ENHANCING NEXT GENERATION THERAPEUTICS - Development of a rapid in vivo screen for a library novel polymeric formulation and their excipients with nem

CHALLENGE: The major obstacles when translating newly identified active pharmaceutical ingredients (APIs) into next generation therapeutics are their solubility in aqueous environments and in vivo bioavailability.
This is primarily due to the use of high throughput, combinatorial screening approaches during drug discovery, where over 40% of APIs result in poorly water soluble high permeable candidates.
Furthermore, humans are large complex animals, which are not completely understood and can be both scientifically and socio-economically challenging to characterise. Therefore, there is a strong international drive to replace, reduce and refine the use of animals in research so that this precious resource is reserved.
PROJECT: This exciting project will directly address this challenge by investigating the development of a platform screening technology that enables APIs with polymeric biodegradable scaffolds and assess their bioavailability in line using the most completely understood animal on the planet, Caenorhabditis elegans.
METHOD. The first phase (Years 1-2, quarters 1-8) of this project will be built upon novel chemistry demonstrated by the supervisory team that have recently shown that novel polymers can be synthesised by exploiting the chemo- and regioselectivity of enzymes to create linear glycerol-based polyesters. These polyesters will be readily conjugated or used to encapsulate APIs. This will produce a library of novel biologically active polymeric- drug delivery systems which will form the basis of next generation therapeutics.

The second phase (Years 2-4, quarters 9-14) of this project will be to assess in vivo biocompatibility, bioavailability and bioactivity in C. elegans populations using the development of high-content imaging. Biocompatibility will be assessed by monitoring motility and nematode lifecycles (progeny production) through the application of time dependent brightfield microscopy analysis methods [Journal of Material Chemistry B. in press]. Bioavailability will be mapped using model fluorescent drugs (e.g. doxorubicin) across the anatomy of larval and adult stages nematodes, with particular emphasis on tracking distribution of therapeutic delivery. Bioactivity will be determined by studying global shifts omic nematode profiles in the nematodes though the application of liquid chromatography mass spectrometry methods (LC-MS).
TRAINING: This project will provide the PhD student with expertise in polymer synthesis, pharmaceutical formulation, whole organism culture and big data analysis. The project will also permit multiple national and international outreach and communication opportunities (Journal of Controlled Release Conference, Las Vegas, C. elegans International Conference, Glasgow) to showcase research and build the foundations for a successful research or industrial career trajectory.
IMPACT: This project has the potential to streamline and optimise formulation pathways for new APIs that will accelerate the development of next generation therapeutics, that could benefit hundreds of millions of people globally. This project has the potential to produce high impact peer reviewed articles for novel polymer synthesis (ACS Macro Letters 7.02, or Biomacromolecules IF 6.99) as well as transformative therapeutic delivery (Journal of Controlled Release IF or 11.47 and Biomaterials IF 15.3). Furthermore, the new materials developed as part of this PhD could contribute the develop of University intellectual property which could form the basis of a patent or licencing opportunity.