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Image guided focused ultrasound to enhance efficacy of cancer therapeutics


Project Description

Biological therapies, such anti-PD-1 checkpoint inhibitor, have been found to effectively treat certain cancers, but they minimally affect others. These “cold” immunotherapy tumours, are usually heterogenous and/or secrete signalling proteins that recruit immune-suppressive cells. However, if drug permeation in cold tumours can be promoted, it could make them more sensitive to immunotherapies and pave the way for designing efficient strategies such as combination immune-therapies or nanoparticles e.g. for silencing/blocking proteins involved in immune-suppression.

In this project the student will aim to improve immune-therapies by developing tools to improve their permeation in tumours. They will investigate if applied focused ultrasound and purpose made bubbles are efficient tools to improve penetration within the tumour microenvironment. Furthermore, antibodies will be prepared as part of the bubble lipid layer. Gas core lipidic bubbles respond to ultrasound by cavitation. When these bubbles collapse their lipidic components, including the antibodies, will be inserted into tumour cells. To monitor these phenomena, the bubbles will be tagged, allowing their bio-distribution to be followed by clinical imaging. The antibodies will be introduced on a lipid-based bubble using chemical coupling (coupling chemistry used in immune-liposomes). Phase change nanodroplets, using the antibodies and the imaging lipids conjugates will be used as bubble precursor. Phase change nanodroplets (200nm) turn to microbubbles (1-2µm) that cavitate and “pop” under the effect of focused ultrasound. This way the antibody and the associated lipids will be “propelled” in the tumour environment, within milliseconds. The bubble platform can accommodate a combination of immune-therapeutics e.g. anti-PD-1 and anti -CTLA4, as part of the lipidic layer. To facilitate the design of this strategy, the project will use mathematical modelling of bio-therapeutics’ diffusion in normal (e.g. breast) and dense (e.g. pancreas) tumour tissue when ultrasound is applied.
The key project objectives are to:
a) Formulate and characterise novel Magnetic resonanceand near infra-red fluorescence (NIRF) labelled phase change nanodroplets for their imaging and ultrasound response properties. The nanodroplets will be labelled using previously developed Gd.DOTA (macrocycle) and XLA750-NIRF/Rhodamine lipid conjugates.
b) Label Anti-PD-1 with NIRF for image tracking in vivo. Balb-C and/or C57BL/6 mice will be used to develop subcutaneous (s.c.) tumours.. NIRF imaging will be used to monitor distribution of antibodies and the carrier of antibodies in tumours.
c) Model mathematically the ultrasound effect on tumour interstitial fluid pressure and calculate macromolecule-lipidic part velocity (propulsion) under ultrasound conditions
d) Investigate the effect of focused ultrasound on immunotherapy carrying nanodroplets’ bio-distribution.
e) Combine derived data from modelling and in vivo bio-distribution data to pilot the focused ultrasound application protocol.
f) Assess the ability of focused ultrasound, anti-PD1-bubbles to stop tumour growth in the murine breast and pancreas models.

The ideal candidate will need to have excellent knowledge of chemistry to develop the biotherapeutics, and a good understanding of ultrasound physics, however, will be supported through the training programme to develop the requisite skill set required to complete this project.

Potential project placements

1. Mathematical modelling for application in focused ultrasound of pancreatic tumours, supervised by Prof Nader Saffari, Ultrasonics Lab, UCL.

2. Monitoring of clinical applications and prioritisation of the clinical hurdles in relation to the MRgFUS supervised by Dr Shahzad Ilyas, Guys’s and St Thomas’s Hospital.

3. Labelling molecules for imaging and preparation of phase change nanodroplets, supervised by Dr Maya Thanou, Nanotechnology lab, King’s.

Funding Notes

Non-EU students are not eligible for this funding

References

Wright, M. et al. Theranostics and image guided drug delivery. Drug discovery series RSC publishing; 2018, Chap. 1,1-28

Centelles, M.N. et al. Image-guided thermosensitive liposomes for focused ultrasound drug delivery: Using NIRF-labelled lipids and topotecan to visualise the effects of hyperthermia in tumours. J Control Release; 2018, 280, 87-98.

Centelles, M.N. et al. Focused ultrasound induced hyperthermia accelerates and increases the uptake of anti-HER-2 antibodies in a xenograft model. Mol Pharm; 2015, 12, 1335-1346.

Wang, M. and Thanou, M. Targeting nanoparticles to cancer. Pharmacol Res, 2010; 62, 90-99.
Gélat, P. et al. Modelling of the acoustic field of a multi-element HIFU array scattered by human ribs. Physics in Medicine & Biology; 2011, 56, 5553 – 558.

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