Research ArticleNanomedicine

Targeted fibrillar nanocarbon RNAi treatment of acute kidney injury

Science Translational Medicine  23 Mar 2016:
Vol. 8, Issue 331, pp. 331ra39
DOI: 10.1126/scitranslmed.aac9647

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Double trouble for kidney toxicity

The kidneys can be damaged by drugs, such as antibiotics and chemotherapy, as well as by surgery, which robs the organs of oxygen. To prevent injury, Alidori et al. devised a nanomedicine treatment approach that delivers two small interfering RNAs (siRNAs) to the main cells of the kidney, the renal proximal tubule cells. siRNAs targeting Mep1b and Trp53 were attached to fibrillar carbon nanotubes and delivered simultaneously to mice before drug-induced kidney insult. With such RNA interference, the kidney cells could not produce meprin-1β and p53—two key proteins involved in kidney injury; the mice lived longer and remained injury-free, but only if given both siRNAs. The nanotube/siRNA complexes were also safe and had favorable pharmacokinetics in monkeys. The next steps will be testing the dual siRNAs in other animal models of 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-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.

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