Principal Supervisor: Professor Zoe PikramenouLink opens in a new window

Co-supervisor: Professor Mike HannonLink opens in a new window, Dr. Nik HodgesLink opens in a new window

PhD project title: Nanoparticles for targeting stem cells

University of Registration: University of Birmingham

Project outline:

Background Stem Cell (SC) based therapy has merged as a key approach in regenerative medicine. Current clinical applications range in many diseases from cardiovascular, digestive system and liver to arthritis and lately cancer. The latter has been particularly controversial and one of the challenges is the lack of targeting and effectiveness. Another approach has been to target and eradicate cancer stem cells which are relatively slow-growing, have the ability to self-renew, differentiate, and initiate new tumors and are resistant to chemotherapy and radiotherapy. The traditional chemotherapeutic drugs are ineffective. There are few reports of some metal complexes effective against stem cell spheroids, but the main problem associated is the deactivation, drug efflux (due to overexpression of efflux transporters) and lack of sphere penetrability, demanding a higher therapeutic dosage. However, the acivity of these SC can be addressed by inhibitors which target and block cellular pathways to decrease cell viability. Nanotechnology is a promising tool to improve the efficacy of drugs by using a single nano-vehicle for delivery and detection which is carrying multiple drugs and tracking agents for delivery

Objective: We will develop sophisticated systems based on gold nanoparticle (NP) as a delivery vehicle and a tracking agent that combines a photostable luminescent agent for tracking, a metallodrug active against SC activity and targeting vectors chosen to inhibit cellular pathways pertinent to SCs activity.

Methods: We will use established methodology in the Pikramenou Hodges groups for modifying gold nanoparticles with luminescent agents to also attach known inhibitors for SCs cellular pathways. We will choose to work with ruthenium and iridium complexes that produce ROS species, and are promising to be active against Pt-resistant cancer. We have chosen to target two pathways of inhibition which are important in SC activity: a) EGFR, an epithelial growth factor receptor and b) the STAT3 pathway which is active in subpopulations of cells enriched for cancer SC marker. Additionally we will also use metal complexes that are known for photodynamic therapy, Ru complex-TLD1433 to NP which in Phase II trial. We will use a series of biochemical assays including western blot studies to study inhibition of the EGFR and STAT3 pathways.

References:

1. D.M. Hoang, P. T. Pham, T. Q. Bach A. T. L. Ngo, Q.T. Nguyen, T.T.K Phan, G.H. Nguyen, P.T. T Le, V. T. Hoang, N.R. Forsyth, M. Heke, L. T. Nguyen, Signal Transduct Target Ther 2022, 7, 271. And Nat. Rev. Cancer 2012, 12,133–143.
2. A.N. Dosumu, S. Claire, S.A.M. Osborne, L. Watson, Z. Pikramenou Z., N.J. Hodges JACS Au 2021, 1, 174-186.
3. S. King, S., R. Teixeira, R., A.N. Dosumu, A., H. Dehghani, H., A. Ward, M.J. Hannon, A., N.J. Hodges, S. Botchway, R. Bicknell, Z. Pikramenou J. Amer. Chem. Soc. 2018, 140, 10242−10249.

 

BBSRC Strategic Research Priority: Integrated Understanding of Health - Ageing

Techniques that will be undertaken during the project:

Gold nanoparticle and metallo drug chemistry

Synthetic chemistry-organic and inorganic

Characterisation techniques

Biochemical scereening: MTT and Sulforhodamine B (SRB) assays, mitochondrial membrane potential, western blot.

Flow cytometery

Microscopy

Contact: Professor Zoe PikramenouLink opens in a new window