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Targeted fibrillar nanocarbon RNAi treatment of acute kidney injury.
- Source :
-
Science translational medicine [Sci Transl Med] 2016 Mar 23; Vol. 8 (331), pp. 331ra39. - Publication Year :
- 2016
-
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.<br />Competing Interests: A patent was filed in July 2015: “Method and composition for targeted delivery of therapeutic agents.”<br /> (Copyright © 2016, American Association for the Advancement of Science.)
- Subjects :
- Acute Kidney Injury genetics
Animals
Cisplatin
Female
Fibrosis
Green Fluorescent Proteins metabolism
HeLa Cells
Humans
Kidney Cortex metabolism
Kidney Cortex pathology
Kinetics
Metalloendopeptidases genetics
Metalloendopeptidases metabolism
Mice, Inbred BALB C
Mice, Inbred C57BL
Nanotubes, Carbon ultrastructure
RNA Transport
RNA, Small Interfering pharmacokinetics
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Acute Kidney Injury therapy
Nanofibers chemistry
Nanotubes, Carbon chemistry
RNA Interference
RNA, Small Interfering metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1946-6242
- Volume :
- 8
- Issue :
- 331
- Database :
- MEDLINE
- Journal :
- Science translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 27009268
- Full Text :
- https://doi.org/10.1126/scitranslmed.aac9647