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Imaging Chemistry and Biology (pre-2019)

Novel theranostic targeted anti-cancer probe for multi-modal imaging on multiple scales

Project ID: 2015_205

Student: Rainbow Lo

1st supervisor: Gilbert Fruhwirth, King’s College London
2nd supervisor: Ramon Vilar, King’s College London

G-quadruplexes (G Qs) are non-canonical secondary structures that can be adopted by guanine-rich DNA and RNA sequences. Such DNA sequences are frequently found in telomeres and regulatory regions of oncogenes (e.g. MYC), thus playing important roles in cancer biology. Furthermore, G Qs of messenger RNA were very recently identified to be responsible for translational control and immune evasion of viruses (e.g. Epstein-Barr virus). Various small molecules were designed to interact with a variety of G Qs most notably some with promising anti-cancer activity in tumour xenograft models, which lately entered phase II clinical trials on cancer patients. However, as with many small molecule drugs systemic administration has significant undesired side-effects. Targeting the drug to tumour cells can resolve this issue with a particular promising concept represented by so-called Antibody-Drug-Conjugates (ADC); they consist of an antibody for tumour targeting, a highly cytotoxic agent, and a linker that must not interfere with the functions of either of the other components; the first ADCs were recently licensed and have entered the market.

The goal of this PhD project is to build on the ADC concept and develop a theranostic probe that will allow tumour imaging at a macroscopic (whole-body) and microscopic level and at the same time deliver selectively a highly cytotoxic agent into tumours. The student will combine a G-quadruplex binder previously developed in the Vilar group, which acts both as an optical probe and cytotoxic agent, with a tumour-targeting moiety and a probe that allows whole-body radionuclide imaging (PET/SPECT). The product will be the first tumour-targeted G Q that can be tracked by in vivo imaging. In addition, we plan to further refine the approach converting the cytotoxic drug into a pro-drug to further reduce off-target cytotoxicity.

This ESPRC-funded CDT PhD studentship covers basic research spanning several disciplines with the candidate benefitting largely from being embedded within an active and truly multidisciplinary research environment at Imperial College London (Department of Chemistry and Institute of Chemical Biology) and King’s College London (Division of Imaging Sciences & Biomedical Engineering embedded into the Comprehensive Cancer Imaging Centre, the Medical Engineering Centre and the Biomedical Research Centre). In particular, the student will obtain experience in targeted drug design and chemical synthesis, cell biological drug evaluation, advanced fluorescence microscopy, preclinical multi-modal whole-body imaging, as well as animal models for oncology.

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