Photochemical Internalization of Etoposide Using Dendrimer Nanospheres Loaded with Etoposide and Protoporphyrin IX on a Glioblastoma Cell Line

Glioblastoma multiforme (GBM) is the most common malignant primary neoplasm of the adult central nervous system originating from glial cells. The prognosis of those affected by GBM has remained poor despite advances in surgery, chemotherapy, and radiotherapy. Photochemical internalization (PCI) is a...

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Autores principales:	Martin Hsiu-Chu Lin, Li-Ching Chang, Chiu-Yen Chung, Wei-Chao Huang, Ming-Hsueh Lee, Kuo-Tai Chen, Ping-Shan Lai, Jen-Tsung Yang
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	etoposide protoporphyrin IX phototherapy dendrimer glioblastoma multiforme Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/5155ed48d98047d28fc32d5a80153ff9
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spelling	oai:doaj.org-article:5155ed48d98047d28fc32d5a80153ff92021-11-25T18:41:22ZPhotochemical Internalization of Etoposide Using Dendrimer Nanospheres Loaded with Etoposide and Protoporphyrin IX on a Glioblastoma Cell Line10.3390/pharmaceutics131118771999-4923https://doaj.org/article/5155ed48d98047d28fc32d5a80153ff92021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1877https://doaj.org/toc/1999-4923Glioblastoma multiforme (GBM) is the most common malignant primary neoplasm of the adult central nervous system originating from glial cells. The prognosis of those affected by GBM has remained poor despite advances in surgery, chemotherapy, and radiotherapy. Photochemical internalization (PCI) is a release mechanism of endocytosed therapeutics into the cytoplasm, which relies on the membrane disruptive effect of light-activated photosensitizers. In this study, phototherapy by PCI was performed on a human GBM cell-line using the topoisomerase II inhibitor etoposide (Etop) and the photosensitizer protoporphyrin IX (PpIX) loaded in nanospheres (Ns) made from generation-5 polyamidoamine dendrimers (PAMAM(G5)). The resultant formulation, Etop/PpIX-PAMAM(G5) Ns, measured 217.4 ± 2.9 nm in diameter and 40.5 ± 1.3 mV in charge. Confocal microscopy demonstrated PpIX fluorescence within the endo-lysosomal compartment, and an almost twofold increase in cellular uptake compared to free PpIX by flow cytometry. Phototherapy with 3 min and 5 min light illumination resulted in a greater extent of synergism than with co-administered Etop and PpIX; notably, antagonism was observed without light illumination. Mechanistically, significant increases in oxidative stress and apoptosis were observed with Etop/PpIX-PAMAM(G5) Ns upon 5 min of light illumination in comparison to treatment with either of the agents alone. In conclusion, simultaneous delivery and endo-lysosomal co-localization of Etop and PpIX by PAMAM(G5) Ns leads to a synergistic effect by phototherapy; in addition, the finding of antagonism without light illumination can be advantageous in lowering the dark toxicity and improving photo-selectivity.Martin Hsiu-Chu LinLi-Ching ChangChiu-Yen ChungWei-Chao HuangMing-Hsueh LeeKuo-Tai ChenPing-Shan LaiJen-Tsung YangMDPI AGarticleetoposideprotoporphyrin IXphototherapydendrimerglioblastoma multiformePharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1877, p 1877 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	etoposide protoporphyrin IX phototherapy dendrimer glioblastoma multiforme Pharmacy and materia medica RS1-441
spellingShingle	etoposide protoporphyrin IX phototherapy dendrimer glioblastoma multiforme Pharmacy and materia medica RS1-441 Martin Hsiu-Chu Lin Li-Ching Chang Chiu-Yen Chung Wei-Chao Huang Ming-Hsueh Lee Kuo-Tai Chen Ping-Shan Lai Jen-Tsung Yang Photochemical Internalization of Etoposide Using Dendrimer Nanospheres Loaded with Etoposide and Protoporphyrin IX on a Glioblastoma Cell Line
description	Glioblastoma multiforme (GBM) is the most common malignant primary neoplasm of the adult central nervous system originating from glial cells. The prognosis of those affected by GBM has remained poor despite advances in surgery, chemotherapy, and radiotherapy. Photochemical internalization (PCI) is a release mechanism of endocytosed therapeutics into the cytoplasm, which relies on the membrane disruptive effect of light-activated photosensitizers. In this study, phototherapy by PCI was performed on a human GBM cell-line using the topoisomerase II inhibitor etoposide (Etop) and the photosensitizer protoporphyrin IX (PpIX) loaded in nanospheres (Ns) made from generation-5 polyamidoamine dendrimers (PAMAM(G5)). The resultant formulation, Etop/PpIX-PAMAM(G5) Ns, measured 217.4 ± 2.9 nm in diameter and 40.5 ± 1.3 mV in charge. Confocal microscopy demonstrated PpIX fluorescence within the endo-lysosomal compartment, and an almost twofold increase in cellular uptake compared to free PpIX by flow cytometry. Phototherapy with 3 min and 5 min light illumination resulted in a greater extent of synergism than with co-administered Etop and PpIX; notably, antagonism was observed without light illumination. Mechanistically, significant increases in oxidative stress and apoptosis were observed with Etop/PpIX-PAMAM(G5) Ns upon 5 min of light illumination in comparison to treatment with either of the agents alone. In conclusion, simultaneous delivery and endo-lysosomal co-localization of Etop and PpIX by PAMAM(G5) Ns leads to a synergistic effect by phototherapy; in addition, the finding of antagonism without light illumination can be advantageous in lowering the dark toxicity and improving photo-selectivity.
format	article
author	Martin Hsiu-Chu Lin Li-Ching Chang Chiu-Yen Chung Wei-Chao Huang Ming-Hsueh Lee Kuo-Tai Chen Ping-Shan Lai Jen-Tsung Yang
author_facet	Martin Hsiu-Chu Lin Li-Ching Chang Chiu-Yen Chung Wei-Chao Huang Ming-Hsueh Lee Kuo-Tai Chen Ping-Shan Lai Jen-Tsung Yang
author_sort	Martin Hsiu-Chu Lin
title	Photochemical Internalization of Etoposide Using Dendrimer Nanospheres Loaded with Etoposide and Protoporphyrin IX on a Glioblastoma Cell Line
title_short	Photochemical Internalization of Etoposide Using Dendrimer Nanospheres Loaded with Etoposide and Protoporphyrin IX on a Glioblastoma Cell Line
title_full	Photochemical Internalization of Etoposide Using Dendrimer Nanospheres Loaded with Etoposide and Protoporphyrin IX on a Glioblastoma Cell Line
title_fullStr	Photochemical Internalization of Etoposide Using Dendrimer Nanospheres Loaded with Etoposide and Protoporphyrin IX on a Glioblastoma Cell Line
title_full_unstemmed	Photochemical Internalization of Etoposide Using Dendrimer Nanospheres Loaded with Etoposide and Protoporphyrin IX on a Glioblastoma Cell Line
title_sort	photochemical internalization of etoposide using dendrimer nanospheres loaded with etoposide and protoporphyrin ix on a glioblastoma cell line
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/5155ed48d98047d28fc32d5a80153ff9
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Photochemical Internalization of Etoposide Using Dendrimer Nanospheres Loaded with Etoposide and Protoporphyrin IX on a Glioblastoma Cell Line

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