Modelling cargo loaded macrophage trafficking across liver endothelium: a new approach to drug delivery in liver cancer.

模拟负载巨噬细胞穿过肝内皮的运输：肝癌药物输送的新方法。

• 批准号: 2890431
• 金额: --
• 依托单位: University of Birmingham
• 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-2890431
• 关键词: Modelling; cargo; loaded; macrophage; trafficking

Liver cancer also known as hepatocellular cancer(HCC) is one of the most lethal tumours in the world and cases are rising dramatically in the United Kingdom. Immunotherapy is one of the recent breakthroughs in treating this cancer and yet only 20% of patients show tumour response and therefore new approaches are urgently needed. To date, the focus of cancer therapy has been on T cells from the adaptive arm of the immune system but therapies focusing on monocytes/macrophages within the innate arm are less well developed. Monocytes are macrophage precursors that circulate in the blood and then migrate across endothelial cells into tissue and tumours and change into tissue resident macrophages. They have intrinsic properties that can profoundly change the tumour microenvironment and can also support drug delivery, therefore could be an ideal form of cell therapy (1). The success of cell therapy depends on the most efficient delivery to the site of disease and yet physical factors that regulate cell trafficking in the liver are still poorly understood, in this project we aim to focus on liver endothelial cells that are the gatekeepers for cell migration from the circulation into diseased liver tissue. We will study both how fluid flow/shear stress exposure and the underlying stiffness of the endothelial barrier impacts on monocyte capture and migration. Using a flow based assay we can perfuse monocytes over human endothelial monolayers and accurately control the flow to reflect the shear stress in the liver/tumour microenvironment (2). Incorporating different matrix coatings reflecting composition seen in liver disease will also alter endothelial stiffness properties. Additionally, we will assess how the pre-activation of monocytes to macrophages and pre-loading with cargo can impact on their migratory pathways.

肝癌也被称为肝细胞癌（HCC）是世界上最致命的肿瘤之一，在英国病例急剧上升。免疫疗法是治疗这种癌症的最新突破之一，但只有20%的患者表现出肿瘤反应，因此迫切需要新的方法。迄今为止，癌症治疗的重点一直是来自免疫系统的适应性臂的T细胞，但专注于先天性臂内的单核细胞/巨噬细胞的疗法开发得不太好。单核细胞是巨噬细胞前体，其在血液中循环，然后穿过内皮细胞迁移到组织和肿瘤中，并变成组织驻留巨噬细胞。它们具有内在特性，可以深刻改变肿瘤微环境，也可以支持药物递送，因此可能是细胞治疗的理想形式。细胞治疗的成功取决于最有效地输送到疾病部位，但调节肝脏细胞运输的物理因素仍然知之甚少，在本项目中，我们的目标是关注肝内皮细胞，它们是细胞从循环迁移到患病肝组织的守门人。我们将研究流体流动/剪切应力暴露和内皮屏障的潜在刚度如何影响单核细胞捕获和迁移。使用基于流动的测定，我们可以在人内皮单层上灌注单核细胞，并准确控制流动以反映肝脏/肿瘤微环境中的剪切应力（2）。制备反映肝病中所见组成的不同基质涂层也将改变内皮硬度特性。此外，我们将评估单核细胞向巨噬细胞的预活化和货物的预加载如何影响其迁移途径。