About the Project
Glioblastoma (GM) is the most common and most aggressive brain tumour, as less than 5% of the patients survive more than 5 years. The current standard of care is surgical resection followed by radio- and chemotherapy. Despite extensive research and clinical trials, only several drugs are currently approved for the treatment of GM. One of the reasons for the failed therapy is vast intra- and inter-tumour heterogeneity as well as the presence of GM stem cells that cannot be removed during resection and have the capacity to renew the tumour. Therefore, a multidisciplinary approach is needed for the treatment of a newly diagnosed glioblastoma. Currently, research efforts are focused to develop advanced in vitro model systems that faithfully recapitulate disease complexity in order to test novel therapeutic approaches. 2D nanomaterials, especially graphene-based ones could offer therapeutic alternative options as, due to the chemical structure, large surface area and favourable cellular interactions, they can be functionalized to carry therapeutic molecules in the proximity or inside tumour cells. Furthermore, due to the capacity to induce intracellular production of reactive oxygen species (ROS), GBMs could represent good candidates to enhance the effect of radiotherapy.
In this project, we will firstly aim to establish GM cancer organoids derived from GM cells taken from the patients after the surgery or using commercially available embryonic stem cells. Subsequently we will study the effects of a panel of graphene based materials (GBMs) on cells within cancer organoids, focussing on cellular uptake and subcellular effects such as oxidative stress, inflammation, migration, proliferation and cell death. In order to develop new therapeutic approaches, we will use GBMs to complex and deliver selected chemotherapeutic agents aiming to supress proliferation and survival of the cells within cancer organoids. Finally, we will look into the effect that GBMs and subsequent irradiation of organoids with protons and photons could have on the survival of cancer cells. We will focus on the endpoints that involve intracellular production of ROS and consequent DNA damage-induced response, cell proliferation and death. Expected scientific outcome of this project would be to unravel the potential of 2D nanomaterials either as therapeutic agents, which can increase sensitivity towards irradiation, or as carriers of relevant drugs within the advanced in vitro glioblastoma cancer models that faithfully recapitulate the disease.
http://www.nanomedicinelab.com/
https://www.christie.nhs.uk/internal-lists/consultant-list/milanovic-dusan
Entry Requirements
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
How to Apply
To be considered for this project you MUST submit a formal online application form. Please select EPSRC PhD Programme on the online application form. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/).
Applications must be submitted by the deadline, as late applications will not be considered. Incomplete applications will not be considered. Please ensure your application is complete and includes all required documentation before submission.
Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
References
1) Mazza, M., Ahmad, H., Hadjidemetriou, M., Agliardi, G., Pathmanaban, O., King, A., Bigger, B., Vranic, S. and Kostarelos, K., 2019. Hampering brain tumor proliferation and migration using peptide nanofiber:siPLK1/MMP2 complexes. Nanomedicine, 14(24), pp.3127-3142.
2) Chen, Y., Rivers-Auty J., Crica, L. E., Rosano, V., Arranz, A. E., Loret T., Spiller, D., Bussy C., Kostarelos, K., Vranic, S., 2021. Dynamic interactions and intracellular fate of label-free GO within mammalian cells: role of lateral sheet size. Nanoscale Adv., 2021,3, 4166-4185.
3) Shin, Y.*, Vranic, S.*, Just-Baringo, X.*, Gali, S., Kisby, T., Chen, Y., Gkoutzidou, A., Prestat, E., Beljonne, D., Larrosa, I., Kostarelos, K. and Casiraghi, C., 2020. Stable, concentrated, biocompatible, and defect-free graphene dispersions with positive charge. Nanoscale, 12(23), pp.12383-12394. *equal contribution.
4) de Lázaro, I., Vranic, S., Marson, D., Rodrigues, A., Buggio, M., Esteban-Arranz, A., Mazza, M., Posocco, P. and Kostarelos, K., 2019. Graphene oxide as a 2D platform for complexation and intracellular delivery of siRNA. Nanoscale, 11(29), pp.13863-13877.
5) Lázaro, I., Sharp, P., Gurcan, C., Ceylan, A., Stylianou, M., Kisby, T., Chen, Y., Vranic, S., Barr, K., Taheri, H., Ozen, A., Bussy, C., Yilmazer, A. and Kostarelos, K., 2020. Deep Tissue Translocation of Graphene Oxide Sheets in Human Glioblastoma 3D Spheroids and an Orthotopic Xenograft Model. Advanced Therapeutics, 4(1), p.2000109.
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