Project ID CM-HD2023_08

ThemeCM-HD

Co Supervisor 1A Institute of Pharmaceutical Science/School of Cancer and Pharmaceutical ScienceWebsite

Co Supervisor 1B Institute of Pharmaceutical Science/School of Cancer and Pharmaceutical ScienceWebsite

Hydrogen selenide (H2Se) optical sensing using a toolkit of near-infrared probes

Selenium (Se), an essential micronutrient known for its incorporation into antioxidant ‘selenoproteins’, links numerous pathological states from cardiovascular conditions to cancer and aging. Recent investigation on the potential therapeutic role of hydrogen selenide (H2Se), a crucial intermediate of Se bioactivity, has highlighted the need for developing effective imaging probes/assays that can enable its selective detection in vivo.

This multidisciplinary project aims to develop and biologically validate a library of novel near-infrared (NIR) fluorescent probes based on the structures of 2,1,3-benzoselenadiazole and 1,2-dithiane-4,5-diol, ensuring specific responsiveness to H2Se. We plan to generate two classes of imaging agents emitting in the NIR-I and -II windows (650−900 and 1000−1700 nm, respectively). Importantly, the NIR-II region is recognised to enhance in vivo imaging procedures, due to the lower tissue autofluorescence, minimal photon scattering/absorption, leading to deeper light penetration/higher resolution/sensitivity.

The project combines chemistry, cellular biology, imaging, in vivo pharmacology and will be conducted in collaboration with Mint Therapeutics.

Objectives:
1. Years 1/2 – synthesise a panel of NIR-probes and optically/biologically characterise them in cell-free systems and cell lines (microscopy). This will confirm sensitivity for H2Se detection and selectivity over other Se forms (selenite, selenocysteine, selenoprotein).
2. Years 2/3 – assess (i) H2Se release from new selenotherapeutics, (ii) subcellular localisation of H2Se, and (iii) monitoring of H2Se delivery/distribution in biological systems of increasing complexity (from organelles to cells to in vivo – C. elegans and mice).
3. Year 3 – use the probes for efficacy testing of selenotherapeutics (e.g. H2Se, selenite, TDN-1042) in aging and cancer models with real-time monitoring of drug distribution/action.

One representative publication from each co-supervisor:

• Cilibrizzi A, Terenghi M, Fedorova M, Woscholski R, Klug D, Vilar R. Small-molecule optical probes for cell imaging of protein sulfenylation and their application to monitor cisplatin induced protein oxidation. Sensors and Actuators B: Chemical 2017; 248, 437-446.

• Samra K, Kuganesan M, Smith W, Kleyman A, Arulkumaran N, Singer M, Dyson A. Pharmacology and therapeutic utility of sodium hydrogen selenide. Int J Mol Sci. 2021; 22:3258.