title: Targeted fibrillar nanocarbon RNAi treatment of acute kidney injury.
abstract: RNA interference has tremendous yet unrealized potential to treat a wide range of illnesses. Innovative solutions are needed to protect and selectively deliver small interfering RNA (siRNA) cargo to and within a target cell to fully exploit siRNA as a therapeutic tool in vivo. Herein, we describe ammonium-functionalized carbon nanotube (fCNT)-mediated transport of siRNA selectively and with high efficiency to renal proximal tubule cells in animal models of acute kidney injury (AKI). fCNT enhanced siRNA delivery to tubule cells compared to siRNA alone and effectively knocked down the expression of several target genes, includingTrp53,Mep1b,Ctr1, andEGFP A clinically relevant cisplatin-induced murine model of AKI was used to evaluate the therapeutic potential of fCNT-targeted siRNA to effectively halt the pathogenesis of renal injury. Prophylactic treatment with a combination of fCNT/siMep1band fCNT/siTrp53significantly improved progression-free survival compared to controls via a mechanism that required concurrent reduction of meprin-1β and p53 expression. The fCNT/siRNA was well tolerated, and no toxicological consequences were observed in murine models. Toward clinical application of this platform, fCNTs were evaluated for the first time in nonhuman primates. The rapid and kidney-specific pharmacokinetic profile of fCNT in primates was comparable to what was observed in mice and suggests that this approach is amenable for use in humans. The nanocarbon-mediated delivery of siRNA provides a therapeutic means for the prevention of AKI to safely overcome the persistent barrier of nephrotoxicity during medical intervention.
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Alidori
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Nima
authors.initials: N
authors.lastname: Akhavein
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Daniel L J
authors.initials: DL
authors.lastname: Thorek
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Katja
authors.initials: K
authors.lastname: Behling
authors.affiliation: Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Romin
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Queen
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Beattie
authors.affiliation: Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Katia
authors.initials: K
authors.lastname: Manova-Todorova
authors.affiliation: College of Nanoscale Science and Engineering, University at Albany, Albany, NY 12203, USA.
authors.forename: Magnus
authors.initials: M
authors.lastname: Bergkvist
authors.affiliation: Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. m-mcdevitt@ski.mskcc.org.
authors.forename: Michael R
authors.initials: MR
authors.lastname: McDevitt
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000628:therapy*; D000818:Animals; D002945:Cisplatin; D005260:Female; D005355:Fibrosis; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D057139:Nanofibers / Q000737:chemistry*; D037742:Nanotubes, Carbon / Q000737:chemistry* / Q000648:ultrastructure; D034622:RNA Interference; D034443:RNA Transport; D034741:RNA, Small Interfering / Q000378:metabolism* / Q000493:pharmacokinetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D037742:Nanotubes, Carbon; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D008666:Metalloendopeptidases; C053833:meprin A; D002945:Cisplatin