Blood brain to tumour barrier permeability of drugs

Primary supervisor: Maya Thanou, King’s College London

Secondary supervisor: J.P. Martinez-Barbera, UCL

Project

Glioblastoma (GBM) in adults and diffuse midline glioma (DMG, including DIPG) in children are among the most lethal brain tumours, with near-uniform fatality despite decades of therapeutic effort. A major reason for this failure is the blood-brain barrier (BBB), which excludes most antibodies and many small-molecule drugs from reaching tumour cells, and the added complexity of the blood brain-tumour barrier (BBTB), which is disrupted unevenly across the tumour mass (GBM) or becomes impermeable (DMG) . Understanding how candidate therapeutics cross these barriers, and where within the tumour they can penetrate, is essential before any treatment can be taken forward into patients.

This PhD project will establish and apply a suite of in vitro and in vivo models to interrogate BBB/BBTB permeability in GBM and DMG. Using SynVivo microfluidics BBB and BBB-tumour chip platforms, the student will build cell-based models incorporating brain endothelial cells, pericytes, astrocytes and patient-derived or established GBM/DMG tumour cells, arranged to recreate the 3D microarchitecture and shear-stress conditions of the neurovascular interface. These microfluidic devices allow real-time, high-resolution imaging and quantification of how antibodies, antibody fragments, nanoparticles and small-molecule drugs cross an undisturbed barrier versus a tumour-disrupted barrier by mechanical forces (e.g. using focused ultrasound cavitation BBB opening), giving mechanistic insight into transport routes (paracellular diffusion, transcytosis, active efflux) and how these differ between GBM and DMG.

Findings from the SynVivo platforms will be validated and extended in orthotopic mouse models of GBM and DMG, generated by stereotactic implantation of tumour cells developed in the Martinez-Barbera laboratory (DMG) or existing at the Thanou lab. The student will assess BBB/BBTB integrity and drug penetration in vivo using approaches such as fluorescent studies, immunohistochemistry, mass spectrometry laser ablatio (LA-ICPMS) and bioimaging (fluorescence and luminescence), correlating permeability data with tumour response to treatment. Together, the in vitro microfluidic and in vivo work will build a validated, predictive pipeline for prioritising candidate therapeutics, including biologics that would otherwise be assumed “BBB-impermeant”, for GBM and DMG.

This is a highly interdisciplinary project spanning nanomedicine, focused ultrasound, microfluidics, tumour biology and in vivo pharmacology, co-supervised by Professor Maya Thanou (King’s College London), an expert in drug and antibody delivery and nanomedicine, and Professor J.P. Martinez-Barbera (UCL), whose laboratory specialises in paediatric brain tumour models including DMG. The student will gain hands-on training in microfluidic device design and operation, cell and tumour biology, in vivo neuro-oncology models, and quantitative pharmacokinetic and permeability analysis, with the opportunity to directly inform which therapeutics progress into preclinical and clinical testing for these devastating brain tumours.

Candidate background

This project would suit candidates with a background in pharmacology, biomedical engineering, biophysics or a related life science discipline, and an interest in drug delivery, the blood-brain barrier, or brain tumour biology. Prior experience with cell culture, microfluidics, or in vivo work is desirable but not essential, as full training will be provided. Enthusiasm for interdisciplinary, translational cancer research bridging engineering and biology is essential.

Potential placements

1. J.P. Martinez-Barbera, Institute of Child Health, UCL
2. Igor Vivanco, Institute of Pharmaceutical Science, King’s College London
3. Antonios Pouliopoulos, Surgical & Interventional Engineering, King’s College London

References

1. Lipid-based nanoparticles for the theranostic treatment of brain tumors using focused ultrasound AACR 2026 Paul Cressey, Chris Payne, Amelia Claxton, Benedetta Arno, Christopher Ireson, Maral Amrahli, David Thurston, Antonios Pouliopoulos, Maya Thanou
2. Bi-modal confirmation of liposome delivery to the brain after focused ultrasound-induced blood-brain barrier opening Chris Payne, Paul Cressey, Anisia Talianu, Elwira Szychot, Darren Hargrave, Maya Thanou, Antonios N Pouliopoulos Heliyon 2024 10,22
3. Characterising the chemical and physical properties of phase-change nanodroplets. Weiqi Zhang, Hilde Metzger, Stavros Vlatakis, Amelia Claxton, M Alejandra Carbajal, Leong Fan Fung, James Mason, KL Andrew Chan, Antonios N Pouliopoulos, Roland A Fleck, Paul Prentice, Maya Thanou, Ultrasonics sonochemistry 2023, 97 106445
4. Recurrent adamantinomatous craniopharyngiomas show MAPK pathway activation, clonal evolution and rare TP53-loss-mediated malignant progression. J. R. Apps, J. M. Gonzalez-Meljem, R. Guiho, J. C. Pickles, E. Prince, E. Schwalbe, N. Joshi, T.J. Stone, O. Ogunbiyi, J. Chalker, A. Bassey, G. Otto, R. Davies,
5. D.Hughes, S. Brandner, E.Tan, V. Lee, C. Hayhurst, C. Kline, S. Castellano, T. Hankinson, T. Deutschbein, T. S. Jacques & J.P. Martinez-Barbera Neuropathol Commun 12, 127 (2024)