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

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

Pharmaceutical technologies underpin healthcare product development. Medicinal products are becoming increasingly complex, and while the next generation of research scientists in the life- and pharmaceutical sciences will require high competency in at least one scientific discipline, they will also need to be trained differently than the current generation. Future research leaders need to be equipped with the skills required to lead innovation and change, and to work in, and connect concepts across diverse scientific disciplines and environments. This CDT will train PhD scientists in cross-disciplinary areas central to the pharmaceutical, healthcare and life sciences sectors, whilst generating impactful research in these fields. The CDT outputs will benefit the pharmaceutical and healthcare sectors and will underpin EPSRC call priorities in the development of low molecular weight molecules and biologics into high value products.

Benefits of cohort research training: The CDT's most direct beneficiaries will be the graduates themselves. They will develop cross-disciplinary scientific knowledge and expertise, and receive comprehensive soft skills training. This will render them highly employable in R&D in the pharmaceutical, healthcare and wider life-sciences sectors, as is evidenced by the employment record in R&D intensive jobs of graduates from our predecessor CDTs. Our students will graduate into a supportive network of alumni, academic, and industrial scientists, aiding them to advance their professional careers.

Benefits to industry: The pharmaceutical sector is a key part of the UK economy, and for its future success and international competitiveness a skilled workforce is needed. In particular, it urgently needs scientists trained to develop medicines from emerging classes of advanced active molecules, which have formulation requirements that are very different from current drugs. The CDT will make a considerable impact by delivering a highly educated and skilled cohort of PhD graduates. Our industrial partners include big pharma, SMEs, CROs, CMOs, CMDOs and start-up incubators, ensuring that CDT training is informed by, and our students exposed to research drivers in, a wide cross-section of industry. Research projects in the CDT will be designed through a collaborative industry-academia innovation process, bringing direct benefits to the companies involved, and will help to accelerate adoption of new science and approaches in the medicines development. Benefit to industry will also be though potential generation of IP-protected inventions in e.g. formulation materials and/or excipients with specific functionalities, new classes of drug carriers/formulations or new in vitro disease models. Both universities have proven track records in IP generation and exploitation. Given the value added by the pharma industry to the UK economy ('development and manufacture of pharmaceuticals', contributes £15.7bn in GVA to the UK economy, and supports ~312,000 jobs), the economic impacts of high-level PhD training in this area are manifest.

Benefits to society: The CDT's research into the development of new medical products will, in the longer term, deliver potent new therapies for patients globally. In particular, the ability to translate new active molecules into medicines will realise their potential to transform patient treatments for a wide spectrum of diseases including those that are increasing in prevalence in our ageing population, such as cardiovascular (e.g. hypertension), oncology (e.g. blood cancers), and central nervous system (e.g. Alzheimer's) disorders. These new medicines will also have major economic benefits to the UK. The CDT will furthermore proactively undertake public engagement activities, and will also work with patient groups both to expose the public to our work and to foster excitement in those studying science at school and inspire the next generation of research scientists.