Bioscience for an integrated understanding of health

Category: Standard Studentships

Designing the next generation of small molecule cell surface targeting agents

Project No. 2228

Primary Supervisor

Dr Jennifer Hiscock – University of Kent

Co-Supervisor(s)

Prof Michelle Garrett – University of Kent

Prof Jonathan Essex – University of Southampton

Dr Hamish Ryder – CRUK Therapeutic Discovery Laboratories

Summary

Supramolecular Self-associating Amphiphiles (SSAs) are a class of molecule invented by JH.

To date, members from a library of ≈ 100 SSAs have been developed collaboratively with MG as both ovarian/glioblastoma anticancer agents and efficacy enhancers for a range of currently used therapies to which there is known resistance, such as cisplatin. 
 
It is hypothesised that the spontaneous self-association of the SSA enables effective delivery of this agent and/or molecular cargo to the surface of the cell. These SSAs then selectively interact with and permeate a target cancer cell membrane resulting in a therapeutic effect and/or the delivery of a molecular cargo to the inside of the cell. 
 
Aims: 
1. Determine bulk membrane self-association and permeation processes for   
     current lead anticancer SSAs. 
2. Characterise the anticancer activity of these SSAs against resistant/non- 
    resistant ovarian cancer cell lines and determine the suitability of these   
    agents for use in the clinic. 
3. Use project outputs to inform design of next generation SSAs. 
 
Scientific approach:  
 
Jennifer Hiscock Lab: 
*   Synthesis and design of novel SSAs (Aims 1, 3). 
*   To perform patch clamp, membrane fluidity and vesicle leakage  
     experiments to ascertain SSA interaction with model cell membranes.    
     (Aims 1, 3) 
 
Jonathan Essex Lab: 
*   To use molecular level simulation to understand SSA cell surface interactions and membrane permeation events (Aims 1, 2). 
 
Michelle Garrett Lab:  
*   Determine cellular cytotoxicity of SSAs on ovarian cancer  
     cells versus normal cells (Aims 2, 3).  
*  Undertake microscopy studies to understand membrane permeation  
    processes (Aim 2). 
 
Therapeutic Discovery Laboratories Lab: 
*   Undertake PK/PD studies within an industrial setting. (Aims 2). 
 
Impact areas:  
1. Health – better therapeutic agents for the treatment of cancer.  
2. Bioeconomy – Commercialisation of SSA technology.  
3. People and talent – Support of women and other marginalised groups within STEM – See later sections for detail.