Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines

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. Ph...

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Autores principales:	Elnaz Yaghini, Ruggero Dondi, Kunal M. Tewari, Marilena Loizidou, Ian M. Eggleston, Alexander J. MacRobert
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4f1101065e3c429892ad59ab68c9d579
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spelling	oai:doaj.org-article:4f1101065e3c429892ad59ab68c9d5792021-12-02T12:32:56ZEndolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines10.1038/s41598-017-06109-y2045-2322https://doaj.org/article/4f1101065e3c429892ad59ab68c9d5792017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06109-yhttps://doaj.org/toc/2045-2322Abstract 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.Elnaz YaghiniRuggero DondiKunal M. TewariMarilena LoizidouIan M. EgglestonAlexander J. MacRobertNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Elnaz Yaghini Ruggero Dondi Kunal M. Tewari Marilena Loizidou Ian M. Eggleston Alexander J. MacRobert Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines
description	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.
format	article
author	Elnaz Yaghini Ruggero Dondi Kunal M. Tewari Marilena Loizidou Ian M. Eggleston Alexander J. MacRobert
author_facet	Elnaz Yaghini Ruggero Dondi Kunal M. Tewari Marilena Loizidou Ian M. Eggleston Alexander J. MacRobert
author_sort	Elnaz Yaghini
title	Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines
title_short	Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines
title_full	Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines
title_fullStr	Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines
title_full_unstemmed	Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines
title_sort	endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/4f1101065e3c429892ad59ab68c9d579
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Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines

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