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

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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