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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2019
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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.
Smirnova, Lena
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Zusammenfassung

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.

Zusammenfassung in einer weiteren Sprache
Fachgebiet (DDC)
570 Biowissenschaften, Biologie
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Nanoparticle, Drug delivery, CNS, iPSC-derived BrainSpheres, 3D LUHMES
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ISO 690LEITE, Paulo Emílio Corrêa, Mariana Rodrigues PEREIRA, Georgina HARRIS, David PAMIES, Lisia Maria Gobbo DOS SANTOS, José Mauro GRANJEIRO, Helena T. HOGBERG, Thomas HARTUNG, Lena SMIRNOVA, 2019. 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. In: Particle and Fibre Toxicology. 2019, 16(1), 22. eISSN 1743-8977. Available under: doi: 10.1186/s12989-019-0307-3
BibTex
@article{Leite2019-06-03Suita-46675,
  year={2019},
  doi={10.1186/s12989-019-0307-3},
  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},
  number={1},
  volume={16},
  journal={Particle and Fibre Toxicology},
  author={Leite, Paulo Emílio Corrêa and Pereira, Mariana Rodrigues and Harris, Georgina and Pamies, David and Dos Santos, Lisia Maria Gobbo and Granjeiro, José Mauro and Hogberg, Helena T. and Hartung, Thomas and Smirnova, Lena},
  note={Article Number: 22}
}
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