Designing the next generation of small molecule cell surface targetting agents

超分子自缔合两亲物（SSA）是JH等人发明的一类分子。迄今为止，来自100个SSA库的成员已与MG合作开发，作为卵巢/胶质母细胞瘤抗癌剂和一系列已知耐药的目前使用的疗法（如顺铂）的疗效增强剂。 假设SSA的自发自缔合能够将该试剂和/或分子货物有效递送至细胞表面。然后，这些SSA选择性地与靶癌细胞膜相互作用并渗透靶癌细胞膜，从而产生治疗效果和/或将分子货物递送至细胞内部。 目的：1.确定当前铅抗癌SSA的本体膜自缔合和渗透过程。2.表征这些SSA对耐药/非耐药卵巢癌细胞系的抗癌活性，并确定这些药物用于临床的适用性。3.使用项目输出为下一代SSA的设计提供信息。 科学方法：JH实验室：* 新型SSA的合成和设计（目标1，3）。* 通过膜片钳、膜流动性和囊泡渗漏实验，确定SSA与模型细胞膜的相互作用。 (Aims 1、3）JE实验室：* 使用分子水平模拟来理解SSA细胞表面相互作用和膜渗透事件（目的1、2）。 MG实验室：* 测定SSA对卵巢癌细胞与正常细胞的细胞毒性（目的2，3）。* 进行显微镜研究，以了解膜渗透过程（目标2）。 TDL实验室：* 在工业环境中进行PK/PD研究。(Aims 2）。 影响范围：1。健康-更好的治疗剂用于治疗癌症。2.生物经济-SSA技术的商业化。3.人员和人才-支持STEM中的妇女和其他边缘化群体-详见下文。

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.