1st Supervisor: Maya Thanou, King’s College London
2nd Supervisor: Kirsten Christensen-Jeffries , King’s College London
Additional supervisors: Laura Peralta, Antonios Pouliopoulos, James Clark, and Alkystis Phinikaridou, King’s College London
Clinical Supervisor: Wady Gedroyc, Imperial College London, and Keyoumars Ashkan, King’s College London
Aim of the PhD Project:
The main aim of the project is to develop super stable nanodroplets to image the blood brain to tumour barrier using the following imaging modalities
- Ultrasound super resolution,
- Magnetic resonance
- Fluorescence imaging
Phase change Nanodroplets respond to ultrasound and allow simultaneous therapeutic and diagnostic applications. Unlike the ultrasound microbubbles, which are unable to enhance image contrast outside blood vessels, nanodroplets can migrate through hyperpermeable vessel walls in tumours and accumulate in the interstitial tissue. This can improve imaging of tumours. Another advantage is that they can retain their nano-scale size in the bloodstream, enabling them to circulate for longer. Nanodroplets with liquid cores are converted to gas bubbles when affected by ultrasound, which makes them good contrast agents for ultrasound imaging.
Ultrasound imaging is broadly used imaging techniques with real-time, non-ionizing, high frame-rate imaging as well as low cost. Ultrasound contrast agents are an excellent tool to investigate sites of inflammation and solid tumour due to highly permeable vascular networks in these tissues.
The vaporisation of nanodroplets results in acoustic emissions, which are usually observed by B-mode (brightness) ultrasound probe. Nanodroplets using highly volatile perfluorocarbons are currently being developed by few research groups that investigate cavitation. Using a highly volatile perfluorocarbon makes nanodroplets more sensitive to acoustic energy. Apart from this, acoustic imaging could also monitor the size of bubbles through harmonic emissions produced by vaporised nandroplets.
However, the low boiling point perfluorocarbons indicate poor colloidal and biological stability of lipid shell nanodroplets. To improve their stability the nanodroplets’ composition should be modified.
The Thanou group has been active in image guided focused ultrasound drug delivery systems and the in vivo proof of concept in tumours in mice. Recently, the team developed new nanodroplets for focused ultrasound brain tumours. The team progressed with in vitro evidence about the mechanism of action of the newly designed sonoresponsive agents. These nanodroplets were developed and tested. The team has developed a series of analytical tests (de novo) that guide the choice of the materials of the nanodroplet composition. For example, FTIR and Flourine NMR data indicated a certain perfluorocarbon mix as the most stable. In a similar manner the team found that the modification of the lipid shell can improve the biological stability in serum for days. Our data show that the nanodroplets still keep their nucleation and cavitation characteristics after the required modifications for improving their stability.
This project will be using both gadolinium contrast enhancing agents and Near infrared fluorescence (NIRF) probes conjugated with lipids as part of the nanodroplets composition . These lipids will be introduced in the lipid shell of the nanodroplets at various ratios. The gadolinium contrast agent will offer ability to image the nanodroplets with MRI. The nanodroplets acoustic vaporisation by ultrasound should also provide a change in the MR contrast enhancement and a confirmation that droplets cavitated.
The NIRF probe is introduced to “tatoo” brain tumours after causing inertial cavitation with Low Intensity Focused Ultrasound. Inertial cavitation will propel the nanodroplets’ lipid components within the tumour (targeted by the focused ultrasound). The propelled imaging lipids will label the tumour. The rational of this method is the following: The labelling of the tumour by Gadolinium can lead to improved radiotherapy as gadolinium is strong radiosensitiser. The labelling of the tumour with NIRF can assist the precise surgical removal. Currently radiotherapy and surgery are the most efficient methods of treating brain tumours. The smart imaging probes developed in this project will be offering the additional feature of improving these treatments.The candidate should have a basic understanding of chemistry and physics. Ideally a biomedical engineers and chemists can be good candidates for this project.