Highly-Functional Poly(amino acids) for Controlled Therapeutic Delivery

Polymeric nanoparticles may be employed as drug delivery vehicles for the controlled release of therapeutic molecules in vivo. Such materials enable efficient drug distribution to the target site, reduce off-target tissue accumulation, and prevent premature drug metabolism. In addition, they enable the distribution of effective, but poorly soluble drug molecules within the bloodstream. Consequently, such materials are biomedically imperative for the efficient delivery of new drug molecules, and the exploitation of potentially active drug molecules that have a poor pharmacokinetic profile.
Polymeric nanoparticles that, crucially, are biodegradable and present cell-binding peripheries are ideal carriers for the targeted delivery of therapeutic compounds. In particular, poly(amino acids) are extremely well-suited for deployment as drug delivery vehicles due to their inherent biodegradability, non-cytotoxicity and capability to present secondary structures upon self-assembly in aqueous solution. A range of stable nanomaterials may be created that are capable of withholding and/or conjugating to therapeutic molecules, prior to controlled drug release at a target site. Although such polymers are excellent candidates as drug delivery vehicles, their application to this area presently remains limited.
This project will create poly(amino acid) architectures as potential drug delivery vehicles by N-carboxyanhydride (NCA) ring-opening polymerisation (ROP). This form of living polymerisation enables the production of polyamides that may have wide-ranging functionality (alcohol, thiol, amine, carboxylic acid) dependent on the amino acid monomer selected. We will expand the range of amino acid monomers beyond the 20 found naturally in the body to create monomers with distinctive functionality, which is transferred to the polymers produced. A range of truly unique, biodegradable, polymers that are readily modifiable with cell targeting groups, fluorescent labels and/or therapeutic compounds will be created. For example, furfurylamine/furfuryl alcohol conjugation to glutamic acid, or furfural conjugation to lysine/serine will be explored and a cyclic monomer created that undergoes NCA ROP to form a furfuryl-presenting poly(amino acid). Such a polymer will readily undergo Diels-Alder 'click' reactions with maleimide moieties, enabling facile coupling to commercially available fluorescent, therapeutic, and/or cell-targeting groups, yielding a bespoke polymer suited to controlled drug delivery, amongst other biomedical/soft matter applications.
Further project aims include the production of branched architectures of poly(amino acids) as drug delivery vehicles by a one-pot reaction by using photolabile protecting groups that create initiation sites for further polymerisation, when irradiated. These types of architectures coupled with precise drug conjugation sites are highly attractive in the drug delivery area owing to their globular structures with less propensity to self-aggregate when conjugated to a hydrophobic drug. A one-pot system is also attractive from an industrial perspective to reduce synthetic steps and complexity and would be extremely valuable if produced using green solvents for monomer/polymer synthesis. Polymers will be labelled with groups that enhance target cell uptake (i.e. maleimide activated glucose), loaded with/conjugated to a therapeutic (i.e. the chemotherapeutic doxorubicin) and assessed versus target cell lines (i.e. triple negative cancer cells). Resultantly, a varied opportunity is presented that ranges from polymer design and synthesis through to analysis of the in vitro therapeutic performance of the unique materials created.

1. PEOPLE. The SOFI2 CDT will have varied economic and societal impacts, the greatest of which will be the students themselves. They will graduate with a broad and deep scientific education as well as an entrepreneurial mind-set combined with business awareness and communication skills. The training programme reflects the knowledge and skills identified by industry partners, the EPSRC, recent graduates and national strategies. Partners will facilitate impact through their engagement in the extensive training programme and through the co-supervision of PhD projects. Responsible Innovation is embedded throughout the training programme to instil an attitude towards research and innovation in which societal concerns and environmental impact are always to the fore. The team-working and leadership skills developed in SOFI2 (including an appreciation of the benefits that diversity brings to an organisation and how to foster an atmosphere of equality and inclusion) will enable our graduates to take on leadership roles in industry where they can, in turn, influence the thinking of their teams.

2. PROJECTS. The PhD research projects themselves are impact pathways. Approximately half the projects will be co-sponsored by external partners and will be aligned to scientific challenges faced by the partner. Even projects funded entirely by the EPSRC/Universities will have an industrial co-supervisor who can provide advice on development of impact. The impact workshops and Entrepreneur in Residence will additionally help students to develop impact from their research, while at the same time developing the mind-set that sees innovation in invention.

3. PUBLIC. The public benefits from innovation that comes from the research in the CDT. It also benefits from the training of a generation of researchers trained in RI who seek out the input of stakeholders in the development of products and processes. The public benefits from the outreach activities that enable them to understand better the science behind contemporary technological developments - and hence to make more informed decisions about how they lead their lives. The younger generations benefit from the excitement of science that might attract them to higher education and careers in STEM subjects.

4. PARTNERSHIPS. SOFI2 involves collaborative research with >25 external partners from large multinationals to small start-ups. In addition to the results of sponsored projects and the possibility of recruiting SOFI2 students, companies benefit from access to training resources, sharing of best practice in RI and EDI, access to the knowledge of the SOFI2 academics and sharing of expertise with other partners in the SOFI2 network. This networking is of particular benefit to SMEs and we have an SME strategy to facilitate engagement of SMEs with SOFI2. SME representation on the Management and Strategic Advisory Boards will support the SME strategy.

CPI/NFC is a key partner both for delivery of training and to connect SOFI2 research, students and staff to a wide network of companies in the formulated products sector.

The unusual partnership with the Leverhulme Research Centre on Forensic Science may lead to a stronger scientific underpinning of forensic evidence with positive impacts on the legal process and the pursuit of justice.

5. PRODUCTS. Partner companies identify areas of fundamental and applied science of interest to them with the knowledge that advances in these areas will help them to overcome technological challenges that will lead to better products or new markets. It is an expectation that scientific discoveries made within the CDT will drive new products, new markets and potentially new companies. SOFI2 CDT seeks also to develop innovative training materials, for example, in RI and in data analytics and AI (in collaboration with the Alan Turing Institute), from which other CDTs and training organisations can benefit.