Our team has expertise in organic, macromolecular and supramolecular chemistry. We are interested in developing new methodologies and technologies that can enable the preparation of synthetic and biological (nano)materials with an optimum level of dimensional (at surfaces), compositional, architectural, topological and functional control. We are also interested in applying the methods, techniques and materials developed to help solve long-term and emerging problems that impact global economic and societal development such as nanotechnology, healthcare technologies and sustainability. If you interested in joining the team or recognise collaborative opportunities please get in touch (p.wilson.1@warwick.ac.uk).

Details of our signature projects are summarised below.

Precision synthesis using nanoscale electrochemistry

Established methods for surface modification and patterning are being superseded by the growing demand for smaller dimensions and higher resolutions. This has led to the development of probe-based methods which can deliver nanoscale design capabilities. The existing state-of-the-art techniques of nanofabrication are (i) dip-pen nanolithography (DPN) which employs AFM tips and arrays to dispense substrates at surfaces with feature sizes of the order of 10-100 nm, and (ii) the fountain-pen probe approach which delivers material to a surface from a reservoir under either electrochemical or ‘electro-less’ conditions. However, there are limitations associated with these technologies including limited ink-substrate compatibility, the need for tip conditioning (DPN) and restricted functional diversity and substrate loading.

ElectraSyn Pro 2.0 and representative schematic for polymerisation using SECCM probes

We are addressing these limitations by adapting scanning electrochemical cell microscopy (SECCM) for the synthesis and deposition of polymers at surfaces. We are identifying suitable reactions and reaction conditions for electrosynthesis and controlled electropolymerisation e.g. electrochemical atom transfer radical polymerisation using IKA's ElecraSyn Pro 2.0. These conditions will then be translated to the nanoscale, using a bespoke electrochemical scanning rig, enabling precise electrochemical synthesis at a variety of functional surfaces. This represents a novel, alternative strategy for surface modification and patterning of conducting (e.g. electrodes), insulating (e.g. polymeric) and biological (e.g. cells) substrates.

References

Oseland, E. E.; Ayres, Z. J.; Basile, A.; Haddleton, D. M.; Wilson, P.; Unwin, P. R., Chem. Commun. 2016, 52, 9929-9932

Novel ligation strategies for polymer-polymer and polymer-protein/peptide coupling

Recent advances in synthetic methods have brought us closer than ever to the precision of nature. For example, the compositional control conferred by reversible deactivation radical polymerization (RDRP) enables us to design and synthesize macromolecules with unprecedented control over not only the polymer chain ends, but also the side chain functionality. Furthermore, this functionality can be exploited to afford chemical modification of peptides, proteins and other polymers, with ever-improving site-specificity and efficiency, yielding a range of well-defined polymeric and protein/peptide-polymer hybrid materials. Such materials benefit from the amalgamation of the properties of proteins/peptides with those of the synthetic (macro)molecules in question.

One recent example of an approach to efficient polymer-polymer and polymer-peptide ligation via sequential native chemical ligation and thiol-ene chemistry

We are constantly exploring, adapting and developing new synthetic methods that enable the synthesis of functional polymers and investigating their use for the preparation of well-defined (block) copolymers and/or protein/peptide-polymer conjugates via the development of efficient ligation strategies. Particular attention is focused on contolling the properties and activity of therapeutic and antimicrobial peptide/protein conjugates.

Engineering peptides/proteins to develop biological (nano)materials based on functional amyloids

Amyloids are high aspect ratio nanofibrils composed of self-assembled proteins and peptides rich in β-sheet conformation. Typically, they are considered to be pathogenic being associated with onset and progression of neurological disorders including Alzheimer’s and Parkinson’s disease. However, there are increasing examples of non-pathogenic amyloids being associated with normal cell physiology which are being referred to as ‘functional’ amyloids. For example, amyloid protein Pmel17, is involved in skin pigmentation, mitigating the cytotoxicity associated with melanin formation. Furthermore, a number of other peptide and protein hormones have been found to be stored in the amyloid state in secretary granules throughout the endocrine system, releasing active monomeric hormones upon demand. One such hormone peptide is somatostatin, which is secreted by the hypothalamus and its known functions include regulation (inhibition) of growth hormone release, inhibition of insulin and glucagon secretion in the pancreas and regulation of amyloid-β (the amyloidogenic peptide associated with Alzheimer’s) in the brain. The secretary granules that act as storage depots for these functional amyloids are rich in glucosaminoglycans (GAGs), which are polysaccharides such as heparin sulfate. They have therefore been implicated in controlling (accelerating) the fibrillation process of hormonal peptides and proteins in vivo. Addition of heparin and related GAGs has been shown to accelerate the fibrillation process of a number of hormonal peptides and proteins in vitro. However, the inability to easily control molecular characteristics (e.g. molecular weight, amount and distribution of charged groups) of polysaccharides results in considerable batch to batch variance which can have a significant effect on the kinetics and structural outcome of the fibrillation process.

