Luminescent Lanthanide Chelate Contrast Agents and Detection of Lesions in the Hamster Oral Cancer Model

Abstract

Lanthanide chelates are a somewhat unique class of molecules that have proven to be useful in the biomedical field due to their extremely large Stokes' shift and long fluorescent lifetimes. The ability of these molecules to produce fluorescence in the low- or zero-back-ground regime makes this class of molecules excellent candidates for use as contrast agents for a wide variety of applications in biological settings. Here we present the preparation, spectroscopic characterization, and application of a new terbium chelate contrast agent, based on the 1,4,7,10-tetraazacyclododecane macrocycle (cyclen), for detection of early-stage malignant lesions in the Syrian hamster cheek pouch. Tb-P(CTMB) delivers bright blue-green luminescence when excited with low photon fluxes of UV light. As a pilot study, the DMBA-treated Golden Hamster Cheek pouch epithelial cancer model was employed and Tb-P(CTMB) was used as a topical agent for the visual detection of diseased tissue. In this preliminary study the agent tended to associate with early-stage malignant lesions, suggesting that Tb-P(CTMB) could be used as a contrast agent to aid in identifying early-stage oral cancer lesions.

A Versatile Ditopic Ligand System for Sensitizing the Luminescence of Bimetallic Lanthanide Bio‐Imaging Probes

“…[25] Tb III -based chelates have also proved useful, as exemplified by a lipid-conjugated chelate that functions as a membrane-staining agent in morphological studies of Swiss albino mouse 3T3 cultured cells, [22] or by Bornhops high brightness macrocyclic labels for in vitro and in vivo analysis of abnormal tissues. [18,26,27] More recently, Parker and co-workers have designed Eu III complexes that specifically stain the nucleoli of several cell lines (CHO, COS, NIH 3T3, HeLa, and HDF). [15,[28][29][30] Most lanthanide ions are also paramagnetic and possess an anisotropic susceptibility tensor that makes them useful for the structural investigation of axial complexes [31] or proteins [32] by NMR spectroscopy, while Gd III has emerged as a universal contrast agent for 3D imaging of biological structures (MRI).…”

Efficiency of the energy transfer in lanthanide-organic chelates; spectral overlap integral

“…The luminescent lanthanide complexes are the promising probes for the detection of the early states of the cancer [1][2][3][4]. In such an application the administered complexes are directed to a particular tissue and they are cumulated in the proximity of the cancer cells to a greater extent than around the healthy cells.…”

Proton-assisted dissociation of a triple-stranded dinuclear europium helicate

“…11 The poor solubility below pH ¼ 6 and the precipitation of the ligand L at pH ¼ 4 prevent the determination of the other protonation constants which were estimated to be at about 5.4 for log K LH 4 and lower than 2 for log K LH 5 and log K LH6 . 15 Under very acidic conditions, below pH ¼ 2, L re-dissolves, due to protonation of the carboxylate functions.…”

“…3b Furthermore, the long excited state lifetimes of several Ln(III) ions are ideally suited for the engineering of immunoassays using time-resolved luminescence for the separation of the probe phosphorescence from the background fluorescence. 2a,b Finally, stimulating developments are presently taking place in which lanthanide probes emitting in the visible allow the imaging of cancer cells, 4 and this methodology is being extended to the near infrared (Nd, Er, Yb), a spectral range in which biological tissues have little absorption. 5 These applications require the design of lanthanide chelates with high thermodynamic stability and kinetic inertness under physiological conditions.…”