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Many potent therapeutics fail in the latter stages of clinical development due to their accumulation in undesirable organs. This is a major bottleneck in the drug discovery journey for a variety of therapeutics, many of which exhibit excellent clinical potential if they reach their biomolecular target. However, off-target accumulation produces significant issues such as dose-related toxicities and/or dose-limited efficacies. Drug delivery platforms have the potential to transcend these limitations and provide a parallel approach to ensure therapeutic payloads reach their desired biological target in the desired cell, tissue, or organ. A prominent approach to delivering therapeutic payloads to a desired cell/tissue type is the use of targeting groups which recognise a unique feature on the cell surface and enhance the uptake of the drug payload. Typically, uptake of a therapeutic candidate into a target cell type results in the encapsulation, and in many cases sequestration of the payload into vesicles called endosomes. If the drug is not released, this reduces or curtails its potency, and the accumulation is a potential source of dose-dependent toxicity. This is particularly problematic for the delivery of therapeutic payloads into the brain in which the blood-brain-barrier provides an additional and formidable blockade for targeting neurodegenerative disorders. Cell penetrating peptides (CPPs) are sequences of natural amino acids typically 12-30 monomeric units in length, which enhance the uptake of therapeutic payloads. Transcending the cell and tissue barriers of therapeutics with sub-optimal drug-like properties can be achieved by either directly attaching a CPP onto the payload or incorporating a CPP into a liposomal envelope which is used as a mini vesicle. Although CPPs have proven cell uptake properties, the current state-of-the-art in CPP development for drug delivery applications has suffered from toxicity which has limited their clinical applications. Our patented technology is based on the identification of synthetic analogues of amino acids, which when incorporated into a CPP, are non-toxic and more effective at enhancing cell uptake and escaping the endosome relative to existing CPPs which are exclusively prepared using natural amino acids. This work leverages earlier BBSRC-funded breakthroughs by expanding the successful first-generation designs. This purpose of this grant is to advance a new delivery platform for cell-selective targeting of therapeutic payloads. Our approach, which is unique to other previous drug delivery strategies, is to develop analogues of the major classes of natural amino acids that will modulate cellular uptake and distribution properties, targeting specific cell types to direct desired target engagement in tissues/organs associated with the clinical condition. These CPPs will be utilized in conjunction with a liposomal delivery vector developed to maximise the versatility of end-user application. The ambition is to enhance cell targeting and uptake features of these amino acids when incorporated into a CPP whilst reducing the toxicity issues related to existing CPP scaffolds.

To generate a new range of radial piston motors able to collect and analyse real time performance data using Internet of Things and predictive data analytics. The resulting advanced decision support system will enable the diagnostic monitoring of equipment in harsh environments.