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

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Abstract

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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Oxidative Stress, Mitochondrial Dysfunction, and Aging

Hang Cui, Yahui Kong, Hong-Hong Zhang (2011)

Aging is an intricate phenomenon characterized by progressive decline in physiological functions and increase in mortality that is often accompanied by many pathological diseases. Although aging is almost universally conserved among all organisms, the underlying molecular mechanisms of aging remain largely elusive. Many theories of aging have been proposed, including the free-radical and mitochondrial theories of aging. Both theories speculate that cumulative damage to mitochondria and mitochondrial DNA (mtDNA) caused by reactive oxygen species (ROS) is one of the causes of aging. Oxidative damage affects replication and transcription of mtDNA and results in a decline in mitochondrial function which in turn leads to enhanced ROS production and further damage to mtDNA. In this paper, we will present the current understanding of the interplay between ROS and mitochondria and will discuss their potential impact on aging and age-related diseases.

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Surface charge affects cellular uptake and intracellular trafficking of chitosan-based nanoparticles.

Yan-Wei Wang, Zhi-Ping Lv, Wei Wei … (2011)

Chitosan-based nanoparticles (NPs) are widely used in drug delivery, device-based therapy, tissue engineering, and medical imaging. In this aspect, a clear understanding of how physicochemical properties of these NPs affect the cytological response is in high demand. The objective of this study is to evaluate the effect of surface charge on cellular uptake profiles (rate and amount) and intracellular trafficking. We fabricate three kinds of NPs (∼ 215 nm) with different surface charge via SPG membrane emulsification technique and deposition method. They possess uniform size as well as identical other physicochemical properties, minimizing any differences between the NPs except for surface charge. Moreover, we extend our research to eight cell lines, which could help to obtain a representative conclusion. Results show that the cellular uptake rate and amount are both positively correlated with the surface charge in all cell line. Subsequent intracellular trafficking indicates that some of positively charged NPs could escape from lysosome after being internalized and exhibit perinuclear localization, whereas the negatively and neutrally charged NPs prefer to colocalize with lysosome. These results are critical in building the knowledge base required to design chitosan-based NPs to be used efficiently and specifically.

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Cytokines and brain excitability.

Michael Galic, Kiarash Riazi, Quentin J Pittman (2012)

Cytokines are molecules secreted by peripheral immune cells, microglia, astrocytes and neurons in the central nervous system. Peripheral or central inflammation is characterized by an upregulation of cytokines and their receptors in the brain. Emerging evidence indicates that pro-inflammatory cytokines modulate brain excitability. Findings from both the clinical literature and from in vivo and in vitro laboratory studies suggest that cytokines can increase seizure susceptibility and may be involved in epileptogenesis. Cellular mechanisms that underlie these effects include upregulation of excitatory glutamatergic transmission and downregulation of inhibitory GABAergic transmission. Copyright © 2012 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Paulo Emílio Corrêa Leite: leitepec@gmail.com

Lena Smirnova:

ORCID: http://orcid.org/0000-0003-0171-3881

lsmirno1@jhu.edu

Journal

Journal ID (nlm-ta): Part Fibre Toxicol

Journal ID (iso-abbrev): Part Fibre Toxicol

Title: Particle and Fibre Toxicology

Publisher: BioMed Central (London )

ISSN (Electronic): 1743-8977

Publication date (Electronic): 3 June 2019

Publication date PMC-release: 3 June 2019

Publication date Collection: 2019

Volume: 16

Electronic Location Identifier: 22

Affiliations

[1 ]ISNI 0000 0001 2226 7417, GRID grid.421280.d, Directory of Metrology Applied to Life Sciences – Dimav, National Institute of Metrology Quality and Technology – INMETRO, ; Av. Nossa Senhora das Graças 50, LABET - Dimav, Predio 27, Duque de Caxias, Xerem, Rio de Janeiro 25250-020 Brazil

[2 ]ISNI 0000 0001 2184 6919, GRID grid.411173.1, Biology Institute, , Fluminense Federal University, ; Niteroi, Rio de Janeiro Brazil

[3 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Center for Alternatives to Animal Testing (CAAT), Bloomberg School of Public Health, , Johns Hopkins University, ; 615 N. Wolfe Street, Baltimore, MD 21205 USA

[4 ]Department of Chemistry, National Institute of Quality Control in Health – INCQS/Fiocruz, Manguinhos, Rio de Janeiro 21040-900 Brazil

[5 ]ISNI 0000 0001 0658 7699, GRID grid.9811.1, University of Konstanz, Biology, ; Konstanz, Germany

[6 ]Dental School, Fluminense Federal University, Niteroi, Rio de Janeiro USA

[7 ]Department of Physiology, University of Lausanne, Lausanne, CH-1015 USA

Author information

Lena Smirnova http://orcid.org/0000-0003-0171-3881

Article

Publisher ID: 307

DOI: 10.1186/s12989-019-0307-3

PMC ID: 6545685

PubMed ID: 31159811

SO-VID: 925684a9-7139-4992-847d-2810029247d5

License:

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.

History

Date received : 6 November 2018

Date accepted : 21 May 2019

Funding

Funded by: FAPERJ

Funded by: CNPQ

Funded by: CAPES

Custom metadata

ScienceOpen disciplines: Toxicology

Keywords: nanoparticle,drug delivery,cns,ipsc-derived brainspheres,3d luhmes

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ScienceOpen disciplines: Toxicology

Keywords: nanoparticle, drug delivery, cns, ipsc-derived brainspheres, 3d luhmes

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

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Abstract

Background

Results

Conclusions

Electronic supplementary material

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Nanoparticles to cross the blood-brain barrier (BBB)

Most cited references 67

Oxidative Stress, Mitochondrial Dysfunction, and Aging

Surface charge affects cellular uptake and intracellular trafficking of chitosan-based nanoparticles.

Cytokines and brain excitability.

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