2. Academic Validation
  3. 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

  • Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):3955-60. doi: 10.1073/pnas.1322937111.
Yizhou Dong 1,  Kevin T Love,  J Robert Dorkin,  Sasilada Sirirungruang,  Yunlong Zhang,  Delai Chen,  Roman L Bogorad,  Hao Yin,  Yi Chen,  Arturo J Vegas,  Christopher A Alabi,  Gaurav Sahay,  Karsten T Olejnik,  Weiheng Wang,  Avi Schroeder,  Abigail K R Lytton-Jean,  Daniel J Siegwart,  Akin Akinc,  Carmen Barnes,  Scott A Barros,  Mary Carioto,  Kevin Fitzgerald,  Julia Hettinger,  Varun Kumar,  Tatiana I Novobrantseva,  June Qin,  William Querbes,  Victor Koteliansky,  Robert Langer,  Daniel G Anderson
Affiliations

Affiliation

  • 1 David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
PMID: 24516150 DOI: 10.1073/pnas.1322937111
Abstract

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.

Keywords

lipopeptide nanomaterials; liver genetic disorders; tissue and cell specificity; translational research.

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