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.
journal_name
Proc Natl Acad Sci U S Aauthors
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,Fitzgeralddoi
10.1073/pnas.1322937111subject
Has Abstractpub_date
2014-03-18 00:00:00pages
3955-60issue
11eissn
0027-8424issn
1091-6490pii
1322937111journal_volume
111pub_type
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