An Amino Acid-based Amphoteric Liposomal Delivery System for Systemic Administration of siRNA

被引：47

作者：

Adami, Roger C. ^{[1
]}

Seth, Shaguna ^{[1
]}

Harvie, Pierrot ^{[1
]}

Johns, Rachel ^{[1
]}

Fam, Renata ^{[1
]}

Fosnaugh, Kathy ^{[1
]}

Zhu, Tianying ^{[1
]}

Farber, Ken ^{[1
]}

McCutcheon, Michael ^{[1
]}

Goodman, Thomas T. ^{[1
]}

Liu, Yan ^{[1
]}

Chen, Yan ^{[1
]}

Kwang, Erin ^{[1
]}

Templin, Michael V. ^{[1
]}

Severson, Greg ^{[1
]}

Brown, Tod ^{[1
]}

Vaish, Narendra ^{[1
]}

Chen, Feng ^{[1
]}

Charmley, Patrick ^{[1
]}

Polisky, Barry ^{[1
]}

Houston, Michael E., Jr. ^{[1
]}

机构：

[1] Marina Biotech Inc, Bothell, WA USA

来源：

MOLECULAR THERAPY | 2011年 / 19卷 / 06期

关键词：

HEXAGONAL PHASE-TRANSITION; ARGININE-RICH PEPTIDES; CATIONIC LIPIDS; GENE DELIVERY; INTRACELLULAR DELIVERY; RNAI THERAPEUTICS; NONHUMAN-PRIMATES; CELLULAR UPTAKE; SURFACE-CHARGE; DRUG-DELIVERY;

D O I：

10.1038/mt.2011.56

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

We demonstrate a systematic and rational approach to create a library of natural and modified, dialkylated amino acids based upon arginine for development of an efficient small interfering RNA (siRNA) delivery system. These amino acids, designated DiLA(2) compounds, in conjunction with other components, demonstrate unique properties for assembly into monodisperse, 100-nm small liposomal particles containing siRNA. We show that DiLA(2)-based liposomes undergo a pH-dependent phase transition to an inverted hexagonal phase facilitating efficient siRNA release from endosomes to the cytosol. Using an arginine-based DiLA(2), cationic liposomes were prepared that provide high in vivo siRNA delivery efficiency and are well-tolerated in both cell and animal models. DiLA(2)-based liposomes demonstrate a linear dose-response with an ED(50) of 0.1 mg/kg against liver-specific target genes in BALB/c mice.

引用

页码：1141 / 1151

页数：11

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