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Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems

There is a strong need for innovative and efficient drug delivery systems for ocular therapy development. However, testing intravitreal drug delivery systems without using live animals is challenging. Ex vivo animal models offer an interesting alternative. We analyzed the potential of using fresh po...

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Autores principales: Christensen, Gustav, Barut, Leon, Urimi, Dileep, Schipper, Nicolaas, Paquet-Durand, François
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309192/
https://www.ncbi.nlm.nih.gov/pubmed/34371707
http://dx.doi.org/10.3390/pharmaceutics13071013
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author Christensen, Gustav
Barut, Leon
Urimi, Dileep
Schipper, Nicolaas
Paquet-Durand, François
author_facet Christensen, Gustav
Barut, Leon
Urimi, Dileep
Schipper, Nicolaas
Paquet-Durand, François
author_sort Christensen, Gustav
collection PubMed
description There is a strong need for innovative and efficient drug delivery systems for ocular therapy development. However, testing intravitreal drug delivery systems without using live animals is challenging. Ex vivo animal models offer an interesting alternative. We analyzed the potential of using fresh porcine eyes obtained from the local slaughterhouse as a model for testing the intravitreal biodistribution and retention of liposomes with or without polyethylene glycol (PEG) conjugation and with different surface charges. The histology of the eyes was analyzed to localize the liposomes, and it was found that liposomes with PEG absorbed rapidly on the retina (within 1 h), with positively charged and PEG-coated liposomes being retained for at least 24 h. In parallel, fluorophotometry was employed on intact eyes, to determine the pharmacokinetics of the fluorophore calcein, as a substitute for a small hydrophilic therapeutic compound. We found a 4.5-fold increase in the vitreous half-life of calcein loaded in liposomes, compared with the free solution. Retinal toxicity was addressed using murine-derived retinal explant cultures. Liposomes were non-toxic up to 500 µg/mL. Toxicity was observed at 5 mg/mL for anionic and cationic liposomes, with 2-fold and 2.5-fold increased photoreceptor cell death, respectively. Overall, we could show that important ocular drug delivery considerations such as pharmacokinetics and biodistribution can be estimated in ex vivo porcine eyes, and may guide subsequent in vivo experiments.
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spelling pubmed-83091922021-07-25 Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems Christensen, Gustav Barut, Leon Urimi, Dileep Schipper, Nicolaas Paquet-Durand, François Pharmaceutics Article There is a strong need for innovative and efficient drug delivery systems for ocular therapy development. However, testing intravitreal drug delivery systems without using live animals is challenging. Ex vivo animal models offer an interesting alternative. We analyzed the potential of using fresh porcine eyes obtained from the local slaughterhouse as a model for testing the intravitreal biodistribution and retention of liposomes with or without polyethylene glycol (PEG) conjugation and with different surface charges. The histology of the eyes was analyzed to localize the liposomes, and it was found that liposomes with PEG absorbed rapidly on the retina (within 1 h), with positively charged and PEG-coated liposomes being retained for at least 24 h. In parallel, fluorophotometry was employed on intact eyes, to determine the pharmacokinetics of the fluorophore calcein, as a substitute for a small hydrophilic therapeutic compound. We found a 4.5-fold increase in the vitreous half-life of calcein loaded in liposomes, compared with the free solution. Retinal toxicity was addressed using murine-derived retinal explant cultures. Liposomes were non-toxic up to 500 µg/mL. Toxicity was observed at 5 mg/mL for anionic and cationic liposomes, with 2-fold and 2.5-fold increased photoreceptor cell death, respectively. Overall, we could show that important ocular drug delivery considerations such as pharmacokinetics and biodistribution can be estimated in ex vivo porcine eyes, and may guide subsequent in vivo experiments. MDPI 2021-07-02 /pmc/articles/PMC8309192/ /pubmed/34371707 http://dx.doi.org/10.3390/pharmaceutics13071013 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Christensen, Gustav
Barut, Leon
Urimi, Dileep
Schipper, Nicolaas
Paquet-Durand, François
Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems
title Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems
title_full Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems
title_fullStr Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems
title_full_unstemmed Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems
title_short Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems
title_sort investigating ex vivo animal models to test the performance of intravitreal liposomal drug delivery systems
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309192/
https://www.ncbi.nlm.nih.gov/pubmed/34371707
http://dx.doi.org/10.3390/pharmaceutics13071013
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