Ultrasound mediated delivery of cancer therapeutics

The number of new cancer diagnosis, in the UK alone, stands at 355,000+ per year, with 160,000+ deaths within the same period. Survival rate for cancer long term (10+) years stands at 50% for England and Wales. Chemotherapy is an important component to treating the disease, however, the drugs employed are not only toxic to cancer cells, so side-effects can be a major limitation and typically transport from the blood vessels to the site of disease is often poor. In this work the therapeutic agents (an mRNA molecule), will be encapsulated in lipid-nanoparticles (LNPs) in order to both limit off-target interactions and protect the agent from being disarmed by the body before reaching the site of action.

I will apply two forms of ultrasonic energy: the first to facilitate the transport of the LNPs from vessels to the interstitium and the second to deliver the therapeutic agent to the cell. The response of the agent to the ultrasound will be detected in order to be able to monitor and map the delivery of the agent.

Aims and Objectives
Combine ultrasound and nanocups to enhance LNP extravasation
Nanocups will be used with the LNPs to determine parameters that result in enhanced delivery into tissue without degrading the LNPs or their therapeutic agent. The transport properties in a phantom and liver will be determined independently using a syringe pump and pressure probes and the phantom recipe adjusted to capture the desired properties.

Mapping of extravasation
The acoustic emissions associated with the cavitation activity will be detected using an ultrasound imaging system; which has been specially configured to passively listen to cavitation activity - rather than use standard pulse-echo strategies for B-mode imaging. The mapping of cavitation activity will then be compared with the measured extravasation and an algorithm developed in order to convert the measured cavitation activity into a metric that quantitatively predicts LNP delivery.

Determine shock wave parameters for enhancing delivery
Acoustic shock waves will be employed to deliver the therapeutic agent; the short time duration of the shock waves results in mechanical disturbance of the LNP and cell membranes resulting in enhanced delivery. Experiments will be initially carried out on CT26 cell lines to determine shock wave parameters that will result in delivery without substantial cell toxicity.

In vivo intravenous delivery
Both nanocups and the LNPs will be co-administered into a mouse with a xenograft tumour. Ultrasound will be used to transport the LNPs through the tumour and then shock waves to trigger the delivery. The delivery of the LNPs will be assessed using fluorescent imaging and the response of the tumour through survival studies.

The novelty in this approach is combining a number of engineering technologies to overcoming barriers to drug delivery: LNP to protection therapeutic agent, nanocups and ultrasound to enhance transport to the cells, passive monitoring to ensure transport, and shock waves to induce delivery to cells. The ultrasound and shock wave technology to be employed are currently CE marked for other applications and so we envision little issue for translation. Success with the mRNA construct envisioned here would allow a pathway for other therapeutic agents to be delivered.

This project falls within the EPSRC healthcare technologies research area. Specifically, clinical technologies for the delivery of drug molecules ultrasound acoustic waves, and medical imaging, where acoustic waves will be monitored as part of ensuring drug delivery.

This work is carried out as part of the EPSRC funded Oxford Centre for Drug Delivery Devices (OxCD3). A pharmaceutical company based in the UK will be collaborating on the drug and LNP aspects of the project. An Oxford University spinout company, OxSonics, will be collaborating on the cavitation nuclei and monitoring aspects.