| الوصف: |
J Justin Mulvey,1,2 Eric R Littmann,3 Lilan Ling,3 Michael R McDevitt,4,5 Eric G Pamer,3,5 David A Scheinberg1,3,5 1Department of Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA; 2Department of Molecular Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 4Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 5Weill Cornell Medicine, New York, NY, USA Background: Amine-modified carbon nanotubes are drug delivery platforms with great potential that have not yet been applied in human clinical trials. Although modified nanotube vectors have the ability to carry multiple effectors, targeting agents, and even wrapped RNA, reports on unmodified, insoluble carbon nanotubes have highlighted inflammation in organs, including the intestine, with disruption of its resident microbiota. Disruption of the microbiota may allow for colonization by pathogenic bacteria, such as Clostridoidies difficile, stimulate immunoinfiltrates into the lamina propria or alter the absorption of therapeutics. Most proposed nanotube drugs are soluble, modified structures that are administered parenterally, and the majority of these soluble macromolecules are renally excreted; however, some are released into the bile, gaining access to the gastrointestinal tract. Methods: Using environmentally isolated BALB/C mice in oral and intraperitoneal dosing models, high dose (3.80 or 4.25 mg/week), we administered amine-modified, soluble carbon nanotubes for 7 or 8 weeks. The general health and weight of the mice were monitored weekly, and upon killing, the diversity and content of their colonic, cecal, and ileal microbiota were assessed using shotgun 16S DNA sequencing. Results and conclusion: We show that while oral administration at suprapharmacological doses modestly altered the α- and β-diversity of the mouse microbiome, these changes did not result in observed changes in clinical end points. Intraperitoneally-dosed mice exhibited none of the toxicities assessed. Keywords: SWCNT, toxicity, 16S sequencing, nanopharmaceuticals |
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