Aim of the PhD Project:
The preparation of Gd-functionalised conjugated polymer nanoparticles with novel structures that allow emission in the biological window and PDT using IR-emitting conjugated polymers. The assemblies aim to combine bright IR emission with greatly enhanced MR contrast through immobilisation and control over the local environment of the Gd units.
Semiconducting polymer nanoparticles (SPNs) are an attractive alternative to quantum dots, which avoid the use of toxic heavy metals. SPNs are generally much brighter than inorganic quantum dots, easier to prepare and show no toxicity issues to prevent their use in clinical applications. The Green group has made substantial contributions to the chemistry and application of SPNs (Green, Thanou, Suhling, Phinikaridou, Botnar et al, Nanoscale 2014, 6, 8376; Green, Rakovich et al, ACS Nano 2021, 15, 8790) and their work with Stream Biosciences, world leaders in conjugated polymer (CP) nanoparticle for imaging, has provided access to some of the brightest emitting polymers and technical expertise. Using a polymer recently discovered to be an IR-emitter, SPNs will be synthesised for use as bright optical imaging agents that emit in the IR region and operate in the biological imaging window (650-900 nm), in which absorption and scattering from blood and water is reduced.
While the limitation of depth penetration for optical imaging agents can be overcome using near-IR emissive materials or optical fibres, an additional non-invasive imaging modality would provide crucial information on biodistribution and localisation. The addition of gadolinium (Gd) units to the outer surface of the SPN would provide this information through their contrast enhancement effect in magnetic resonance imaging (MRI). It would also lead to a great increase in the performance of the immobilised Gd units, as observed by Wilton-Ely and Botnar for Gd-functionalised gold nanoparticles (Wilton-Ely, Botnar et al, Chem. Eur. J., 2019, 25, 10895; Wilton-Ely, Botnar et al, Chem. Eur. J., 2020, 26, 4552). Furthermore, the synthetic expertise in the Wilton-Ely group has enabled the development of Gd units with dramatically reduced internal rotation freedom, enhancing the MR contrast still further.
While monometallic Gd surface units would be used, current work in the Wilton-Ely group is focused on bringing multiple Gd centres together within one molecular unit (Wilton-Ely, Botnar et al, Inorg. Chem., 2020, 59, 10813). This approach would be exploited to increase the Gd loading still further, allowing the attachment of polygadolinium units, boosting the local concentration of Gd units (and hence contrast enhancement).
As well as being some of the most efficient optical imaging materials currently available, SPNs are much simpler to prepare than existing optical probes. We will make use of this fact to solve any issues encountered (e.g., aggregation) through the modification of the polymer or adding targeting units (e.g., for proteins over-expressed in tumours). We will also explore the opportunity to mix conjugated polymers, making polymer blend particles which have been demonstrated to increase emission brightness. Previous work by the Green/Rakovich groups have uncovered the potential of a therapeutic function using controlled surface chemistry, ultimately shown to exhibit photodynamic therapeutic action (Green, Rakovich et al, ACS Nano 2021, 15, 8790).
The combination of the various modalities would allow pre-clinical imaging, uptake and targeting studies to be carried out in cells (IR emission), while both the IR emission and MRI contrast enhancement would allow investigation of the probes in animals. Ultimately, clinical application would benefit from a non-invasive imaging technique (MRI) with our assembly, allowing the use of much lower Gd concentrations and targeted contrast enhancement. The incorporation of a photoswitchable therapeutic technique that is co-localised within the imaging probe would allow therapy to be applied only where needed (either through the skin or via fibre optic endscope), avoiding collateral damage in the treatment of disease.
The ideal candidate would have a degree in chemistry, materials or in a biology-related field, provided they have experience of synthesis. The applicant should have a strong academic record, an interest in preclinical imaging, excellent communication skills and be able to work in a collaborative, interdisciplinary environment. The student will be trained in tissue culture and molecular imaging using optical/MRI techniques.