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

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.

authors

Dong Y,Love KT,Dorkin JR,Sirirungruang S,Zhang Y,Chen D,Bogorad RL,Yin H,Chen Y,Vegas AJ,Alabi CA,Sahay G,Olejnik KT,Wang W,Schroeder A,Lytton-Jean AK,Siegwart DJ,Akinc A,Barnes C,Barros SA,Carioto M,Fitzgerald

doi

10.1073/pnas.1322937111

subject

Has Abstract

pub_date

2014-03-18 00:00:00

pages

3955-60

issue

11

eissn

0027-8424

issn

1091-6490

pii

1322937111

journal_volume

111

pub_type

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