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Cited by 92Nanoparticle-Based Drug DeliveryBarrier Structure and Function StudiesNanoparticles: synthesis and applications

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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Leite, Paulo Emílio Corrêa, Pereira, Mariana Rodrigues, Harris, Georgina, Pamies, David, dos Santos, Lisia Maria Gobbo, Granjeiro, José Mauro, Hogberg, Helena T., Hartung, Thomas +1 more·2019·Particle and Fibre Toxicology
DOI 10.1186/s12989-019-0307-3PMC PMC6545685
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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.

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  • Additional markers of cellular integrity, including lactate dehydrogenase release, caspase activation, and changes in mitochondrial membrane potential, have been adapted to evaluate apoptotic and necrotic responses within 3D tumor models.

    “Additional markers of cellular integrity, including lactate dehydrogenase release, caspase activation, and changes in mitochondrial membrane potential, have also been adapted to evaluate apoptotic and necrotic responses within 3D tumor models [186,308,309,310].”

    From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [310]

    The Methods sections on LDH release and mitochondrial membrane potential describe both assays in 3D human neural spheroids, and the Results use them to assess cell damage and viability. The paper does not establish their use in 3D tumor models or report caspase activation as an assay for apoptotic responses. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Leite, P. E. C., Pereira, M. R., Harris, G., Pamies, D., dos Santos, L. M. G., Granjeiro, J. M., Hogberg, H. T., Hartung, T., & Smirnova, L.
Affiliations
  • Instituto Nacional de Metrologia, Qualidade e Tecnologia (BR)
  • Universidade Federal Fluminense (BR)
  • Johns Hopkins University (US)
Corresponding author
  • Leite, Paulo Emílio Corrêa
  • Smirnova, Lena
ORCID
Venue
Particle and Fibre Toxicology
Publisher
Springer Science and Business Media LLC
Published
2019-06-03
Volume
16
Issue
1
Pages
22-22
ISSN
1743-8977 (ISSN-L)
DOI
10.1186/s12989-019-0307-3
PMC
PMC6545685
OpenAlex
W2949003121
Cited by
92
References
115
Citations by year
2026: 11 · 2025: 9 · 2024: 7 · 2023: 17 · 2022: 16 · 2021: 15 · 2020: 15 · 2019: 2
FWCI
3.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Particle and Fibre Toxicology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • SERVAL (Université de Lausanne) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • IRIS (submittedVersion, cc-by)
  • KOPS (University of Konstanz) (submittedVersion, cc-by)
Funders
  • FAPERJ
  • CNPQ
  • CAPES
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Physical Sciences › Materials Science › Materials Chemistry › Nanoparticles: synthesis and applications
Keywords
gold nanoparticles, polylactic acid nanoparticles, nanoparticle neurotoxicity, blood-brain barrier, brain drug delivery, dopaminergic neurons, LUHMES cells, PEGylated nanoparticles, mitochondrial membrane potential, reactive oxygen species, oxidative stress, cytokine and chemokine secretion, glial cells, biocompatibility assessment
MeSH terms
Sodium Citrate, Brain, Cell Line, Cell Survival, Gold, Humans, Models, Biological, Polyesters, Polyethylene Glycols, Surface Properties, Gene Expression, Drug Delivery Systems, Oxidative Stress, Spheroids, Cellular, Cell Culture Techniques, Membrane Potential, Mitochondrial, Metal Nanoparticles, Dopaminergic Neurons

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