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J Nanobiotechnology. 2019 Feb 5;17(1):24. doi: 10.1186/s12951-019-0456-4.

Two distinct cellular pathways leading to endothelial cell cytotoxicity by silica nanoparticle size.

Author information

1
Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
2
Center for Nano-Bio Measurement, Korea Research Institute of Standards and Science (KRISS), 267 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea.
3
Research Center for Metabolic Regulation, KRIBB, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
4
Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea.
5
Stem Cell Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
6
Immunotherapy Convergence Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
7
Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero Seocho-gu, Seoul, 06591, Republic of Korea.
8
Korea Research Institute of Standards and Science (KRISS), 267 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea. nwsong@kriss.re.kr.
9
Research Center for Metabolic Regulation, KRIBB, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea. khbae@kribb.re.kr.
10
Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea. jekmin@kribb.re.kr.
11
Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea. jekmin@kribb.re.kr.

Abstract

BACKGROUND:

Silica nanoparticles (SiNPs) are widely used for biosensing and diagnostics, and for the targeted delivery of therapeutic agents. Safety concerns about the biomedical and clinical applications of SiNPs have been raised, necessitating analysis of the effects of their intrinsic properties, such as sizes, shapes, and surface physicochemical characteristics, on human health to minimize risk in biomedical applications. In particular, SiNP size-associated toxicological effects, and the underlying molecular mechanisms in the vascular endothelium remain unclear. This study aimed to elucidate the detailed mechanisms underlying the cellular response to exposure to trace amounts of SiNPs and to determine applicable size criteria for biomedical application.

METHODS:

To clarify whether these SiNP-mediated cytotoxicity due to induction of apoptosis or necrosis, human ECs were treated with SiNPs of four different non-overlapping sizes under low serum-containing condition, stained with annexin V and propidium iodide (PI), and subjected to flow cytometric analysis (FACS). Two types of cell death mechanisms were assessed in terms of production of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress induction, and autophagy activity.

RESULTS:

Spherical SiNPs had a diameter of 21.8 nm; this was further increased to 31.4, 42.9, and 56.7 nm. Hence, we investigated these effects in human endothelial cells (ECs) treated with these nanoparticles under overlap- or agglomerate-free conditions. The 20-nm SiNPs, but not SiNPs of other sizes, significantly induced apoptosis and necrosis. Surprisingly, the two types of cell death occurred independently and through different mechanisms. Apoptotic cell death resulted from ROS-mediated ER stress. Furthermore, autophagy-mediated necrotic cell death was induced through the PI3K/AKT/eNOS signaling axis. Together, the present results indicate that SiNPs within a diameter of < 20-nm pose greater risks to cells in terms of cytotoxic effects.

CONCLUSION:

These data provide novel insights into the size-dependence of the cytotoxic effects of silica nanoparticles and the underlying molecular mechanisms. The findings are expected to inform the applicable size range of SiNPs to ensure their safety in biomedical and clinical applications.

KEYWORDS:

Apoptosis; Autophagy; Necroptosis; ROS; Silica nanoparticles

PMID:
30722792
PMCID:
PMC6362579
DOI:
10.1186/s12951-019-0456-4
[Indexed for MEDLINE]
Free PMC Article

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