Targeted fibrillar nanocarbon RNAi treatment of acute kidney injury Journal Article

Authors: Alidori, S.; Akhavein, N.; Thorek, D. L. J.; Behling, K.; Romin, Y.; Queen, D.; Beattie, B. J.; Manova-Todorova, K.; Bergkvist, M.; Scheinberg, D. A.; McDevitt, M. R.
Article 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, including Trp53, Mep1b, Ctr1, and EGFP. 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/ siMep1b and fCNT/siTrp53 significantly improved progression-free survival compared to controls via a mechanism that required concurrent reduction of meprin-1b 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.
Journal Title: Science Translational Medicine
Volume: 8
Issue: 331
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2016-03-23
Start Page: 331ra39
Language: English
DOI: 10.1126/scitranslmed.aac9647
PROVIDER: scopus
PUBMED: 27009268
PMCID: PMC5004247
Notes: Article -- Export Date: 2 May 2016 -- Source: Scopus
Citation Impact
MSK Authors
  1. Michael R Mcdevitt
    120 Mcdevitt
  2. Bradley Beattie
    117 Beattie
  3. Yevgeniy Romin
    16 Romin
  4. Dawn Suisun Queen
    1 Queen