About the Project
One of the biggest health challenges in the developed world is the safe and effective treatment of cancer. Whilst excellent in vitro drug and gene treatments for cancer are available, often they cannot be taken into the clinic due to their high toxicity and poor tumour selectivity properties resulting in unacceptable side effects. Our group is interested in the development of calixarenes, macrocyclic phenolic compounds, as selective drug and gene delivery systems and we have experience in investigating them as drug solubilising agents,1 as cell-specific protein binders,2,5 as cell penetration agents3 and, in the case of multicalixarenes, as DNA transfection vectors.4
In this interdisciplinary project, successful candidate will be developing routes for the synthesis of fluorescently labelled drug and protein conjugates of calixarenes and investigating how they interact with cells and their uptake into cells with the aim of providing cell-level targeted release of these biologically active molecules. By tailoring the calixarene structure the student will develop a suite of molecules that can exploit different endocytotic uptake processes, including receptor-mediated endocytosis, and thus can be selectively targeted. Thus, the project will involve both synthetic chemistry and also biological evaluation and is particularly suited to students with a background in Chemistry, Biochemistry or Pharmacy.
As part of this project the PhD student will gain skills in the synthesis of small heterocycles, macrocycles and peptides/proteins and a range of analysis techniques including NMR, mass spectroscopy and chromatography. They will also learn 2D and 3D cell culture, toxicity assays, fluorescence techniques (confocal microscopy, flow cytometry), for the evaluation of drug release and uptake giving the student a multidisciplinary background for future employment.
The student will become part of the vibrant medicinal chemistry and drug-delivery groups at UEA and part of the Next Generation Therapeutics Research Theme (https://www.uea.ac.uk/pharmacy/nextgen). Additionally you will receive research skills training through the Science Graduate School.
For more information on the supervisor for this project, please go here: https://www.uea.ac.uk/pharmacy/people/profile/susan-matthews
Type of programme: PhD
Start date of project: October 2018
Mode of study: Full time
Funding Notes
This PhD project is offered on a self-funding basis. It is open to applicants with funding or those applying to funding sources. Details of tuition fees can be found at http://www.uea.ac.uk/study/postgraduate/research-degrees/fees-and-funding.
A bench fee is also payable on top of the tuition fee to cover specialist equipment or laboratory costs required for the research. The amount charged annually will vary considerably depending on the nature of the project and applicants should contact the primary supervisor for further information about the fee associated with the project.
Acceptable first degree: Chemistry, Pharmacy, Biochemistry.
The standard minimum entry requirement is 2:1.
References
1) E. V. Ukhatskaya, S. V. Kurkov, S. E. Matthews, A. E. Fagui, C. Amiel, F. Dalmas, T. Loftsson. Evaluation of a cationic calix[4]arene: Solubilization and self-aggregation ability. Int. J. Pharmaceutics 2010, 402, 10-19
2) S. Ceconi, R. Lalor, B. Blanchard, J-P. Praly, A. Imberty, S. E. Matthews, S. Vidal. Achieving high affinity towards a bacterial lectin through multivalent topological isomers of calix[4]arene glycoconjugates. Chem. Eur. J. 2009, 13232-13240
3) R. Lalor, H. Baillie-Johnson, C. Redshaw, S. E. Matthews, A. Mueller. Cellular uptake of a fluorescent calix[4]arene derivative. J. Am. Chem. Soc. 2008, 130, 2892-2893
4) R. Lalor, J. L. DiGesso, A. Mueller, S. E. Matthews* Efficient gene transfection with functionalised multicalixarenes. Chem. Commun. 2007, 4907-4909
5) A. M. Boukerb, A. Rousset, N. Galanos, J.-B. Méar, M. Thepaut, T. Grandjean, E. Gillon, S. Cecioni, C. Abderrahmen, K. Faure, D. Redelberger, E. Kipnis, R. Dessein, S. Havet, B. Drablade, S. E. Matthews, S. de Bentzmann, B. Guéry, B. Cournoyer, A. Imberty, S. Vidal. Anti-adhesive properties of glycoclusters against Pseudomonas aeruginosa lung infection. J. Med. Chem., 2014, 57, 10275-10289
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