One-year chronic toxicity evaluation of single dose intravenously administered silica nanoparticles in mice and their Ex vivo human hemocompatibility

JOURNAL OF CONTROLLED RELEASE

卷:324

Article

Mohammadpour, Raziye^1,2  Cheney, Darwin L.^1,2  Grunberger, Jason W.^1,2,3  Yazdimamaghani, Mostafa^1,2,3  Jedrzkiewicz, Jolanta^2,4  Isaacson, Kyle J.^1,2,5  Dobrovolskaia, Marina A.⁶  Ghandehari, Hamidreza^1,2,3,5 

[1] Nano Inst Utah, Utah Ctr Nanomed, Salt Lake City, UT 84112 USA

[2] Univ Utah, Salt Lake City, UT 84112 USA

[3] Nano Inst Utah, Dept Pharmaceut & Pharmaceut Chem, Salt Lake City, UT USA

[4] Nano Inst Utah, Dept Pathol, Salt Lake City, UT USA

[5] Univ Utah, Dept Biomed Engn, Salt Lake City, UT USA

[6] NCI, Nanotechnol Characterizat Lab, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA

关键词: Chronic toxicity;    Nanotoxicology;    Silica nanoparticles;    Porosity;    Hemocompatibility;    Complement;    One-year;    BALB/c mice;   

DOI  :  10.1016/j.jconrel.2020.05.027

来源: Elsevier

【 摘 要 】

Chronic toxicity evaluations of nanotechnology-based drugs are essential to support initiation of clinical trials. Ideally such evaluations should address the dosing strategy in human applications and provide sufficient information for long-term usage. Herein, we investigated one-year toxicity of non-surface modified silica nano particles (SNPs) with variations in size and porosity (Stober SNPs 46 +/- 4.9 and 432.0 +/- 18.7 nm and mesoporous SNPs 466.0 +/- 86.0 nm) upon single dose intravenous administration to female and male BALB/c mice (10 animal/sex/group) along with their human blood compatibility. Our evidence of clinical observation and blood parameters showed no significant changes in body weight, cell blood count, nor plasma biomarker indices. No significant changes were noted in post necropsy examination of internal organs and organ-to-body weight ratio. However, microscopic examination revealed significant amount of liver inflammation and aggregates of histocytes with neutrophils within the spleen suggesting an ongoing or resolving injury. The fast accumulation of these plain SNPs in the liver and spleen upon IV administration and the duration needed for their clearance caused these injuries. There were also subtle changes which were attributed to prior infarctions or resolved intravascular thrombosis and included calcifications in pulmonary vessels, focal cardiac fibrosis with calcifications, and focal renal injury. Most of the pathologic lesions were observed when large, non-porous SNPs were administered. Statistically significant chronic toxicity was not observed for the small non-porous particles and for the mesoporous particles. This one-year post-exposure evaluation indicate that female and male BALB/c mice need up to one year to recover from acute tissue toxic effects of silica nanoparticles upon single dose intravenous administration at their 10-day maximum tolerated dose. Further, ex vivo testing with human blood and plasma revealed no hemolysis or complement activation following incubation with these silica nanoparticles. These results can inform the potential utility of silica nanoparticles in biomedical applications such as controlled drug delivery where intravenous injection of the particles is intended.

【 授权许可】

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