Motivation behind the research
A variety of bond cleavage chemical reactions are gaining high momentum due to applications in targeted drug release in physiological conditions. Metals such as palladium and ruthenium could be used as a catalyst for such chemical reactions to convert an innocuous compound (prodrug) into a cytotoxic drug (that kills cancer). However, these metals are inherently toxic and can lead to undesirable side-effects.
Metallic gold is broadly regarded as the most biocompatible metal and is frequently used in dentistry, experimental medicine and biotechnology. In addition, gold has the ability to accelerate – or catalyse – numerous chemical reactions. Interestingly, while the catalytic properties of gold are widely recognized, the use of metallic gold as a catalyst to trigger safe reactions in living systems have been neglected to date. The well-established safety of gold and its promising catalytic potential would make this metal a powerful alternative for prodrug activation in patients.
Our lab has pioneered the field of metal catalysis in biological systems for prodrug-into-drug conversion strategies. During the past years, we have been working in this emerging field of research that aims to exploit the selective reactivity and high biocompatibility of some transition metal catalysts. Based on the safety and catalytic capabilities of gold, we envisioned that the properties of this precious metal could be used in living systems with minimal (if any) direct toxic effects. We made tiny spherical devices containing gold nanoparticles (catalyst). This catalyst enabled the conversion of prodrugs into cytotoxic drugs to kill cancer cells. Our novel gold device was also shown to catalyse a bioorthogonal chemical reaction (i.e. activation of a fluorescent agent) when implanted in the brain of zebrafish (model organism), indicating that it can be used in complex in-vivo models (living animals).
There are still a number of barriers to overcome, such as the improvement in the lifetime of the device and development of an optimal method to implant the device to the site of the cancerous tumour.
People have made huge advances in anti-cancer therapies in recent years. However, many cancers continue to be life-threatening and in some cases, incurable. Most generic anticancer therapies have terrible side effects. The challenge is to find safer and more selective treatments with minimal side effects.
Metallic gold provides a unique technology where one could control the release of the drug at the site of a tumour, whilst avoiding the harmful systemic side-effects of chemotherapy. Our next efforts will be focused on the development of an optimal method to target cancer within living animals by using our device with multiple prodrugs. There is still substantial work to be done before we can use this technology on patients. However, this initial study has been a promising step forward.
Research Article: Gold-Triggered Uncaging Chemistry in Living Systems, Angewandte Chemie 2017.