Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates

Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates

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/...

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Bibliographic Details
Main Authors: Dong, Yizhou, Love, Kevin T., Dorkin, Joseph Robert, Sirirungruang, Sasilada, Zhang, Yunlong, Chen, Delai, Bogorad, Roman, Yin, Hao, Chen, Yi, Vegas, Arturo, Alabi, Christopher A., Sahay, Gaurav, Olejnik, Karsten, Wang, Weiheng, Schroeder, Avi, Lytton-Jean, Abigail K. R., Siegwart, Daniel J., Akinc, Akin, Barnes, Carmen, Barros, Scott A., Carioto, Mary, Fitzgerald, Kevin, Hettinger, Julia, Kumar, Varun, Novobrantseva, Tatiana I., Qin, June, Querbes, William, Kotelianski, Victor E., Langer, Robert, Anderson, Daniel Griffith
Other Authors: Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Format: Article
Language:en_US
Published: National Academy of Sciences (U.S.) 2014
Online Access:http://hdl.handle.net/1721.1/91468
https://orcid.org/0000-0002-2100-1171
https://orcid.org/0000-0002-4680-3832
https://orcid.org/0000-0001-5786-0659
https://orcid.org/0000-0001-5629-4798
https://orcid.org/0000-0001-6898-3793
https://orcid.org/0000-0003-3298-6022
https://orcid.org/0000-0001-9522-8208
https://orcid.org/0000-0003-4255-0492
Description
Summary: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.

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