Design and development of new Lipid Nano Particle delivery systems for new RNA-based c therapeutics: A rationally designed chemistry and microfluidics

设计和开发新型脂质纳米粒子递送系统，用于新型基于 RNA 的 c 疗法：合理设计的化学和微流体

• 批准号: 2889386
• 金额: --
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2889386
• 关键词: Design; development; new; Lipid; Nano

The potential of messenger ribonucleic acid (mRNA) based therapeutics which exhibit their effect by the silencing of specific genes or overexpression of therapeutic proteins has now been proven as basis of the Pfizer and Moderna COVID-19 vaccines. As delivery of oligonucleotides therapeutics into the patient is limited due to the instability and undesirable physicochemical properties of the parent molecules, efficacy is achieved by incorporation into a lipid based nanoparticle (LNP). LNPs typically, have diameters of between 50-100 nm and are comprised of a PEGylated lipid that helps control particles size, diasteraroylphosphatidylcholine to help form the structure of the nanoparticle and cholesterol which also contributes to the structure. Most importantly, they also contain an ionisable cationic lipid that encapsulates the negatively charged oligonucleotide and helps to increase the stability of the RNA. The approach in this project is to combine synthetic lipid chemistry with microfluidics to design tailor made ionisable cationic lipids to be incorporated into optimum LNP delivery systems for COVID and/or RNA cancer therapeutics. In a rational approach, a series of modified ionisable lipids will be prepared, incorporated into the LNP and loaded with the specific oligonucleotide before undergoing physicochemical property investigations to determine particle size, encapsulation loading and pKa (both individual lipid and LNP system). Following potency evaluation in specific chosen assays (to be confirmed during the course project as appropriate) and subsequent stability studies, a structure activity relationship profile will be generated which will be used to drive forward an iterative synthesis campaign to find the optimum LNP systems.The specific technical skills that the student will gain as part of this PhD are listed below:Standard and parallel synthesis of highly functionalised lipid moleculesCharacterisation and analysis of lipids using NMR, LCMS, IR, MALDI, HRMS, CHNPurification of lipid molecules and their pre-cursors, by flash column chromatographyPreparation of oligo-lipid nano particle systems via microfluids/micromixerAnalysis of physicochemical properties of LNP systems eg Z-average, PDI, zeta-potential, pKa determination, DLS and oligo encapsulation/adsorption efficiency.

现在证明，基于信使核糖核酸（mRNA）疗法的潜力通过沉默的特定基因或治疗蛋白的过表达表现出其作用，现在已被证明是辉瑞和现代Covid-19疫苗的基础。由于由于不稳定和不良的物理化学特性，寡核苷酸疗法递送到患者中受到限制，因此通过掺入脂质的纳米粒子（LNP）来实现疗效。 LNP通常的直径在50-100 nm之间，由聚乙二醇化的脂质组成，该脂质有助于控制颗粒尺寸，映射二磷脂酰胆碱，有助于形成纳米颗粒和胆固醇的结构，这也有助于结构。最重要的是，它们还包含一个可离子的阳离子脂质，该阳离子脂质封装了负电荷的寡核苷酸，并有助于提高RNA的稳定性。该项目中的方法是将合成脂质化学与微流体化学相结合，以设计量身定制的裁缝，可将电离的阳离子脂质纳入用于共vid和/或RNA癌症治疗剂的最佳LNP递送系统中。在合理的方法中，将准备一系列可改进的电离脂质，并掺入LNP中并加载特定的寡核苷酸，然后进行物理化学特性研究，以确定颗粒大小，封装载荷和PKA（单个脂质和LNP系统）。 Following potency evaluation in specific chosen assays (to be confirmed during the course project as appropriate) and subsequent stability studies, a structure activity relationship profile will be generated which will be used to drive forward an iterative synthesis campaign to find the optimum LNP systems.The specific technical skills that the student will gain as part of this PhD are listed below:Standard and parallel synthesis of highly functionalised lipid moleculesCharacterisation and analysis of lipids using NMR，LCMS，IR，MALDI，HRMS，脂质分子及其前载体，通过闪光色谱柱通过微流体/微流体/微米分析LNP系统的物理化学特性的少量脂质纳米颗粒系统的闪光色谱柱色谱映射eg z- z- a-a-a-a-a-afeverence z-a-a-a-a-pdi and z-pdi，pa-pa-pa and pa-pot，pa-pot and pa-pot，pa-pot，pa-pot，pa-pot，pa-pot and pa-pot，pa-pot，pa-pot，pa-pot，pa-pot and dl，寡核封装/吸附效率。