title: Toward single-walled carbon nanotube-gadolinium complex as advanced MRI contrast agents: pharmacodynamics and global genomic response in small animals.
abstract: Gadolinium nanoparticle-catalyzed single-walled carbon nanotubes (Gd-SWCNTs) have recently shown potential in vitro as high-performance T1 magnetic resonance imaging (MRI) contrast agents (CAs). Their preclinical safety assessment at nontoxic dosages is essential for MRI applications. Herein, the in vivo (in rats) pharmacodynamics of Gd-SWCNTs (water solubilized with the amphiphilic polymer PEG-DSPE) at the organ, tissue, molecular, and genetic level is reported. Gd-SWCNT, commercially available iron catalyzed SWCNTs (Fe-SWCNTs, control 1) and PEG-DSPE (control 2) solutions were intravenously injected at a potential nontoxic therapeutic dose (0.5 mg/kg body weight, single bolus). Postinjection, bright-field optical microscopy showed their macroscale distribution in lung, liver, kidney, brain, and spleen up to 5 days. Raman and transmission electron microscopy (TEM) showed their presence at the nanoscale within hepatocytes. Their effects on the host organ tissue, molecular, and genetic level were analyzed after 1, 5, 10, 20, and 30 days by histology, biomolecular [lipid peroxidation, plasma tumor necrosis factor TNF-α assay, microarrays] assays. The results indicate that Gd-SWCNTs neither cause any inflammation, nor damage to the above organs, nor any significant change in the lipid peroxidation or plasma proinflammatory cytokine (TNF-α) levels for all the groups at all time points. Global gene expression profile of liver (main organ for the metabolism) after day 1 treatment with Gd-SWCNTs shows that the gene regulation is directed toward maintaining normal homeostasis. The results taken together indicate that PEG-DSPE water-solubilized Gd-SWCNTs at potentially nontoxic dosages have pharmacodynamics similar to other commercially available Fe-SWCNTs and are suitable for future preclinical development as in vivo MRI CAs.
authors.affiliation: Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York 11794-5281, USA.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Avti
authors.forename: Yahfi
authors.initials: Y
authors.lastname: Talukdar
authors.forename: Matvey V
authors.initials: MV
authors.lastname: Sirotkin
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Shroyer
authors.forename: Balaji
authors.initials: B
authors.lastname: Sitharaman
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000494:pharmacology; D003287:Contrast Media / Q000737:chemistry / Q000494:pharmacology; D005682:Gadolinium / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008422:Materials Testing; D037742:Nanotubes, Carbon / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D001672:Biocompatible Materials; D003287:Contrast Media; D037742:Nanotubes, Carbon; D005682:Gadolinium
keywords: animal model; biomaterials availability; histology; molecular imaging; nanomedicine
references.citation: Toxicol Lett. 2008 Oct 1;181(3):182-9
references.pmid: 18760340
references.citation: Biomaterials. 2010 Dec;31(36):9482-91
references.pmid: 20965562
references.citation: Nat Nanotechnol. 2011 Feb;6(2):121-125
references.pmid: 21278749
references.citation: Nat Nanotechnol. 2010 May;5(5):354-9
references.pmid: 20364135
references.citation: Nano Res. 2009 Feb 1;2(2):85-120
references.pmid: 20174481
references.citation: Tissue Eng Part C Methods. 2011 Jan;17(1):19-26
references.pmid: 20666611
references.citation: Toxicology. 2008 Jun 27;248(2-3):77-88
references.pmid: 18440117
references.citation: Nano Lett. 2007 Apr;7(4):861-7
references.pmid: 17335265
references.citation: Contrast Media Mol Imaging. 2007 May-Jun;2(3):139-46
references.pmid: 17583898
references.citation: J Biomed Mater Res A. 2010 Jun 15;93(4):1454-62
references.pmid: 19927368
references.citation: Angew Chem Int Ed Engl. 2004 Oct 18;43(41):5456-64
references.pmid: 15384128
references.citation: Annu Rev Pharmacol Toxicol. 1995;35:655-77
references.pmid: 7598511
references.citation: Br J Pharmacol. 2007 Nov;152(6):838-54
references.pmid: 17592500
references.citation: Nano Lett. 2008 Jan;8(1):232-6
references.pmid: 18088153
references.citation: Nanomedicine. 2010 Aug;6(4):563-9
references.pmid: 20060075
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3357-62
references.pmid: 16492781
references.citation: Gastroenterology. 2007 Oct;133(4):1099-105; quiz 1340-1
references.pmid: 17919486
references.citation: J Biomed Mater Res A. 2013 Dec;101(12):3580-91
references.pmid: 23686792
references.citation: Int J Nanomedicine. 2006;1(3):291-5
references.pmid: 17717970
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1410-5
references.pmid: 18230737
references.citation: Chem Rev. 1999 Sep 8;99(9):2293-352
references.pmid: 11749483
references.citation: PLoS One. 2012;7(3):e30923
references.pmid: 22479306
references.citation: Q J Nucl Med. 1997 Jun;41(2):155-62
references.pmid: 9203854
references.citation: Nat Nanotechnol. 2007 Jan;2(1):47-52
references.pmid: 18654207
references.citation: Contrast Media Mol Imaging. 2010 Jan-Feb;5(1):34-8
references.pmid: 20101755
references.citation: Chem Commun (Camb). 2011 Feb 7;47(5):1607-9
references.pmid: 21113509
references.citation: Clin Chim Acta. 1988 Jun 15;174(3):263-9
references.pmid: 3134146
references.citation: Toxicol Sci. 2004 Jan;77(1):117-25
references.pmid: 14514968
references.citation: Cancer Invest. 1999;17(5):376-7
references.pmid: 10370368
references.citation: ACS Nano. 2012 May 22;6(5):4147-56
references.pmid: 22463369
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):18882-6
references.pmid: 17135351
references.citation: J Nucl Med. 2007 Jul;48(7):1180-9
references.pmid: 17607040
references.citation: Nanotechnology. 2008 Feb 20;19(7):075101
references.pmid: 21817626
references.citation: J Appl Phys. 2013 Apr 7;113(13):134308
references.pmid: 23653487
references.citation: J Appl Toxicol. 2011 Jan;31(1):75-83
references.pmid: 20737426
references.citation: Toxicol Sci. 2004 Jan;77(1):126-34
references.pmid: 14514958
references.citation: Anesthesiology. 2001 Mar;94(3):489-95
references.pmid: 11374611