Peptide-based solutions for light-triggered delivery of macromolecular therapeutics and nanoparticles

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The use of several important biopharmaceuticals is severely hampered by their limited ability to reach intracellular targets. This is either due to poor diffusion across the cell membrane or endosomal/lysosomal sequestration upon uptake . Photochemical internalisation (PCI) is a promising solution which exploits the photodynamic action of sub-toxic doses of photosensitisers to promote rupture of lysosomal vesicles, so that entrapped drugs can reach their targets. PCI is designed to use red light where tissue absorption is relatively weak, unlike blue or UV light, so light-triggered, site-specific drug release can be effected at therapeutically useful depths in tissue.
We aim to develop innovative solutions to 3 key challenges in the PCI approach, using peptide-based delivery systems.
1) Photosensitisers for PCI must be lysosomotropic, to localise in the same vesicles as administered drugs. This makes many photosensitisers clinically used for photodynamic therapy unsuitable for PCI. We aim to overcome this by conjugating photosensitisers to cell-penetrating peptides (CPPs) to both improve their uptake and control sub-cellular localisation.
2) PCI requires the photosensitiser and drug to localise in the SAME intracellular vesicle. We can achieve this by covalently attaching a drug cargo to a peptide carrier, from which it may dissociate and reach its target post-PCI. Alternatively, a peptide carrier, with the photosensitiser attached, may be used to generate a drug-encapsulating nanoparticle, such as a liposome.
3) For maximum efficacy, the combination of photosensitiser and drug should be delivered only to specific tissues. A CPP construct that is activated for uptake by disease-dependent levels of a protease activity is an ideal way to achieve this.
We will characterise our constructs in detail with respect to their photophysical properties and efficiency at delivering diverse drug molecules in a variety of in vitro cell models and validate them in vivo.

Our research has the potential to deliver impact for a wide range of beneficiaries, including clinicians and their patients, biomedical scientists and the pharmaceutical industry, as well as the direct academic participants at Bath and UCL. For the general public, novel methodologies that can facilitate the delivery of poorly absorbed chemotherapeutic agents will lead to the development of safer and more effective treatments, allowing the use of lower doses and reduction in chemotherapy side effects/morbidity. This outcome will have an impact upon quality of life in the UK and increase the effectiveness of public healthcare. In the pharmaceutical sector, biotherapeutics now comprise a significant proportion of all drugs on the market. Achieving the efficient delivery of such large often hydrophilic molecules to targeted tissues is a major challenge that can limit the therapeutic potential of otherwise promising clinical candidates, and may result in their abandonment, despite huge investments in their discovery and development. The development of tools that expand the scope of the PCI technique are likely to be of great benefit to the pharmaceutical industry in the next 5-10 years (half the new drugs in late-stage clinical trials will soon be antibodies, peptides, nucleic acids, and other macromolecules). For companies in the UK, this could impact positively on economic performance and competitiveness in the global market place, and thus the wealth of the UK.

As well as being of direct benefit to academic researchers in the field of drug delivery, our research will also be of benefit to the academic community at large, who will gain from the knowledge and reagents obtained in these studies that can be applied to other research endeavours (e.g. in gene therapy). The research will also have a key impact for the academic institutions involved, in that our work should produce intellectual property that would be considered very valuable by pharmaceutical companies, thus leading to the possibility to benefit from revenue streams obtained from licensing opportunities. Finally, the researchers who will perform the proposed studies will benefit from the opportunities to participate in a multidisciplinary research project, with valuable training in a range of chemical and biological techniques. This will greatly enhance their value for ultimate employment in either industrial or academic settings. As such, the project will constitute a long-term training investment in the researchers and the creative output of the UK.

We are already in discussion with potential beneficiaries and end users of our proposed research in both the clinical and commercial arena. For example, the Norwegian pharmaceutical company PCI Biotech AS (specialists in the development of PCI technology), and their research director, Dr Anders Hogset; and Mr Colin Hopper, Academic Head of the Unit of Oral and Maxillofacial Surgery, at UCL Hospital. We have similarly taken taken steps to engage with other leading academic figures in light-based drug delivery research (Prof. Kristian Berg, Institute for Cancer Research, University of Oslo, and Prof. Alex Lou, National Taiwan University). Furthermore, the National Medical Laser Centre, where the UCL group are based, is a translational research institute with extensive experience of converting fundamental bioscience into clinical applications and also exploiting its commercial potential. We are therefore very well placed to both identify results of potential interest to beneficiaries in the biomedical and pharmaceutical arenas and also maximise their economic and societal impact.