George Herbert is a final year PhD student in Professor Stephen J. Archibald’s research group based in the Department of Biomedical Sciences at the University of Hull. He completed an integrated masters (MChem Chemistry with Molecular Medicine) in the group before progressing to his PhD in 2018. George’s research aims to develop and validate pulmonary drug delivery systems using fluorine-18 radiolabelling and positron emission tomography technology.

Based in the Positron Emission Tomography Research Centre (PETRC), the groups work focuses at the interface of chemistry and biology, developing new PET radiotracers for the diagnosis and treatment of disease (oncology, cardiovascular and infection). Research performed in the PETRC is progressed from concept to pre-clinical in vivo assessment. The new Medical Imaging Research Centre (MIRC) based at Castle Hull hospital is a custom-built facility that will allow leading-edge research to translated through clinical development.

Following the success of the work supported by the DDL Career Development Grant, George was able to secure a job as a Lead Radiochemist based at GE Healthcare. Starting in the autumn of 2021, he is in the final stages of completing his research and hopes to submit his thesis by December 2021.

Project summary

Compared to the conventional oral and intravenous routes, pulmonary drug delivery offers the opportunity for superior drug concentrations in the lung for rapid onset of action in addition to improved patient compliance. However, the development and validation of effective inhaled medications is often challenging. Patients with respiratory disease innately suffer from compromised pulmonary systems and therefore high drug output from minimum patient effort is a desirable quality. Nebulisers, DPI’s and pMDI’s are among the most commonly employed devices however suffer various drawbacks including variable output efficiencies and device-formulation complications. Vapes present as alternative drug delivery devices which could address some of these issues, yet remain vastly underexplored.

Non-invasive medical imaging can serve as an invaluable tool to aid the drug development process. Positron emission tomography (PET) is a highly sensitive and quantitative medical imaging modality which has been previously successfully employed to validate novel drug delivery systems. Organic radioisotopes can be covalently attached to drug molecules in place of their native, non-radioactive isotopes creating structurally identical imaging probes. Fluorine-18 (18F) benefits from high positron yields and low positron energies, promoting sensitive measurements. PET can be employed in pre-clinical proof-of-concept in vitro studies and more complex in vivo studies focussing on pulmonary penetration, deposition and clearance. Results from these studies can be used to optimise performance by making informed changes to the device or formulation.

This project aims to assess the output and drug delivery potential of vape devices using 18F labelled drug molecules. In order to quantify the output and aerosol parameters of the device, the vape liquid was first labelled with a radioactive tag. An organic molecule was designed and synthesised to ensure desirable miscibility, volatility and stability. This molecule was labelled with 18F in high yields and included into vape liquid with high efficiency. Preliminary results from a short 2 second vape indicate a 20x improved output efficiency compared to jet nebulisers. Following device assessment, various drugs will be radiolabelled with 18F and assessed for their vaporisation stability and output characteristics. One such drug is fluticasone propionate, a corticosteroid used to treat asthma and COPD, which possesses a native fluorine atom and hence favours 18F radiolabelling. Variable flow rate pumps will be used alongside valves operating on timers to ensure accurate control over the device puff volume. These can also be used to replicate the forced inhalation volume and flow rates of different disease states. Initially these formulations will be assessed in vitro using impactors to determine the MMAD, GSD, FPF and ED. Following the success of these studies, the devices will be evaluated in vivo using animal models.

Career Development Award Proposal

In order to fulfil the aims of this project and successfully evaluate the drug delivery potential of vape devices, a broad range of interdisciplinary knowledge and skills will be required. My research experiences to-date provide me with a strong foundation in the relevant disciplines necessary to begin working towards addressing the research aims.

