Endocytosis of emerging nanomedicines: Understanding the influence of shape of 3D nanoprinted soft matter materials

新兴纳米药物的内吞作用：了解 3D 纳米打印软物质材料形状的影响

• 批准号: 2333342
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2333342
• 关键词: Endocytosis; emerging; nanomedicines; Understanding; influence

REMIT: This "Basic Bioscience" project addresses BBSRC's strategic research priority 3, "Bioscience for Health" as it aims to develop basic bioscience underpinning the formulation and effectiveness of emerging nanomedicines that will benefit the maintenance and promotion of health.THE PROBLEM:Little is known how the interdependency of size, shape, and surface chemistry can influence the biodistribution, cellular internalization, and intracellular trafficking of nanomaterials. Insights into the effect of shape, patterning, and deformability on cellular uptake and biodistribution are emerging with the increase in sophisticated techniques to manufacture nanomedicines such as 3D nanoprinting that can generate monodisperse products of specific geometry and deformability. Patterning on surfaces can also influence protein adsorption and consequently cellular responses.CONTEXT:With the first regulatory approved 3D printed medicine in 2015, the precendence was set for the use of 3D printing in the pharmaceutical industry and interest in exploring capabilities in the nanoscale (I.e. 3D nanoprinting) is rapidly increasing. One of the attractive advantages of 3D printing its versatility and diversity which can be exploited in the health sector to develop personalised medicines. 3D nanoprinting in healthcare extends capabilities and potential into the relm of nanomedicines.Nanomedicines can employ multiple pathways for cellular entry, which are currently insufficiently understood.Various mechanisms of endocytosis are available to nanomedicines including phagocytosis and pinocytosis through clathrin-dependent and clathrin-independent pathways.PROJECT AIMS:This project will explore to process of endocytosis of 3D nanoprinted soft matter materials and investigate the shape effect of these nanomaterials on cellular internalization, and intracellular trafficking.PhD WORK PROGRAMME:Key resources to be used:- Nikon Imaging Centre: The world renowed Nikon Imaging Centre was established in 2012 at King's College London. As one of only 8 Nikon Imaging Centres in the world and the only one in the UK, the £4.5 million centre houses ten different cutting-edge research microscopes. This project will involve imaging the dynamics of endocytosis in animal and plant cell lines using cutting edge research microscopic techniques such as the Ti2 live cell imaging systems available at the Nikon Imaging centre.- London Centre for Nanotechnology (LCN): LCN is a multidisciplinary research centre in physical and biomedical nanotechnology in London. King's College London recently joined the LCN and Dr Raimi- Abraham has an ongoing collaboration with Dr Richard Thorogate (BioNano Laboratory) in the area of quantitative nanomechanical characterisation of soft matter nanomaterials. The project will explore the assessment of morphological changes of plasma membrane and protein assembly during endocytosis utilizing high-speed atomic force microscopy (HS-AFM) combined with concofocal laser scanning unit.YEAR ONE (KCL):- Student training in project relevant techniques such as 3D nanoprinting, cell culture, high resolution electron microscopy (for imaging of cells and their interaction with 3D nanoprinted soft matter materials), intra-vtiral microscopy, atomic force microscpy and confocal microscopy).ii) Fabricate templates for 3D nanoprinting.YEAR TWO (KCL & BASF):- Formulation of 3D nanofeatures with various shapes- Characterisation of surface properties such as roughness and understanding of potential interaction with the cells for uptake.YEAR THREE (KCL):- Analyze the effects of nanopatterns on the biological function of living animal (such as Caco-2 cell line or TR146 cell line) and plant cells (such as Tobacco BY-2 cells)YEAR FOUR (KCL & BASF):- Feedback the results of biological studies to redefine and generate new knowledge based on cell- material interactions at nanometre scales.

这个“基础生物科学”项目解决了BBSRC的战略研究重点3，“健康生物科学”，因为它旨在发展基础生物科学，支持新兴纳米药物的配方和有效性，这将有利于维护和促进健康。问题：人们对纳米材料的大小、形状和表面化学的相互依赖性如何影响其生物分布、细胞内化和细胞内运输知之甚少。形状、图案和可变形性对细胞摄取和生物分布的影响随着制造纳米药物的复杂技术的增加而出现，例如3D纳米打印，可以产生具有特定几何形状和可变形性的单分散产品。表面图案也可以影响蛋白质吸附，从而影响细胞反应。背景：随着2015年第一个监管部门批准3D打印药物，3D打印在制药行业的应用成为了优先事项，对纳米级（即3D纳米打印）探索能力的兴趣正在迅速增加。3D打印的一个吸引人的优势是它的多功能性和多样性，可以在卫生部门开发个性化药物。医疗保健领域的3D纳米打印扩展了纳米药物领域的能力和潜力。纳米药物可以通过多种途径进入细胞，目前对这些途径的了解还不够充分。纳米药物的内吞作用机制多种多样，包括吞噬作用和胞饮作用，可通过网格蛋白依赖性和非网格蛋白依赖性途径实现。项目目的：本项目将探索3D纳米打印软物质材料的内吞过程，并研究这些纳米材料的形状对细胞内化和细胞内运输的影响。-尼康成像中心：世界知名的尼康成像中心于2012年在伦敦国王学院成立。作为世界上仅有的8个尼康成像中心之一，也是英国唯一的一个，这个价值450万英镑的中心拥有10种不同的尖端研究显微镜。该项目将使用尖端的研究显微技术，如尼康成像中心提供的Ti2活细胞成像系统，对动物和植物细胞系的内吞作用动力学进行成像。-伦敦纳米技术中心（LCN）： LCN是伦敦物理和生物医学纳米技术的多学科研究中心。伦敦国王学院最近加入了LCN， Raimi- Abraham博士与Richard Thorogate博士（BioNano实验室）在软物质纳米材料的定量纳米力学表征领域进行了持续的合作。本项目将利用高速原子力显微镜（HS-AFM）结合共聚焦激光扫描装置，探讨胞吞过程中质膜和蛋白质组装的形态学变化。第一年（KCL）：学生在项目相关技术方面的培训，如3D纳米打印，细胞培养，高分辨率电子显微镜（用于细胞成像及其与3D纳米打印软物质材料的相互作用），病毒内显微镜，原子力显微镜和共聚焦显微镜)。ii)制作3D纳米打印模板。第二年（KCL & BASF）：-各种形状的3D纳米特征的配方-表面特性的表征，如粗糙度和理解与细胞摄取的潜在相互作用。第三年（KCL）：-分析纳米模式对活体动物（如Caco-2细胞系或TR146细胞系）和植物细胞（如烟草BY-2细胞）生物功能的影响。第四年（KCL & BASF）：-反馈生物学研究结果，以重新定义和产生基于纳米尺度细胞-物质相互作用的新知识。