contrast agents consisting of a Gd(III)-based chelate conjugated to near-IR dyes, 14 rhodamine, 15,16 cyanine7, 17 and fluorescein. 17 Typically, these agents have been shown to have relatively low relaxivities and limited water solubility.…”