(Digital Presentation) Peptide Targeting of Photosensitisers for Photodynamic Therapy and Drug Delivery Applications

Abstract

The conjugation of photosensitisers to proteins or targeting peptides is a well-established approach for enhancing solubility and tissue selectivity for both photodynamic therapy (PDT) of cancer and light-activated drug delivery. A key innovation in the development of such targeted photosensitisers is the application of biorthogonal ligation techniques (e.g. azide-alkyne “click” chemistries) which allow the efficient attachment of various photosensitiser molecules to multifunctional peptides. Some of our work in this area will be described towards the generation of specific targeted conjugates between porphyrin and chlorin photosensitiser derivatives and tumour-homing or cell-penetrating peptide carriers [1, 2]. Conjugation of hydrophobic photosensitiser molecules to cationic cell-penetrating peptides (e.g. HIV Tat 48-57) can provide derivatives with improved water solubility, amphiphilicity, enhanced uptake and predictable sub-cellular localisation. This is very attractive for the light-triggered delivery of macromolecular therapeutics by photochemical internalisation (PCI), which will be illustrated in the application of these compounds for the delivery of the protein toxin, saporin [3].Peptide targeting strategies are also of interest for PDT with 5-aminolevulinic acid (ALA) [4]. In ALA-PDT, administered ALA is converted within cells via the heme biosynthetic pathway to a classical photosensitiser- protoporphyrin IX. In this context, some recent chemical and biological data will be presented on the use of peptide targeting to enhance the delivery of multiple ALA units to a specific cell type [5].[1] Dondi, R., Yaghini, E., Tewari, K. M., Wang, L., Giuntini, F., Loizidou, M., MacRobert, A. J. and Eggleston, I. M., Org. Biomol. Chem. 2016, 14, 11488-11501; [2] Yaghini, E., Dondi, R., Tewari, K. M., Loizidou, M., Eggleston, I. M. and MacRobert, A. J., Sci. Rep. 2017, 7, 6059; [3] Yaghini, E, Dondi, R., Edler, K. J., Loizidou, M., MacRobert, A. J. and Eggleston, I. M., Nanoscale 2018, 10, 20366-20376; [4] Tewari, K. M. and Eggleston, I. M., Photochem. Photobiol. Sci. 2018, 17, 1553-1572; [5] Tewari, K. M., Dondi, R., Yaghini, E., Pourzand, C., MacRobert, A. J. and Eggleston, I. M., Bioorg. Chem. 2021, 109, 104667.