PMID- 31047961 OWN - NLM STAT- MEDLINE DCOM- 20200909 LR - 20231013 IS - 1873-4995 (Electronic) IS - 0168-3659 (Print) IS - 0168-3659 (Linking) VI - 304 DP - 2019 Jun 28 TI - Subchronic toxicity of silica nanoparticles as a function of size and porosity. PG - 216-232 LID - S0168-3659(19)30244-5 [pii] LID - 10.1016/j.jconrel.2019.04.041 [doi] AB - Despite increasing reports of using silica nanoparticles (SNPs) for controlled drug delivery applications, their long-term toxicity profile following intravenous administration remains unexplored. Herein, we investigated the acute (10-day) and subchronic (60-day and 180-day) toxicity of nonporous SNPs of approximately 50 nm (Stober SNPs50) and approximately 500 nm in diameter (Stober SNPs500), and mesoporous SNPs of approximately 500 nm in diameter (MSNPs500) upon single-dose intravenous injection into male and female immune-competent inbred BALB/c mice. The Maximum Tolerated Dose (MTD) of the particles was determined 10 days post-injection. The MTD of SNPs was administered and toxicity evaluated over 60 and 180 days. Results demonstrate that Stober SNPs50 exhibit systemic toxicity with MTD of 103 +/- 11 mg.kg(-1) for female and 100 +/- 6 mg.kg(-1) for male mice, respectively. Toxicity was alleviated by increasing the size of the particles (Stober SNPs500). MTD values of 303 +/- 4 mg.kg(-1) for female and 300 +/- 13 mg.kg(-1) for male were observed for Stober SNPs500. Mesoporous SNPs500 showed considerable systemic sex-related toxicity, with MTDs ranging from 40 +/- 2 mg.kg(-1) to 95 +/- 2 mg.kg(-1) for male and female mice, respectively. Studies of SNPs showed blood toxicity as a function of physiochemical properties such as significant differences in the mean corpuscular hemoglobin (MCHC) and platelet number at day 10 and white blood cell count at day 60. Histological examination also showed size-, porosity- and time-dependent tissue toxicity. Stober SNPs500 caused major toxic effects such as lung thrombosis, cardiac wall fibrosis and calcifications, brain infarctions with necrotizing inflammatory response, infiltrate, retinal injuries with calcification and focal gliosis, renal parenchymal damage and liver lobular inflammation dependent on the dose and time of exposure. However, tissue toxicity and accumulation of SNPs in liver observed at day 10 was greater than at day 60 and much greater than at day 180. In contrast, a dramatic increase in cytokine levels was observed at day 60. Despite the relatively high doses, SNPs did not cause subchronic toxicity at day 180 after single-dose intravenous injection. However, they showed distinct differences in the 60 day in vivo subchronic toxicity and inflammation profile as a function of surface area and size. CI - Copyright (c) 2019 Elsevier B.V. All rights reserved. FAU - Mohammadpour, Raziye AU - Mohammadpour R AD - Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, United States. FAU - Yazdimamaghani, Mostafa AU - Yazdimamaghani M AD - Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, United States; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, United States. FAU - Cheney, Darwin L AU - Cheney DL AD - Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, United States. FAU - Jedrzkiewicz, Jolanta AU - Jedrzkiewicz J AD - Department of Pathology, University of Utah, Salt Lake City, UT, United States. FAU - Ghandehari, Hamidreza AU - Ghandehari H AD - Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, United States; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, United States; Department of Bioengineering, University of Utah, Salt Lake City, UT, United States. Electronic address: hamid.ghandehari@utah.edu. LA - eng GR - R01 DE019050/DE/NIDCR NIH HHS/United States GR - R01 ES024681/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20190430 PL - Netherlands TA - J Control Release JT - Journal of controlled release : official journal of the Controlled Release Society JID - 8607908 RN - 0 (Cytokines) RN - 7631-86-9 (Silicon Dioxide) SB - IM MH - Animals MH - Cytokines/metabolism MH - *Drug Delivery Systems MH - Female MH - Injections, Intravenous MH - Male MH - Maximum Tolerated Dose MH - Mice MH - Mice, Inbred BALB C MH - Nanoparticles/administration & dosage/*toxicity MH - Particle Size MH - Porosity MH - Sex Factors MH - Silicon Dioxide/*chemistry MH - Time Factors MH - Tissue Distribution MH - Toxicity Tests, Subchronic PMC - PMC6681828 MID - NIHMS1531305 OTO - NOTNLM OT - Drug delivery OT - Inflammation OT - Physiochemical properties OT - Silica nanoparticles OT - Subchronic toxicity COIS- Disclosure: The authors declare no commercial affiliations that might pose a potential, perceived or real conflict of interest with these studies. EDAT- 2019/05/03 06:00 MHDA- 2020/09/10 06:00 PMCR- 2020/06/28 CRDT- 2019/05/04 06:00 PHST- 2019/02/08 00:00 [received] PHST- 2019/04/20 00:00 [revised] PHST- 2019/04/28 00:00 [accepted] PHST- 2019/05/03 06:00 [pubmed] PHST- 2020/09/10 06:00 [medline] PHST- 2019/05/04 06:00 [entrez] PHST- 2020/06/28 00:00 [pmc-release] AID - S0168-3659(19)30244-5 [pii] AID - 10.1016/j.jconrel.2019.04.041 [doi] PST - ppublish SO - J Control Release. 2019 Jun 28;304:216-232. doi: 10.1016/j.jconrel.2019.04.041. Epub 2019 Apr 30.