Designing the next generation of small molecule cell surface targetting agents

超分子自缔合两亲体（SSAs）是JH发明的一类分子。迄今为止，已与MG合作开发了100个SSAs库中的成员，作为卵巢/胶质母细胞瘤抗癌药物和目前使用的一系列已知耐药疗法（如顺铂）的疗效增强剂。据推测，SSA的自发自结合能够有效地将该剂和/或分子货物运送到细胞表面。然后，这些ssa选择性地与靶癌细胞膜相互作用并渗透，从而产生治疗效果和/或将分子货物运送到细胞内部。目的:1。确定当前抗肿瘤ssa的大体积膜自结合和渗透过程。2. 表征这些SSAs对耐药/非耐药卵巢癌细胞系的抗癌活性，并确定这些药物在临床应用的适用性。3. 利用项目成果为下一代SSAs的设计提供信息。科学方法：JH实验室：*合成和设计新型SSA（目标1,3）。*通过膜片钳、膜流动性和囊泡泄漏实验来确定SSA与模型细胞膜的相互作用。乙脑实验室：*利用分子水平模拟来了解SSA细胞表面相互作用和膜渗透事件（目标1,2）。MG实验室：*测定SSAs对卵巢癌细胞与正常细胞的细胞毒性（目标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。(目标2)。影响范围：1；健康——更好的治疗癌症的药剂。2. 生物经济- SSA技术的商业化。3. 人员和人才-在STEM中支持妇女和其他边缘化群体-详见后面的章节。

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.