Magnetic resonance imaging (MRI) guided monitoring of drug release from targeted designer nanocomposites

该项目旨在开发新型靶向药物递送纳米复合材料，其具有可控和可调的治疗释放，可以使用非侵入性磁共振成像（MRI）进行真实的实时监测。该项目将进一步探讨这些材料的制备使用连续流processing.真实的时间跟踪治疗药物释放系统的可扩展性是非常重要的个性化医疗的发展，是至关重要的，在了解药物释放系统在体内的药代动力学，并在避免患者的不良反应。尽管近年来出现了大量的研究，证明了纳米结构材料作为药物递送载体的功效，但仍然无法使用标准临床技术原位监测治疗释放。因此，真实的需要能够使用临床仪器真实的实时监测药物释放的材料。造影剂（例如钆螯合物、氧化铁颗粒）通常在临床上应用于患者，以通过磁相互作用改善成像信号，提高图像质量和分辨率。来自造影剂的成像信号取决于其结构和直接环境-材料参数和外部环境的变化可能对它们可以表现出的造影信号水平产生显著影响。因此，这些材料可以被改性以赋予响应于其外部环境或在其周围环境变化时改变其信号的能力。在这个项目中，这种行为将被利用在一种纳米复合材料中，这种纳米复合材料被设计成与药物部分一起容纳造影剂物质;复合材料在体内的降解（例如，在到达目标疾病部位时或响应于生理疾病环境本身）将导致治疗剂与造影剂物质一起的受控/触发释放，由于造影剂环境的变化而引起的MRI信号的变化，提供了一种以非侵入性方式监测同时治疗释放的手柄。在该项目中，将设计一种MRI活性核@壳纳米颗粒系统，允许特异性靶向疾病部位，治疗剂的受控和可调释放，同时MRI信号的变化允许真实的时间内跟踪药物释放。主要目标包括：-使用批处理方法制备含有药物种类和钆螯合物或氧化铁纳米颗粒（分别为阳性和阴性MRI造影剂）的核@壳MRI活性纳米颗粒，其具有pH或温度响应性外壳，然后进行可扩展的连续流处理，并评估生物流体中的胶体性质。监测MRI信号变化和响应pH或温度变化的同时药物释放。制备能够选择性靶向的抗体片段，具有允许定向附着到纳米颗粒表面的位点选择性修饰，并使用新型定量工具评估结合亲和力。体外复合系统功效评估。该跨学科项目将利用所有项目合作伙伴的专业知识，并为学生提供不同技术的培训，包括使用批量和连续处理方法制备颗粒，抗体片段制备，颗粒表面改性，以及表征技术，包括NMR，电子显微镜，动态光散射，小角度X射线散射，石英晶体微天平与耗散监测，MRI研究和细胞生物学。该项目与先进产品设计和复杂产品表征的CDT主题以及EPSRC研究优先事项保持一致，包括颗粒技术，医学成像，材料工程-复合材料

This project aims to develop novel targeted drug delivery nanocomposites with controllable and tuneable therapeutic release which can be monitored in real time using non-invasive magnetic resonance imaging (MRI). The project will further explore the scalability of the preparation of these materials using continuous flow processing.Real time tracking of therapeutic release from drug delivery systems is of fundamental importance for the development of personalised medicine and is vital in both understanding the pharmacokinetics of drug delivery systems in the body and in avoiding adverse patient effects. Although a vast body of research has emerged in recent years demonstrating the efficacy of nanostructured materials as drug delivery vehicles, there remains an inability to monitor therapeutic release in situ using standard clinical techniques. There is, therefore, a real need for materials capable of real time monitoring of drug release using clinical instrumentation.MRI is a non-invasive medical imaging tool commonly used for diagnosis and monitoring of disease. Contrast agents (e.g. gadolinium chelates, iron oxide particles) are commonly applied to patients clinically to improve imaging signal through magnetic interactions, improving image quality and resolution. Imaging signal from contrast agents is dependent on their structure and immediate environment - changes in material parameters and external environment can have a dramatic effect on the level of contrast signal that they can exhibit. As such, these materials can be modified to bestow the ability to change their signal in response to their external environment, or upon changes in their surroundings. In this project, this behaviour will be harnessed in a nanocomposite designed to house a contrast agent species alongside drug moieties; degradation of the composite in the body (for example, upon reaching a target disease site or in response to the physiological disease environment itself) will result in controlled/triggered release of the therapeutic alongside the contrast agent species, with changes in MRI signal due to changes in the contrast agent environment providing a handle to monitor concurrent therapeutic release in a non-invasive manner.In this project, an MRI-active core@shell nanoparticle system will be designed, allowing specific targeting to a disease site, controlled and tuneable release of a therapeutic, with concurrent change in MRI signal allowing tracking of drug release in real time. Major objectives include:- Preparation of core@shell MRI-active nanoparticles containing drug species and gadolinium chelates or iron oxide nanoparticles (positive and negative MRI contrast agents respectively) with a pH- or temperature-responsive shell, using batch approaches, followed by scalable continuous flow processing, and assessment of colloidal properties in biological fluids.- Monitoring of MRI signal change and concurrent drug release in response to pH or changes in temperature.- Preparation of antibody fragments capable of selective targeting, with site-selective modification allowing oriented attachment to nanoparticle surfaces and assessment of binding affinity using novel quantitative tools.- Assessment of efficacy of composite systems in vitro.This interdisciplinary project will exploit the expertise of all project partners and provide student training in different techniques, including particle preparation using batch and continuous processing methods, antibody fragment preparation, particle surface modification, and characterisation techniques including NMR, electron microscopy, dynamic light scattering, small-angle X-ray scattering, quartz crystal microbalance with dissipation monitoring, MRI studies, and cell biology. The project aligns with the CDT themes of Advanced Product Design and Complex Product Characterisation and with EPSRC research priorities, including particle technology, medical imaging, materials engineering-composites