Targeting small molecule drugs to lymph nodes and brain by highly lipophilic prodrugs approach

通过高亲脂性前药方法将小分子药物靶向淋巴结和大脑

• 批准号: 2436275
• 金额: --
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2436275
• 关键词: Targeting; small; molecule; drugs; lymph

The main aim of this project is to develop a combined chemistry-based and formulation-based approaches to deliver active therapeutic agents (small immune-oncology compounds) to tumour microenvironment in the brain, and to lymph nodes. CDT themes This project aligns with three CDT themes - Predictive Pharmaceutical Sciences, Advanced Product Design, Complex Product Characterisation Predictive Pharmaceutical Sciences - Development of an improved in silico model for prediction of association of drugs with chylomicrons and the intestinal lymphatic transport Advanced Product Design - In silico model-assisted design and synthesis of highly lipophilic prodrugs of small molecule immuno-oncology drugs. This will be also combined with design of appropriate lipid-based drug delivery systems for the selected lead candidate prodrugs. Complex Product Characterisation - In vitro and ex vivo assessment of the synthesized prodrugs for selection of lead candidates for in vivo studies (association with artificial and natural chylomicrons, biorelevant intestinal fluids stability with esterase activity added, lymph/plasma stability. We will also perform in vivo assessment of pharmacokinetics and biodistribution of selected prodrugs and the parent drugs, followed by pharmacokinetic analysis, modelling and simulation. EPSRC remit This project fully aligns with EPSRC remit of Transformative Healthcare Technologies

该项目的主要目的是开发一种基于化学和配方的组合方法，将活性治疗剂（小免疫肿瘤化合物）递送到大脑中的肿瘤微环境和淋巴结。CDT主题该项目与三个CDT主题-预测性药物科学，先进产品设计，复杂产品表征预测性药物科学-开发用于预测药物与乳糜微粒和肠淋巴转运相关性的改进的计算机模型先进产品设计-计算机模型辅助设计和合成小分子免疫肿瘤药物的高度亲脂性前药。这也将与所选先导候选前药的适当脂质基药物递送系统的设计相结合。复杂产品表征-合成前药的体外和离体评估，用于选择体内研究的主要候选药物（与人工和天然乳糜微粒的相关性、添加酯酶活性的生物相关肠液稳定性、淋巴/血浆稳定性）。我们还将对选定的前药和母体药物的药代动力学和生物分布进行体内评估，然后进行药代动力学分析，建模和模拟。EPSRC职权范围本项目完全符合EPSRC变革性医疗保健技术的职权范围