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

该项目旨在开发新型靶向给药纳米复合材料，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)进行实时监测。该项目将进一步探索使用连续流动过程制备这些材料的可扩展性。实时跟踪药物输送系统的治疗释放对于开发个性化药物至关重要，对于了解药物输送系统在体内的药代动力学和避免对患者的不利影响都是至关重要的。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载体的有效性，但仍然无法使用标准的临床技术来现场监测治疗性释放。因此，确实需要能够使用临床仪器实时监测药物释放的材料。磁共振成像是一种非侵入性的医学成像工具，通常用于疾病的诊断和监测。临床上常使用造影剂(如Gd络合物、氧化铁颗粒)，通过磁相互作用改善成像信号，提高图像质量和分辨率。造影剂的成像信号依赖于它们的结构和即时环境-材料参数和外部环境的变化会对它们所表现出的对比度信号的水平产生巨大的影响。因此，可以对这些材料进行修改，以赋予其响应外部环境或环境变化而改变其信号的能力。在这个项目中，这种行为将被利用在一种纳米复合材料中，该复合材料旨在与药物部分一起容纳造影剂种类；化合物在体内的降解(例如，当到达目标疾病部位或响应生理疾病环境本身)将导致治疗性药物与造影剂种类一起被控制/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个手柄，以非侵入性的方式监测同时治疗释放。在这个项目中，将设计一种MRI活性的核壳纳米颗粒系统，允许针对疾病部位进行特定的靶向，可控制和可调节地释放治疗性药物，同时MRI信号的变化允许实时跟踪药物释放。主要目标包括：-利用分批方法，制备含有药物种类和具有pH或温度响应性外壳的药物的核心@壳层磁共振活性纳米颗粒和Gd螯合物或氧化铁纳米颗粒(分别为阳性和阴性磁共振造影剂)，随后进行可扩展的连续流动处理，并评估生物流体中的胶体性质。-监测磁共振信号的变化和药物对pH或温度变化的反应。-制备能够选择性靶向的抗体片段，这一跨学科项目将利用所有项目合作伙伴的专业知识，为学生提供不同技术方面的培训，包括使用批次和连续加工方法制备颗粒、抗体片段制备、颗粒表面修饰和表征技术，包括核磁共振、电子显微镜、动态光散射、小角X射线散射、具有耗散监测的石英晶体微天平、核磁共振研究和细胞生物学。该项目符合CDT的先进产品设计和复杂产品表征的主题，并符合EPSRC的研究重点，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