Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines.
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| Abstract |
A major problem with many promising nano-sized biotherapeutics including macromolecules is that owing to their size they are subject to cellular uptake via endocytosis, and become entrapped and then degraded within endolysosomes, which can significantly impair their therapeutic efficacy. Photochemical internalisation (PCI) is a technique for inducing cytosolic release of the entrapped agents that harnesses sub-lethal photodynamic therapy (PDT) using a photosensitiser that localises in endolysosomal membranes. Using light to trigger reactive oxygen species-mediated rupture of the photosensitised endolysosomal membranes, the spatio-temporal selectivity of PCI then enables cytosolic release of the agents at the selected time after administration so that they can reach their intracellular targets. However, conventional photosensitisers used clinically for PDT are ineffective for photochemical internalisation owing to their sub-optimal intracellular localisation. In this work we demonstrate that such a photosensitiser, chlorin e6, can be repurposed for PCI by conjugating the chlorin to a cell penetrating peptide, using bioorthogonal ligation chemistry. The peptide conjugation enables targeting of endosomal membranes so that light-triggered cytosolic release of an entrapped nano-sized cytotoxin can be achieved with consequent improvement in cytotoxicity. The photoproperties of the chlorin moiety are also conserved, with comparable singlet oxygen quantum yields found to the free chlorin.
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| Authors | Elnaz Yaghini, Ruggero Dondi, Kunal M Tewari, Marilena Loizidou, Ian M Eggleston, Alexander J MacRobert |
| Journal | Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 6059 (07 20 2017) ISSN: 2045-2322 [Electronic] England |
| PMID | 28729656 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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