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Biomolecules 2019, 9(1), 14; https://doi.org/10.3390/biom9010014

Toxicity Mechanism of Low Doses of NaGdF4:Yb3+,Er3+ Upconverting Nanoparticles in Activated Macrophage Cell Lines

1
Hirszfeld Institute of Immunology and Experimental Therapy, PAS, 53-114 Wroclaw, Poland
2
Faculty of Chemistry, University of Wroclaw, 50-383 Wroclaw, Poland
3
PORT Polish Center for Technology Development, 54-066 Wroclaw, Poland
*
Author to whom correspondence should be addressed.
Received: 20 November 2018 / Revised: 15 December 2018 / Accepted: 21 December 2018 / Published: 3 January 2019
(This article belongs to the Special Issue Nanoparticles for Cancer Therapy)
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Abstract

Gadolinium-doped nanoparticles (NPs) are regarded as promising luminescent probes. In this report, we studied details of toxicity mechanism of low doses of NaGdF4-based fluorescent nanoparticles in activated RAW264.7, J774A.1 macrophages. These cell lines were specifically sensitive to the treatment with nanoparticles. Using nanoparticles of three different sizes, but with a uniform zeta potential (about −11 mV), we observed rapid uptake of NPs by the cells, resulting in the increased lysosomal compartment and subsequent superoxide induction along with a decrease in mitochondrial potential, indicating the impairment of mitochondrial homeostasis. At the molecular level, this led to upregulation of proapoptotic Bax and downregulation of anti-apoptotic Bcl-2, which triggered the apoptosis with phosphatidylserine externalization, caspase-3 activation and DNA fragmentation. We provide a time frame of the toxicity process by presenting data from different time points. These effects were present regardless of the size of nanoparticles. Moreover, despite the stability of NaGdF4 nanoparticles at low pH, we identified cell acidification as an essential prerequisite of cytotoxic reaction using acidification inhibitors (NH4Cl or Bafilomycin A1). Therefore, approaching the evaluation of the biocompatibility of such materials, one should keep in mind that toxicity could be revealed only in specific cells. On the other hand, designing gadolinium-doped NPs with increased resistance to harsh conditions of activated macrophage phagolysosomes should prevent NP decomposition, concurrent gadolinium release, and thus the elimination of its toxicity. View Full-Text
Keywords: gadolinium; nanoparticles; upconversion; macrophages; lanthanides; fluorescent; toxicity; cytotoxicity; mitochondria; contrast agents gadolinium; nanoparticles; upconversion; macrophages; lanthanides; fluorescent; toxicity; cytotoxicity; mitochondria; contrast agents
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Wysokińska, E.; Cichos, J.; Kowalczyk, A.; Karbowiak, M.; Strządała, L.; Bednarkiewicz, A.; Kałas, W. Toxicity Mechanism of Low Doses of NaGdF4:Yb3+,Er3+ Upconverting Nanoparticles in Activated Macrophage Cell Lines. Biomolecules 2019, 9, 14.

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