Selective and responsive lanthanide/peptide based true dual probe for cyclin A/D

Project: Research project

Project Details

Description

Cyclin-dependent kinases (CDKs), the cyclin regulatory subunits and their natural inhibitors, the CDKIs, are central to cell cycle regulation; their functions are commonly altered in tumor cells. It has been shown that CDK’s isoform and substrate-selective inhibition can be achieved and they can potently inhibit CDK2/Cyclin A and CDK4/Cyclin D1 kinase activity. The transducible form of Cyclin groove inhibitor (CGI) peptides have also been shown to induce cell cycle arrest and selective apoptosis in tumor cells in vitro.

However CGI is not practical enough as clinical anti-tumor agents. The major drawbacks of the CGI as anti-tumor agent in vitro/in vivo are the cell internalization, its sensitivity to enzymes in vivo and effectiveness monitoring/evaluate via in-direct screening. The real-time evaluation of the anti-cancer effectiveness and in vitro/in vivo imaging for cyclin A/D specific peptides is still very difficult.

Recent research on CGI has been carried out to detect the level of cyclin in solution samples and as in vitro imaging probes via conjugation with organic fluorophores. Although, they are sensitie enough for decent prognosis, these chemosensors have broad emission bands, short luminescence lifetime (~ns) and low signal-to-noise ratio. Lanthanide ions have large Stokes shifts, sharper fingerprint emission peaks and longer emission lifetimes (~ms) and therefore could overcome the above problems. Furthermore, our blueprint also includes cyclin-specific lanthanide complexes with particular peptides and chromophores that could be excited in the near infra-red region via multi-photon excitation.

Our research team has the knowledge on lanthanide coordination chemistry, spectroscopy, peptide chemistry and in vitro biological applications, which are proved 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 cyclin A-specific europium complex with tailor made synthetic peptides that could be excited linearly and by two-photon to give responsive fingerprint europium emission; 2) improved rate of cellular uptake; and 3) photocleavage linker for the release of the peptide in solution via suitable excitation.

This proposal could be a big step forward in developing a new generation of lanthanide complexes conjugated with responsive chromophore and cyclin specific peptide as dual probes – imaging and anti-tumors. It is hoped that success in research could also lead to success in practical usage.
StatusFinished
Effective start/end date1/11/1231/10/15

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