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Suitability of 3D human brain spheroid models to distinguish toxic effects of gold and poly-lactic acid nanoparticles to assess biocompatibility for brain drug delivery

BACKGROUND: The blood brain barrier (BBB) is the bottleneck of brain-targeted drug development. Due to their physico-chemical properties, nanoparticles (NP) can cross the BBB and accumulate in different areas of the central nervous system (CNS), thus are potential tools to carry drugs and treat brai...

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Autores principales: Leite, Paulo Emílio Corrêa, Pereira, Mariana Rodrigues, Harris, Georgina, Pamies, David, dos Santos, Lisia Maria Gobbo, Granjeiro, José Mauro, Hogberg, Helena T., Hartung, Thomas, Smirnova, Lena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545685/
https://www.ncbi.nlm.nih.gov/pubmed/31159811
http://dx.doi.org/10.1186/s12989-019-0307-3
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author Leite, Paulo Emílio Corrêa
Pereira, Mariana Rodrigues
Harris, Georgina
Pamies, David
dos Santos, Lisia Maria Gobbo
Granjeiro, José Mauro
Hogberg, Helena T.
Hartung, Thomas
Smirnova, Lena
author_facet Leite, Paulo Emílio Corrêa
Pereira, Mariana Rodrigues
Harris, Georgina
Pamies, David
dos Santos, Lisia Maria Gobbo
Granjeiro, José Mauro
Hogberg, Helena T.
Hartung, Thomas
Smirnova, Lena
author_sort Leite, Paulo Emílio Corrêa
collection PubMed
description BACKGROUND: The blood brain barrier (BBB) is the bottleneck of brain-targeted drug development. Due to their physico-chemical properties, nanoparticles (NP) can cross the BBB and accumulate in different areas of the central nervous system (CNS), thus are potential tools to carry drugs and treat brain disorders. In vitro systems and animal models have demonstrated that some NP types promote neurotoxic effects such as neuroinflammation and neurodegeneration in the CNS. Thus, risk assessment of the NP is required, but current 2D cell cultures fail to mimic complex in vivo cellular interactions, while animal models do not necessarily reflect human effects due to physiological and species differences. RESULTS: We evaluated the suitability of in vitro models that mimic the human CNS physiology, studying the effects of metallic gold NP (AuNP) functionalized with sodium citrate (Au-SC), or polyethylene glycol (Au-PEG), and polymeric polylactic acid NP (PLA-NP). Two different 3D neural models were used (i) human dopaminergic neurons differentiated from the LUHMES cell line (3D LUHMES) and (ii) human iPSC-derived brain spheroids (BrainSpheres). We evaluated NP uptake, mitochondrial membrane potential, viability, morphology, secretion of cytokines, chemokines and growth factors, and expression of genes related to ROS regulation after 24 and 72 h exposures. NP were efficiently taken up by spheroids, especially when PEGylated and in presence of glia. AuNP, especially PEGylated AuNP, effected mitochondria and anti-oxidative defense. PLA-NP were slightly cytotoxic to 3D LUHMES with no effects to BrainSpheres. CONCLUSIONS: 3D brain models, both monocellular and multicellular are useful in studying NP neurotoxicity and can help identify how specific cell types of CNS are affected by NP. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12989-019-0307-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-65456852019-06-06 Suitability of 3D human brain spheroid models to distinguish toxic effects of gold and poly-lactic acid nanoparticles to assess biocompatibility for brain drug delivery Leite, Paulo Emílio Corrêa Pereira, Mariana Rodrigues Harris, Georgina Pamies, David dos Santos, Lisia Maria Gobbo Granjeiro, José Mauro Hogberg, Helena T. Hartung, Thomas Smirnova, Lena Part Fibre Toxicol Research BACKGROUND: The blood brain barrier (BBB) is the bottleneck of brain-targeted drug development. Due to their physico-chemical properties, nanoparticles (NP) can cross the BBB and accumulate in different areas of the central nervous system (CNS), thus are potential tools to carry drugs and treat brain disorders. In vitro systems and animal models have demonstrated that some NP types promote neurotoxic effects such as neuroinflammation and neurodegeneration in the CNS. Thus, risk assessment of the NP is required, but current 2D cell cultures fail to mimic complex in vivo cellular interactions, while animal models do not necessarily reflect human effects due to physiological and species differences. RESULTS: We evaluated the suitability of in vitro models that mimic the human CNS physiology, studying the effects of metallic gold NP (AuNP) functionalized with sodium citrate (Au-SC), or polyethylene glycol (Au-PEG), and polymeric polylactic acid NP (PLA-NP). Two different 3D neural models were used (i) human dopaminergic neurons differentiated from the LUHMES cell line (3D LUHMES) and (ii) human iPSC-derived brain spheroids (BrainSpheres). We evaluated NP uptake, mitochondrial membrane potential, viability, morphology, secretion of cytokines, chemokines and growth factors, and expression of genes related to ROS regulation after 24 and 72 h exposures. NP were efficiently taken up by spheroids, especially when PEGylated and in presence of glia. AuNP, especially PEGylated AuNP, effected mitochondria and anti-oxidative defense. PLA-NP were slightly cytotoxic to 3D LUHMES with no effects to BrainSpheres. CONCLUSIONS: 3D brain models, both monocellular and multicellular are useful in studying NP neurotoxicity and can help identify how specific cell types of CNS are affected by NP. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12989-019-0307-3) contains supplementary material, which is available to authorized users. BioMed Central 2019-06-03 /pmc/articles/PMC6545685/ /pubmed/31159811 http://dx.doi.org/10.1186/s12989-019-0307-3 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Leite, Paulo Emílio Corrêa
Pereira, Mariana Rodrigues
Harris, Georgina
Pamies, David
dos Santos, Lisia Maria Gobbo
Granjeiro, José Mauro
Hogberg, Helena T.
Hartung, Thomas
Smirnova, Lena
Suitability of 3D human brain spheroid models to distinguish toxic effects of gold and poly-lactic acid nanoparticles to assess biocompatibility for brain drug delivery
title Suitability of 3D human brain spheroid models to distinguish toxic effects of gold and poly-lactic acid nanoparticles to assess biocompatibility for brain drug delivery
title_full Suitability of 3D human brain spheroid models to distinguish toxic effects of gold and poly-lactic acid nanoparticles to assess biocompatibility for brain drug delivery
title_fullStr Suitability of 3D human brain spheroid models to distinguish toxic effects of gold and poly-lactic acid nanoparticles to assess biocompatibility for brain drug delivery
title_full_unstemmed Suitability of 3D human brain spheroid models to distinguish toxic effects of gold and poly-lactic acid nanoparticles to assess biocompatibility for brain drug delivery
title_short Suitability of 3D human brain spheroid models to distinguish toxic effects of gold and poly-lactic acid nanoparticles to assess biocompatibility for brain drug delivery
title_sort suitability of 3d human brain spheroid models to distinguish toxic effects of gold and poly-lactic acid nanoparticles to assess biocompatibility for brain drug delivery
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545685/
https://www.ncbi.nlm.nih.gov/pubmed/31159811
http://dx.doi.org/10.1186/s12989-019-0307-3
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