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

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The effectiveness of many important drugs is much reduced because they cannot be adequately delivered to the fluid inside cells where their biological targets are located. This means that higher doses are needed, leading to an increase in potential side effects and reduced patient quality of life. Such drugs are often poorly absorbed in the body because they are taken up into cells by endocytosis, where the cell wall or membrane envelops drug molecules leaving them trapped inside small compartments (endosomes, lysosomes) within the cell from which they must escape in order to reach the right part of the cell (e.g. the nucleus). If the drug cannot escape efficiently, it may instead be broken down by enzymes, or expelled from the cell. The technique of photochemical internalisation (PCI) is a novel way to get around this problem. Here, the drug of interest is administered along with a photosensitiser, a molecule that can facilitate the escape process when activated by light. Ideally, the photosensitiser is activated with a low dose of red light which causes minimal damage to healthy tissue and also allows light-activation to take place deep within the target tissue, as tissue absorption at red light wavelengths is weak. In contrast, UV light-activated drug release cannot be used effectively in tissue not only due its mutagenic effects, but also because tissue absorption of UV light is too strong and limits the effect to a depth of few cell layers from the surface. Drugs that can be delivered with PCI range from toxins for cancer treatment to molecular agents for gene therapy, and light can either be shone directly onto the target tissue or guided from a laser down optical fibres placed within the tissue to allow illumination of larger volumes. When cells are exposed to PCI light treatment, to activate the photosensitiser, these molecules absorb energy and generate short-lived reactive chemical compounds that break down the walls of the drug-containing compartments, releasing the drug to allow it to reach its target. However, in order for PCI to work effectively, the drug and photosensitiser employed must be incorporated into the same compartment inside the cell and must of course both efficiently enter the cell in the first place. The initial aim of our project is therefore to develop new photosensitiser molecules for PCI that are water-soluble, cross cell membranes effectively, and are also taken up into cells by endocytosis so that they may be localised in the right cell compartments with drugs that are administered at the same time. We have already shown that prototype molecules of this sort give a much more efficient PCI effect than that obtained with a simple photosensitiser. To further improve the PCI approach, we then want to develop systems where both a drug and a photosensitiser are associated with the same carrier molecule so that the uptake of both components is enhanced and their localisation in exactly the same cell compartment is guaranteed. To make this approach as general and as flexible as possible, we aim to develop systems where the carrier and photosensitiser can be easily interchanged, and a wide range of drug molecules can be incorporated in such a way that they can be released from the carrier inside the cell once the PCI light treatment has been carried out. As a final refinement, we will also look at the possibility of making delivery systems that can be targeted to a specific part of the body and switched on specifically in diseased tissue only, so that the PCI therapy can be performed with pin-point selectivity, exactly where it is required.All the results of this project will be of direct benefit to the healthcare field by providing a new means to more effectively deliver diverse chemotherapeutic agents, improving efficacy, lowering dosage, and minimising side-effects.