A molecular toolkit for immunological imaging

Lead Research Organisation: University of Oxford
Department Name: SABS IDC

Abstract

Molecular imaging has the potential to become a widely applied platform to study drug properties in vivo and mechanistic measures of pharmacology. However, relative to the emergence of new measurement methods (e.g. clinical optical) and a wide range of molecular probes there remains a reliance upon well-established tracers (e.g. [18F]-PET). However better tools are needed to study the behaviour of inflammatory cells in vivo with a view to understanding disease and developing effective therapeutics.
Addressing the dichotomous demands remains a challenge: whole-body measures are needed in addition to high spatial resolution in disease relevant tissues; high specificity to a target is required in addition to high detection sensitivity. This can only be addressed with a multi-modal approach by combining the primary benefits of each method within a single experiment. While some of this will be achieved using label-free measurements, only probe-based approaches are likely to provide the necessary specificity required for imaging cells and a broad range of molecular processes.
The primary objective of this study will be to develop better tools to provide localised measurements of inflammatory cells with a focus on emerging measurement technologies such as photoacoustic (PA) imaging. This will be achieved by developing a series of probe molecules that are specific to important immune cell types and able to report through measurement platforms across scales (e.g. localised measurements with optical, whole body with MR or PET) and bridging between those scales through PA techniques.
Our intention is to use biorthogonal chemistry to link modular building blocks together to allow access to each of these targets with minimal synthetic effort. We will develop a molecular toolkit in which modular components (signalling group, vector and linker) can be combined to provide a set of imaging agents to target multiple cell types and other in vivo processes. Key imaging building blocks for use in the studies envisaged will all incorporate cyclooctyne domains for bio-orthogonal conjugation to azide labelled vectors (initially folate derivatives and tuftsin conjugates targeted to macrophages). We will expand our studies to explore vectors for neutrophils and T-cells in the later stages of the project.
In the second rotation project, I was working on developing a synthetic route for a metal binding component with the cyclooctyne for use in biorthogonal click chemistry to prepare vectored conjugates. Initially, we will target the folate receptors on macrophage cells, developing the first set of complexes and evaluating their potential with each of the relevant imaging modalities. In the process, we will also compare the efficacy of these probes with other, tuftsin-derivatised agents targeted to activating macrophages.
In parallel, we will work to address additional cell types such as T-cells where lower populations will challenge detection limits. A project aim will be to evaluate and support the development of PA imaging as a potential method to study processes deeper into tissue at high sensitivity and specificity. To this end, we will collaborate with the Oxford Imaging network to develop and test the next generation of photoacoustic chromophores.
Our aim is to produce a set of imaging agents able to support an information-rich approach to drug development. From the outset, we envisage that this will be a collaborative project. As well as the core (Oxford and GSK), we intend to work closely with the nascent Rosalind Franklin Institute (Optoacoustic), the Rutherford Complex at Harwell (time resolved microscopy) and other collaborators driven by project needs (e.g. National Physical Laboratory). We will also collaborate extensively across Oxford and particularly with ROB and DPAG.
This project falls within the EPSRC Chemical Biology and Biological Chemistry and Medical Imaging (including medical image and vision computing) research areas.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/R512333/1 01/10/2017 30/09/2021
1940083 Studentship EP/R512333/1 01/10/2017 30/09/2021 Grace McMullon