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

该项目的主要目的是开发一种基于化学和基于配方的组合方法，将活性治疗剂(小免疫肿瘤化合物)输送到大脑中的肿瘤微环境和淋巴结。CDT主题本项目与三个CDT主题保持一致--预测药学、高级产品设计、复杂产品特性预测药学--开发一种改进的电子计算模型，用于预测药物与乳杆菌微粒和肠道淋巴转运的关联--电子计算模型--辅助设计和合成小分子免疫肿瘤药物的高亲脂性前体药物。这还将与为选定的主要候选前体药物设计适当的脂基给药系统相结合。复杂的产品特性-对用于选择体内研究候选先导药物的合成前药进行体外和体外评估(与人工和天然乳糜粒、添加了酯酶活性的生物悬浮剂肠液的稳定性、淋巴/血浆稳定性)。我们还将对选定的前体药物和母体药物进行体内药代动力学和生物分布的评估，然后进行药代动力学分析、建模和模拟。EPSRC REMIT本项目完全符合EPSRC的变革性医疗技术职责

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