Controlled drug release in the brain

Brain cancer is a tumour type of unmet needs. Its survival remains low, and has changed little in over a generation. Only around 15 out of every 100 people with a cancerous brain tumour survive for 10 years or more after being diagnosed. 

Thanks to multiple collaborations between clinicians, biologists, chemists, multidisciplinary scientists and engineers, brain cancer research is one of Edinburgh’s strengths combining stimulating work environment with unique discovery opportunities. Cancer Research UK Edinburgh Centre, also recognised as CRUK Brain Tumour Centre of Excellence, hosts several projects aiming to develop more effective treatments and better drug delivery methods for this devastating disease.   

One of these projects, led by Professor Asier Unciti-Broceta in the Institute of Genetics and Cancer, aims to create innovative brain cancer therapeutics using bioorthogonal chemistry approaches (the term bioorthogonal chemistry refers to any chemical reaction that can occur inside of living systems without interfering with native biochemical processes). Over the past few years his research group and collaborators pioneered synthesis of biologically active drugs from harmless chemical compounds (prodrugs) in direct proximity of a tumour utilising catalytic reactions mediated by transition metals such as palladium and gold (so called bioorthogonal organometallic reactions). The strategy provides high degree of control over activity of drugs within the body therefore increasing their effectiveness and reducing undesired side effects. This could be particularly important in the brain, which is the centre of our cognitive functions.

Although there is still a lot to be done before this technology can be tested in humans, the team makes steady progress continuously providing exciting new developments. In a recent study, titled “Truly-biocompatible gold catalysis enables vivo-orthogonal intra-CNS release of anxiolytics” and published in the journal Angewandte Chemie, the group described generation of  gold based catalyst that is compatible with living systems, both in terms of safety and functionality. While the catalyst showed no signs of toxicity or adverse effects on its own, it was capable of turning properly designed prodrugs into fully active components in the brain of a living zebrafish after its implantation into the head. For proof of principle experiments the researchers used prodrug version of anxiolytic agent fluoxetine (also known as Prozac) which, upon activation by the implanted catalyst, changed swim pattern of fish. It is expected that similar approach could be also used for delivery of other drugs including brain cancer therapeutics.    

The work represents a significant step in preclinical development of bioorthogonal organometallic approaches and may provide new avenues for their potential transition into clinical trials. It was driven by postdoctoral researcher Dr M. Carmen Ortega-Liebana (Marie Skłodowska-Curie individual fellowship from the European Council) and supported by funding from Engineering and Physical Sciences Research Council (EPSRC), Cancer Research UK (CRUK) and European Union (Horizon 2020 Programme).        

This work expands the scope of gold chemistry and in vivo bioorthogonal catalysis, offering a new methodology to study neurological function by producing bioactive agents exclusively at the brain. We hope that in the future it might be adapted for localised treatment of brain tumours and neurological disorders. Because of the safety of gold, this strategy could not only be used to treat cancer, but also neuropathic pain associated to cancer surgery at peripheral nerves, which would be essential to reduce opioid addiction.

Professor Asier Unciti-Broceta

Related Links

Article in Angewandte Chemie: https://onlinelibrary.wiley.com/doi/10.1002/anie.202111461

Innovative Therapeutics Group web page: https://www.ed.ac.uk/cancer-centre/research/unciti-broceta-group

Information about brain tumours: https://www.cancerresearchuk.org/about-cancer/brain-tumours

General information about nanoparticles: https://en.wikipedia.org/wiki/Nanoparticle

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