TY - JOUR
T1 - Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates
AU - Dong, Yizhou
AU - Love, Kevin T.
AU - Dorkin, J. Robert
AU - Sirirungruang, Sasilada
AU - Zhang, Yunlong
AU - Chen, Delai
AU - Bogorad, Roman L.
AU - Yin, Hao
AU - Chen, Yi
AU - Vegas, Arturo J.
AU - Alabi, Christopher A.
AU - Sahay, Gaurav
AU - Olejnik, Karsten T.
AU - Wang, Weiheng
AU - Schroeder, Avi
AU - Lytton-Jean, Abigail K R
AU - Siegwart, Daniel J.
AU - Akinc, Akin
AU - Barnes, Carmen
AU - Barros, Scott A.
AU - Carioto, Mary
AU - Fitzgerald, Kevin
AU - Hettinger, Julia
AU - Kumar, Varun
AU - Novobrantseva, Tatiana I.
AU - Qin, June
AU - Querbes, William
AU - Koteliansky, Victor
AU - Langer, Robert
AU - Anderson, Daniel G.
PY - 2014/3/18
Y1 - 2014/3/18
N2 - siRNA therapeutics have promise for the treatment of a wide range of genetic disorders. Motivated by lipoproteins, we report lipopeptide nanoparticles as potent and selective siRNA carriers with a wide therapeutic index. Lead material cKK-E12 showed potent silencing effects in mice (ED50 ̃ 0.002 mg/kg), rats (ED50 < 0.01 mg/kg), and nonhuman primates (over 95% silencing at 0.3 mg/kg). Apolipoprotein E plays a significant role in the potency of cKK-E12 both in vitro and in vivo. cKK-E12 was highly selective toward liver parenchymal cell in vivo, with orders of magnitude lower doses needed to silence in hepatocytes compared with endothelial cells and immune cells in different organs. Toxicity studies showed that cKK-E12 was well tolerated in rats at a dose of 1 mg/kg (over 100-fold higher than the ED50). To our knowledge, this is the most efficacious and selective nonviral siRNA delivery system for gene silencing in hepatocytes reported to date.
AB - siRNA therapeutics have promise for the treatment of a wide range of genetic disorders. Motivated by lipoproteins, we report lipopeptide nanoparticles as potent and selective siRNA carriers with a wide therapeutic index. Lead material cKK-E12 showed potent silencing effects in mice (ED50 ̃ 0.002 mg/kg), rats (ED50 < 0.01 mg/kg), and nonhuman primates (over 95% silencing at 0.3 mg/kg). Apolipoprotein E plays a significant role in the potency of cKK-E12 both in vitro and in vivo. cKK-E12 was highly selective toward liver parenchymal cell in vivo, with orders of magnitude lower doses needed to silence in hepatocytes compared with endothelial cells and immune cells in different organs. Toxicity studies showed that cKK-E12 was well tolerated in rats at a dose of 1 mg/kg (over 100-fold higher than the ED50). To our knowledge, this is the most efficacious and selective nonviral siRNA delivery system for gene silencing in hepatocytes reported to date.
KW - Lipopeptide nanomaterials
KW - Liver genetic disorders
KW - Tissue and cell specificity
KW - Translational research
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U2 - 10.1073/pnas.1322937111
DO - 10.1073/pnas.1322937111
M3 - Article
C2 - 24516150
AN - SCOPUS:84896519424
SN - 0027-8424
VL - 111
SP - 3955
EP - 3960
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
ER -