Fundamentals to Applications: The Practical Luminescence Lanthanide Toolbox for Imaging of Key Cell Cycle Regulators (Plk1) and Inhibition of Tumor Cells

Polo-like kinase 1 (Plk1), involved in many key steps throughout mitosis, is found to be of great important in cancer treatment since its activity appears to be limited to mitosis in proliferating cells. However, the lack of selective small-molecule inhibitors of the kinase remains a major obstacle to further elucidate its precise functions. For instance, using anticancer agents that target microtubules may engender various adverse effects partially because of the diverse functions of microtubules in the cell. To date, only few small molecules can show the very specificity to Plk1 for imaging and inhibition. It is self-evident that the enhanced understanding of Plk1 activities will considerably favour the design and imple¬mentation of future experiments in the research, preclini¬cal, and clinical settings, adding muscle to our war against cancer.

Although decent prognosis can be achieved by these small molecules, such chemosensors (i.e. BI 2536) are not without disadvantages: broad emission bands, short luminescence lifetimes (~ns) and ease of photo-bleaching. In contrast, lanthanide complexes, in this regard, do surpass all their counterparts, having large Stokes shifts, sharper fingerprint emission peaks, longer emission lifetimes (~ms) and higher photo-stability. Our blueprint includes the cyclin-specific lanthanide complexes with particular peptides and chromophores that can be excited in the near infra-red region via multi-photon excitation, and, above all, be Plk1-specific.

Our research team is experienced in lanthanide coordination chemistry, spectroscopy, peptide chemistry and in vitro biological applications, as justified by our previous publications on responsive luminescent lanthanide materials towards various biological tasks in solution/in-vitro. To further support our work, we have performed several proof-of-concept experiments to consolidate our proposal: (1) synthesis of a Plk1- specific europium complex with tailor-made synthetic peptides that could be excited linearly and by two-photon(s) to give responsive fingerprint europium emission; (2) molecular docking shows our complexes can fit in the Plk1; and (3) they are all cell permeable and available for in-vitro imaging.

This proposal will pave the way for the development of a new generation of lanthanide complexes conjugated with responsive chromophores and Plk1 specific peptides as dual probes – imaging and anti-tumor. It is hoped that the success in research could also lead to the success in practice, thereby providing more powerful tools (especially available to combine multi-photon and time-resolved technology) to get a more complete picture of the role of Plk1 kinase.