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.

基于信使核糖核酸（mRNA）的治疗剂通过沉默特定基因或过表达治疗性蛋白质来发挥作用，其潜力现已被证明是辉瑞和Moderna COVID-19疫苗的基础。由于母体分子的不稳定性和不期望的物理化学性质，寡核苷酸治疗剂向患者中的递送受到限制，因此通过掺入基于脂质的纳米颗粒（LNP）中来实现功效。LNP通常具有50-100 nm之间的直径，并且由有助于控制粒度的PEG化脂质、有助于形成纳米颗粒结构的二硬脂酰磷脂酰胆碱和也有助于该结构的胆固醇组成。最重要的是，它们还含有可电离的阳离子脂质，其封装带负电荷的寡核苷酸并有助于增加RNA的稳定性。该项目的方法是将联合收割机合成脂质化学与微流体技术相结合，以设计定制的可电离阳离子脂质，并将其纳入用于COVID和/或RNA癌症治疗的最佳LNP递送系统中。在合理的方法中，将制备一系列改性的可电离脂质，将其掺入LNP中并加载特定的寡核苷酸，然后进行理化性质研究以确定粒度、包封负载和pKa（单个脂质和LNP系统）。在特定选定试验中进行效价评价后（将在课程项目中酌情确认）和随后的稳定性研究，将生成结构活性关系曲线，用于推动迭代合成活动，以找到最佳的LNP系统。作为该博士学位的一部分，学生将获得的具体技术技能如下所示：高功能化脂质分子的标准和平行合成使用NMR、LCMS、IR、MALDI、HRMS、CHN对脂质进行表征和分析脂质分子及其前体的纯化，通过快速柱色谱法通过微流体/微混合器制备低聚脂质纳米颗粒系统分析LNP系统的物理化学性质，例如Z-平均值、PDI、zeta-电位、pKa测定、DLS和低聚脂质包封/吸附效率。