TY - JOUR
T1 - Targeted fibrillar nanocarbon RNAi treatment of acute kidney injury
AU - Alidori, Simone
AU - Akhavein, Nima
AU - Thorek, Daniel L.J.
AU - Behling, Katja
AU - Romin, Yevgeniy
AU - Queen, Dawn
AU - Beattie, Bradley J.
AU - Manova-Todorova, Katia
AU - Bergkvist, Magnus
AU - Scheinberg, David A.
AU - McDevitt, Michael R.
N1 - Funding Information:
We thank R. Bowman and J. Joyce for the EGFP mice; M. Fleisher for advice on the renal biomarker studies; E. Skolnik and E. Jaimes forexpert opinion on renal biology and pathology; J. Lewis for the copper-64; J. Gardner for help with the survival studies. A. C. McDevitt for the graphic illustration; M. Kharas for the critical readingof the manuscript;and M. Turkekul, N. Fan, D. Yarilin, A. Barlas, and M. Brendel from the Molecular Cytology Core Facility. This work was supported by the Office of Science [BER (Biological and Environmental Research)], U.S. Department of Energy (award DE-SC0002456), NIH MSTP (Medical Scientist Training Program) (grants GM07739, R21CA128406, R01CA166078, R01CA55349, R25TCA046945, R24CA83084, P30CA08748, P01CA33049, and F31CA167863), Memorial Sloan Kettering Center for Molecular Imaging and Nanotechnology (CMINT), and Memorial Sloan Kettering Experimental Therapeutics Center.
PY - 2016/3/23
Y1 - 2016/3/23
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84961779115&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aac9647
DO - 10.1126/scitranslmed.aac9647
M3 - Article
C2 - 27009268
AN - SCOPUS:84961779115
SN - 1946-6234
VL - 8
JO - Science translational medicine
JF - Science translational medicine
IS - 331
M1 - 331ra39
ER -