Lanthanide-functionalized vitamin B12 probes for targeted tumor bio-imaging: from rational design to biological evaluation

Polisicchio, Rosy
Lanthanide luminescent complexes offer great potential as diagnostic agents. Thanks to low photobleaching, large Stokes shifts, long lifetimes, and emission tunability, they provide advantages compared to organic chromophores. However, the synthetic design requires careful consideration to generate stable and inert complexes using appropriate ligands that can fulfil the lanthanide coordination sphere, while sensitizing metal-centred luminescence. Moreover, to obtain suitable diagnostic agents for cancer, the overall probe must selectively detect tumour cells. Vitamin B12 (aka cyanocobalamin) is an essential nutrient with very low bioavailability. Since tumour cells require higher amounts of cyanocobalamin to support their abnormal proliferation rate, it turns out to be a very attractive carrier for conjugation to rationally designed imaging agents, to specifically target tumour sites. Vitamin B12 can be functionalized at the 5’-hydroxo group of the ribose unit with a suitable luminescent probe through a rigid linker without affecting its recognition by transport proteins. Starting from this rationale, the present PhD research work focuses on the design and synthesis of luminescent lanthanide-vitamin B12 imaging agents in which the cyanocobalamin scaffold would be functionalized with selected non-toxic lanthanide (III)-DOTA-based luminescent probes with a focus on Eu(III), Tb(III) and Gd(III). The goal is to take advantage of the increased demand for vitamin B12 in tumours by exploiting its carrier properties to generate site-specific “Trojan Horse”-type diagnostic bioconjugates. Preliminary in vitro cytotoxicity studies are presented towards MCF-7 cells showing a dose-dependency toxicity only when the carrier is incorporated. No fluorescence was detected with optical microscope in vitro, hence more analysis using confocal microscope are required to confirm the efficiency of the probes as luminescent agents.
University of Galway
Publisher DOI
Attribution-NonCommercial-NoDerivatives 4.0 International