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

• Published in: Particle and fibre toxicology 2019-06, Vol.16 (1), p.22-22, Article 22
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 3D LUHMES; Animal models; Apoptosis; Biocompatibility; Biopolymers; Blood-brain barrier; Brain; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain diseases; Care and treatment; Cell culture; Cell Culture Techniques; Cell interactions; Cell Line; Cell Survival - drug effects; Central nervous system; Chemical properties; Chemokines; Citric acid; CNS; Cytokines; Cytotoxicity; Dopamine receptors; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Drug delivery; Drug Delivery Systems; Drug development; Gene expression; Gene Expression - drug effects; Gene regulation; Gold; Gold - metabolism; Gold - toxicity; Growth factors; Health aspects; Humans; Inflammation; iPSC-derived BrainSpheres; Lactic acid; Ligands; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Metal Nanoparticles - toxicity; Mitochondria; Models, Biological; Morphology; Nanomaterials; Nanoparticle; Nanoparticles; Nervous system; Neurodegeneration; Neurodevelopmental disorders; Neurotoxicity; Neurotoxicity syndromes; Organic chemistry; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; Physiological effects; Physiology; Polyesters - chemistry; Polyesters - metabolism; Polyethylene glycol; Polyethylene Glycols - chemistry; Polylactic acid; Reactive oxygen species; Risk assessment; Sodium citrate; Sodium Citrate - chemistry; Spheroids; Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism; Stem cells; Studies; Surface Properties; Testing; Three dimensional models; Viability
• ISSN: 1743-8977; 1743-8977
• DOI: 10.1186/s12989-019-0307-3

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. 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. 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.