Dual labelled phase change nanodroplets for ultrasound guided drug therapies

Aim of the PhD Project:
To develop multimodal smart imaging probes that will enable emerging imaging and image-guided interventions for cancer treatment.
Objectives:

To synthesise dual label MR and Near IR Fluorescence (NIRF) - nanodroplets, (iNDs) that undergo phase change when ultrasound is used (core changes from liquid to gas)
To characterise iNDs for their MR and NIRF contrast enhancement, ultrasound imaging and focused ultrasound induced cavitation after the phase change.
To investigate iNDs efficacy of improving drug distribution in phantom gels (tumour mimicking tissue) and in cells in culture.
To develop a combination therapy of image guided iNDs and drugs as part of the lipid membrane in an in vivo murine tumour model.
Project Description / Background:

Image guided drug delivery has emerged as a novel tool for several treatments. Nanoparticles that image tumours have been widely used during the last two decades to improve drug delivery and efficacy. One category of these nanoparticles is the sono-responsive nanoparticles in combination with focused ultrasound. Phase change nanodroplets have appeared in research as a new chemical entity with the potential to improve imaging and drug delivery.

Currently, commercially available gas-cored microbubbles are used as contrast enhancers for ultrasound imaging and experimentally in the clinic for cavitation induced drug delivery. But these bubbles have very limited blood half-life. Nanodroplets have been suggested to have a superior blood half life and a better penetration in lesions such as tumours due to their small size. They are characterised by chemical versatility and the ability to transform to microbubbles that oscillate and cavitate. Cavitation then promotes the propulsion of nanodroplet's components in cells and tissues. If these components contain therapeutics, then a superior localised drug delivery can be achieved.

In our previous work we have developed lipid-based nanoparticles that respond to ultrasound and at the same time can be imaged with both MRI and NIRF imaging. In the current project we aim to prepare perfluorocarbon (PFC)-cored, lipid-shelled phase change nanodrolets (ND). These will be composed of lipids coupled to markers for MR and NIRF and lipids as therapeutics. These imaging NDs (iNDs) will have a small size (100-500 nm diameter) and will have a coat of a biocompatible polymer (e.g. PEG). The coating will allow for acceptable blood circulation times and the labels for their tracking in the tumour. Upon activation with ultrasound iNDs will inflate to ~1-3 micrometer gas-cored bubbles, which then provide excellent ultrasound contrast.

Previous research has demonstrated that localised cavitation will enhance nanoparticle extravasation from tumour blood vessels and delivery of co-delivered or co-encapsulated therapeutic agents.

These therapeutic agents will be embedded to the lipid shell. The lack of an aqueous core restricts drug delivery either to highly non-polar materials. The lipidic or lipophile-anchored therapeutics embedded into the ND shell will be carried in the blood as part of the inactive particle. Previous studies suggest that labelled lipids delivered in this way using lipid based nanoparticles and ultrasound are retained in tumour tissues for days to weeks. There is evidence they are also taken up into tumour cell membranes. This suggests a delivery/localisation mechanism that might combine well with tumour cell targeted drugs.

This project will develop these dually labelled nanodroplets as a new class of imaging agents that respond and are able to provide superior targeted drug delivery to tumours.

Strains on the healthcare system in the UK create an acute need for finding more effective, efficient, safe, and accurate non-invasive imaging solutions for clinical decision-making, both in terms of diagnosis and prognosis, and to reduce unnecessary treatment procedures and associated costs. Medical imaging is currently undergoing a step-change facilitated through the advent of artificial intelligence (AI) techniques, in particular deep learning and statistical machine learning, the development of targeted molecular imaging probes and novel "push-button" imaging techniques. There is also the availability of low-cost imaging solutions, creating unique opportunities to improve sensitivity and specificity of treatment options leading to better patient outcome, improved clinical workflow and healthcare economics. However, a skills gap exists between these disciplines which this CDT is aiming to fill.

Consistent with our vision for the CDT in Smart Medical Imaging to train the next generation of medical imaging scientists, we will engage with the key beneficiaries of the CDT: (1) PhD students & their supervisors; (2) patient groups & their carers; (3) clinicians & healthcare providers; (4) healthcare industries; and (5) the general public. We have identified the following areas of impact resulting from the operation of the CDT.

- Academic Impact: The proposed multidisciplinary training and skills development are designed to lead to an appreciation of clinical translation of technology and generating pathways to impact in the healthcare system. Impact will be measured in terms of our students' generation of knowledge, such as their research outputs, conference presentations, awards, software, patents, as well as successful career destinations to a wide range of sectors; as well as newly stimulated academic collaborations, and the positive effect these will have on their supervisors, their career progression and added value to their research group, and the universities as a whole in attracting new academic talent at all career levels.

- Economic Impact: Our students will have high employability in a wide range of sectors thanks to their broad interdisciplinary training, transferable skills sets and exposure to industry, international labs, and the hospital environment. Healthcare providers (e.g. the NHS) will gain access to new technologies that are more precise and cost-efficient, reducing patient treatment and monitoring costs. Relevant healthcare industries (from major companies to SMEs) will benefit and ultimately profit from collaborative research with high emphasis on clinical translation and validation, and from a unique cohort of newly skilled and multidisciplinary researchers who value and understand the role of industry in developing and applying novel imaging technologies to the entire patient pathway.

- Societal Impact: Patients and their professional carers will be the ultimate beneficiaries of the new imaging technologies created by our students, and by the emerging cohort of graduated medical imaging scientists and engineers who will have a strong emphasis on patient healthcare. This will have significant societal impact in terms of health and quality of life. Clinicians will benefit from new technologies aimed at enabling more robust, accurate, and precise diagnoses, treatment and follow-up monitoring. The general public will benefit from learning about new, cutting-edge medical imaging technology, and new talent will be drawn into STEM(M) professions as a consequence, further filling the current skills gap between healthcare provision and engineering.

We have developed detailed pathways to impact activities, coordinated by a dedicated Impact & Engagement Manager, that include impact training provision, translational activities with clinicians and patient groups, industry cooperation and entrepreneurship training, international collaboration and networks, and engagement with the General Public.