Designing the next generation of small molecule cell surface targetting agents

点击翻译按钮获取中文摘要

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 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: JH 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) JE Lab: * To use molecular level simulation to understand SSA cell surface interactions and membrane permeation events (Aims 1, 2). MG 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). TDL 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.