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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 11; pp. 3955 - 3960
• Main Authors: Dong, Yizhou, Love, Kevin T., Dorkin, J. Robert, Sirirungruang, Sasilada, Zhang, Yunlong, Chen, Delai, Bogorad, Roman L., Yin, Hao, Chen, Yi, Vegas, Arturo J., Alabi, Christopher A., Sahay, Gaurav, Olejnik, Karsten T., 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, Koteliansky, Victor, Langer, Robert, Anderson, Daniel G.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.03.2014; National Acad Sciences
• Series: From the Cover
• Subjects: Amino acids; Animals; Apolipoproteins E - metabolism; B lymphocytes; Cryoelectron Microscopy; Drug Delivery Systems - methods; Endothelial cells; Gene Silencing; Genetic disorders; HeLa cells; Hepatocytes; Hepatocytes - metabolism; Lipopeptides - chemistry; Lipoproteins; Macaca fascicularis; Medical treatment; Mice; Nanoparticles; Nanoparticles - chemistry; Peptides; Physical Sciences; Primates; Rats; Ribonucleic acid; RNA; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - therapeutic use; Rodents; Small interfering RNA; T lymphocytes; translational research; liver genetic disorders; lipopeptide nanomaterials; tissue and cell specificity
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1322937111

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.