A Master’s degree in medicinal chemistry has educated me in the core disciplines of chemistry with a focus on synthetic organic chemistry for drug development. Theory and practical skills developed during this course will be useful for the synthesis of radiolabelled drug molecule that will be required to validate the vape devices. As a second year PhD student, my first year was spent acquiring proficiencies in new skills including organic radiochemistry, in vitro biological assays and in vivo PET analysis of novel tracers. In addition, my first year has taught me how to conduct research effectively, from planning experiments to interpreting the data and ultimately executing on-task problem solving. I am a motivated, hard-working and ambitious individual, and I believe my positive can-do attitude will allow me to overcome the challenges associated with fundamental scientific research allowing for time efficient progress.

Due to the diverse nature of the project, a small research team must be assembled to meet the demand of specialist knowledge. Working as part of a broad and dynamic team would allow me to further strengthen my communication skills, both verbal and written, which are essential for successful research collaboration and career progression. Furthermore, working closely alongside members of this research team provides the opportunity to develop new expertise in areas that will compliment my current knowledgebase. This will allow me to mature into a well-rounded scientist equipped with a desirable range of knowledge for career growth.

Drug development has remained a passion of mine since early in my undergraduate degree and my research experience to-date has taught me that molecular imaging can be a valuable asset in this process. The discovery of new molecular entities is a notoriously slow, expensive and often without success. Imaging modalities, such as PET, can increase the success rate of this process by evaluating the in vivo performance of new drug candidates before initiating costly and time-consuming clinical trials. In the short-term, following the completion of my PhD, I would like to further expand my organic radiochemistry toolbox, specifically using carbon-11 to radiolabel drug-like molecules. Compared to fluorine, carbon is much more abundant in pharmacological molecules and therefore would provide the opportunity for a larger library of drug candidates to be radiolabelled. In the long-term, I hope to apply my knowledge in organic radiochemistry to aid the development process of new drug candidates for a range of applications. This will speed up the bench-to-bedside translation of new molecular entities which could have a significant positive impact in disease management; I feel this would be particularly beneficial in pulmonary drug development which is inherently complex.

In order to achieve my career goals, I will need to possess a range of specialist knowledge and skills. This research experience presents the opportunity to build on existing proficiencies and will also stimulate the development of new expertise/ skills that will be invaluable for career progression. My synthetic knowledge and skills will be further expanded by the synthesis of clinically established molecular structures and their derivatisation for radiolabelling. Furthermore, I aim to develop an expertise in fluorine-18 radiochemistry and its numerous analytical and QC techniques. As aforementioned, the development of drugs for pulmonary administration presents with additional complications compared to the conventional intravenous and oral routes. This project will give me a unique insight into the tools required to validate drug delivery devices and provides me with a highly bespoke collection of skills for the evaluation radiolabelled aerosols. This will include the assembly, calibration and operation of impactors and the translation of drug formulations to pre-clinical animal models for in vivo evaluation. Specifically, this element of the project will provide me with the opportunity to become well-practised in animal handling and common in vivo and ex vivo experiments. This understanding will allow me to bridge the interdisciplinary gap between chemistry and biology and streamline the translation of new drug formulations to pre-clinical assessment throughout my career. Furthermore, I will develop the ability to efficiently assess risks and implement measures to mitigate the likelihood of these occurring. This is a highly transferrable and valuable asset for the progression of a safe scientific career.

More broadly, the research experience will allow me to assemble core skills that are intrinsic in successful project development. This ranges from conceptualisation by identifying a gap in the research through experimental design, data analysis and ultimately communication of the results. The hands-on experience will also encourage me to fine-tune my creative and resourceful problem-solving ability. Other core research skills, including time management and teamwork, will also be refined through this experience.

At the projects conclusion, I will have the opportunity to present the results from this research to a broad audience. This experience will allow me to network and become known in scientific community which is essential for career progression.

Collectively, my existing knowledge, experiences to-date and support of a specialist research team provide me with a strong foundation to generate results in an achievable timeframe. As the project progresses, new skills and applied knowledge will be acquired in addition to the further concretion of existing expertise. Ultimately this experience should allow me to develop into an independent and confident researcher endorsed with a range of expert scientific knowledge and valuable personal qualities.