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): a novel class of cell membrane active therapeutic agents?

To date, members from a library of ≈ 100 SSAs have been developed 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.

SSAs are known to self-associate to from vesicle-like structures that we hypothesise to enable the effective delivery of this agent and/or a 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 (Hamish Ryder) Lab:
* Undertake PK/PD studies within an industrial setting. (Aim 2).

Impact areas:
1. Health – better therapeutic agents for the treatment of cancer.
2. Bioeconomy – Bringing SSA technology from the lab bench into the clinic.