Bioorthogonal Chemistry and Fluorescent Post-Labeling for Real-Time Tracking of a Platinum-based Anticancer Drug
Dr D Griffith
Dr D O’Shea
Monday, December 02, 2019
Competition Funded PhD Project (Students Worldwide)
Metal-based drugs have a wide range of medicinal applications and are routinely used clinically as therapeutic and diagnostic agents. In particular platinum (Pt) drugs such as cisplatin, carboplatin and oxaliplatin, have played a very important and well documented role in treating cancer and are employed in nearly 50% of anti-cancer regimens.
The cytotoxicity of Pt drugs, which hydrolyse (loss of chlorido or carboxylato ligands) inside cells, has traditionally been primarily attributed to their ability to covalently bind DNA, forming DNA adducts, leading to DNA damage responses and ultimately programmed cell death, apoptosis.
Significantly, it is becoming increasingly clear that the exact biomolecular mechanisms of action of Pt drugs have not been fully elucidated. It has been demonstrated recently for example that oxaliplatin, in contrast to cisplatin and carboplatin, does not kill cells via the DNA-damage response but by inducing ribosome biogenesis stress.
Trackable metal-based drugs which incorporate an organic fluorophore for example offer the prospect of real-time imaging of important biological processes in vitro and providing vital information concerning the biodistribution, cellular transport, subcellular localization, and mechanisms of action and resistance to metallotherapeutics.
The near-infrared (NIR) spectral region (700–900 nm) provides ideal imaging spectral wavelengths, reduced light toxicity and does not interfere with competing endogenous chromophore absorbance. Significantly NIR probes have been successfully employed to image tumours in vitro and in vivo and as sensors for ROS, RNS, thiols, ions, pH and enzyme activities.
Bioorthogonal chemistry describes chemical reactions that can occur in living systems without interfering with native biochemical processes. Bioorthogonal chemical ligation strategies include for example 1,3-dipolar cycloaddition between azides and cyclooctynes, between nitrones and cyclooctynes, oxime/hydrazone formation from aldehydes and ketones, tetrazine ligation and the quadricyclane ligation for example.
This multidisciplinary project, which will incorporate medicinal chemistry, cell biology and imaging, will employ bioorthogonal chemistry to develop Pt anticancer compound surrogates that feature reactive biocompatible handles that can be tagged with a reporter NIR fluorophore in cellulo. Such conjugates will play an important role in the ongoing investigation into the non DNA-binding effects of Pt-based drugs.