Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates
| Autor: | Christopher A. Alabi, Tatiana Novobrantseva, Roman L. Bogorad, William Querbes, Weiheng Wang, Abigail K. R. Lytton-Jean, Daniel G. Anderson, Avi Schroeder, Akin Akinc, Arturo J. Vegas, Hao Yin, Carmen Barnes, Yi Chen, Delai Chen, Kevin Fitzgerald, J. Robert Dorkin, June Qin, Scott A Barros, Victor Koteliansky, Yizhou Dong, Robert Langer, Julia Hettinger, Sasilada Sirirungruang, Gaurav Sahay, Kevin T. Love, Daniel J. Siegwart, Mary Carioto, Varun Kumar, Yunlong Zhang, Karsten Olejnik |
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| Rok vydání: | 2014 |
| Předmět: |
Pharmacology
Biology Mice Lipopeptides chemistry.chemical_compound Apolipoproteins E Drug Delivery Systems Therapeutic index Immune system In vivo Commentaries Animals Gene silencing Gene Silencing RNA Small Interfering Multidisciplinary Cryoelectron Microscopy Lipopeptide Orders of magnitude (mass) In vitro Rats Macaca fascicularis chemistry Physical Sciences Toxicity Immunology Hepatocytes Nanoparticles |
| Zdroj: | Proceedings of the National Academy of Sciences. 111:3955-3960 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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