Human 3D Cultures as Models for Evaluating Magnetic Nanoparticle CNS Cytotoxicity after Short- and Repeated Long-Term Exposure
Open accessAbstract
Since nanoparticles (NPs) can translocate to the brain and impact the highly vulnerable central nervous system (CNS), novel in vitro tools for the assessment of NP-induced neurotoxicity are advocated. In this study, two types of CNS spheroids have been developed from human D384 astrocyte- and SH-SY5Y neuronal-like cells, and optimized in combination with standard assays (viability readout and cell morphology) to test neurotoxic effects caused by Fe3O4NPs, as NP-model, after short- (24–48 h; 1–100µg/ml) and long-term repeated exposure (30days; 0.1–25µg/ml). Short-term exposure of 3D-spheroids to Fe3O4NP induced cytotoxicity at 10 µg/mL in astrocytes and 25 µg/mL neurons. After long-term repeated dose regimen, spheroids showed concentration- and time-dependent cell mortality at 10 µg/mL for D384 and 0.5 µg/mL for SH-SY5Y, indicating a higher susceptibility of neurons than astrocytes. Both spheroid types displayed cell disaggregation after the first week of treatment at ≥0.1 µg/mL and becoming considerably evident at higher concentrations and over time. Recreating the 3D-spatial environment of the CNS allows cells to behave in vitro more closely to the in vivo situations, therefore providing a model that can be used as a stand-alone test or as a part of integrated testing strategies. These models could drive an improvement in the species-relevant predictivity of toxicity testing.
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In spheroid-based assays, drug efficacy is often assessed by comparing changes in spheroid size over time relative to untreated controls.
“In spheroid-based assays, drug efficacy is often assessed by comparing changes in spheroid size over time relative to untreated controls [301,302,303].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [302]
Methods §4.7 describes measuring spheroid size before and after treatment and monitoring growth over time; §4.5 identifies untreated control spheroids. But this study evaluates magnetic-nanoparticle cytotoxicity, not drug efficacy, and the cited passages do not establish that efficacy is often assessed by comparing size changes with untreated controls. Page numbers are unavailable in our copy. (LLM, conf=0.85)
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- Authors
- De Simone, U., Roccio, M., Gribaldo, L., Spinillo, A., Caloni, F., & Coccini, T.
- Affiliations
- Laboratory of Clinical and Experimental Toxicology, Toxicology Unit, ICS Maugeri SpA-BC, IRCCS Pavia, 27100 Pavia, Italy
- University of Pavia (IT)
- European Commission (BE)
- University of Milan (IT)
- Istituti Clinici Scientifici Maugeri (IT)
- Corresponding author
- Coccini, Teresa
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2018-07-08
- Volume
- 19
- Issue
- 7
- Pages
- 1993
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC6073335
- OpenAlex
- W2816246267
- Cited by
- 55
- References
- 66
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 8 · 2023: 5 · 2022: 11 · 2021: 7 · 2020: 8 · 2019: 7
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Joint Research Centre (European Commission) (submittedVersion)
- Topics
- Physical Sciences › Materials Science › Materials Chemistry › Nanoparticles: synthesis and applications
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- magnetic nanoparticles, Fe3O4 nanoparticles, neurotoxicity, central nervous system, multicellular spheroids, astrocytes, SH-SY5Y cells, repeated-dose exposure, cytotoxicity, cell viability, cell morphology, cell disaggregation, in vitro toxicity models, integrated testing strategies
- MeSH terms
- Cells, Cultured, Central Nervous System, Dose-Response Relationship, Drug, Humans, Models, Biological, Time Factors, Spheroids, Cellular, Cell Culture Techniques, Magnetite Nanoparticles
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