Engineering Precision Medicine for the 21st Century

The UK is facing a care crisis due to its aging population and the concomitant increase in diseases such as cancer, stroke, Alzheimer's and drug resistant infections whose prevalence increases with age. We urgently need better therapeutic solutions to manage these conditions, prevent premature deaths, enable patients to continue living independently and ease the burden on care providers. Our aim in the proposed research is to bring together scientists from the disparate fields of quantum physics and pharmaceutical chemistry with biomedical engineers, immunologists, and clinicians in order to provide those solutions. Our approach is based upon the exciting new finding that microbubbles, currently used as imaging contrast agents can be stimulated with low intensity ultrasound to produce light, offering a unique method for delivery targeted therapy. Whilst photoactivated therapies have been the subject of both pre-clinical and clinical research for decades, their usefulness has been drastically hindered by the poor penetration of light through tissue. In our approach this barrier is eliminated. Since ultrasound can be precisely focused almost anywhere in the body from an external probe, light generation can be triggered remotely and non-invasively to deliver highly localised treatment with minimal off-target toxicity. This has the potential to transform the delivery of cancer chemotherapy, stroke treatment, antimicrobial agents and also newer treatments such as immunostimulatory and optogenetic therapies. The initial proof of concept phase confirmed that: light was emitted from microbubbles driven at ultrasound frequencies from 0.5-3 MHz with peak negative pressures 0.1-1 MPa, i.e. conditions that are well within the range currently used for clinical applications; that light emissions were broadband (300-600 nm) and proportional in amplitude to acoustic emissions; the spectrum of light emissions was altered by the presence of photoactivatable drugs absorbing at specific optical wavelengths; and that cancer cell death could be efficiently generated in cell culture and also spheroid models. Quantification of the light emissions showed these to be substantially lower than those produced by lasers used in light activated therapies. Investigation of this discrepancy indicated that this was likely due to the fact that ultrasound-driven microbubbles also promote mass transport of drug molecules through tissue and intracellular drug uptake, both of which increase the efficacy of a given dose. Phase II will build on these promising findings to: develop optimised photoactivatable agents and drug-microbubble conjugates for key clinical targets identified with our clinical and industrial collaborators as representing both an urgent need and having a clear translational pathway; configure a clinical ultrasound system for treatment delivery and identify optimal exposure parameters; elucidate the fundamental physical and biological mechanisms underpinning drug activation and effect; and generate pre-clinical safety and efficacy data in relevant disease models. Our overall goal is to develop a complete treatment system, consisting of new therapeutic agents together with systems for treatment delivery and monitoring, ready for clinical development. This will provide the foundations for a pipeline of new treatments to transform therapeutic delivery by 2050.