Preliminary TEM images of the somatostatin functional amyloids formed in the presence of sulfonated star polymers (provided by Caroline Bray previously in Prof Seb Perrier's group, see ref)

This project is focused on two strategies designed to intervene and influence the in vitro fibrillation of somatostatin and synthetic analogues; octreotide and lanreotide. The first strategy involves the synthesis of sulfonated polymers with controlled composition, arcitecture and topology using reversible deactivation radical polymerisation techniques. Fibrillation kinetics and dynamics are therefore being explored as a function of molecular composition and architecture. The somatostatin peptides are cyclic peptides containing a disulfide bond, which in somostatin itself, has a significant influence on the fibrillation process. In the second strategy we are exploring the fibrillation kinetics, dynamics and subsequent properties of the fibrils as a function of the targeted modification of the peptides at the disulfide bond.

A long-term goal is to develop drug storage and delivery systems that mimic the somatostatin functional amyloid present in the secretary granules.

References

C. Bray et al. Biomacromolecules 2019, 20, 285−293

Polymeric arsenicals as a functional platform for nanomaterials and nanomedicine

The discrete and distinctive reactivity of arsenic, which can be readily incorporated into organic molecules, make it an ideal reactive handle for incorporation into polymers and nanomaterials. Inspired by the clinical success of arsenic trioxide (treatment of acute promyelocytic leukaemia) and organic arsenicals (for the treatment of much broader spectrum malignancies), we are incorporating organic arsenicals into polymers prepared by RDRP (RAFT, ATRP/SET) and have exploited the reactivity to develop novel methods for protein/peptide-polymer conjugation (J. Am. Chem. Soc., 2015, 137, 4215-4222), post-polymerisation modification (Chem. Commun. 2017, 53 (60), 8447-8450), responsive polymeric nanoparticles (Polym. Chem. 2018, 9, 1551-1556, Macromolecules 2019, 52, 992-1003) and macroscopic hydrogel materials (J. Mater. Chem. B, 2019,7, 4263-4271).

Overview of our current work on polymeric arsenicals as a platform for functional (nano)materials

The arsenic functional group enables the formation of gels and nanoparticles under reductive coupling conditions via the formation of labile cyclic oligoarsine (As-As) bonds. We are investigating the properties of these (nano)materials as a function of polymeric arsenical composition, architecture and topology which can be controlled by intercepting these cyclic oligoarsines under a variety of reaction conditions. One interesting strategy is sequential reductive and radical cross-linking route, via a proposed ring-collapse radical alternating copolymerization (RCRAC, J. Am. Chem. Soc. 2002, 124 (23), 6600-6603) of the cyclic oligoarines in the presence of functional acetylenes, resulting in the formation of vinylene-arsine cross-linked nanoparticles (Polym. Chem. 2020,11, 2519-2531). This strategy is orthogonal with functional groups including alcohols, amines and carboxylic acids, offering access to functional handles for single/multi-modal loading of therapeutics/imaging motifs and the vinylene-arsine group itself has interesting optical properties and possesses a conjugated/semi-conducting polymer backbone.

Though the use of arsenicals in polymer and biomaterials science is not widespread, there are examples of polymeric arsenicals being employed for a variety of applications ranging from flocculants to macromolecular chemotherapeutics has significantly expanded the current landscape and highlighted the potential of arsenic-functionalized nanomaterials (see the following review for details). We firmly believe that the diverse chemistry of organic/polymeric arsenicals and the potential for synergy, with respect to biological activity, can be exploited for the development of a functional platform of reactive/responsive polymer/materials design