The valency of fatty acid conjugates impacts siRNA pharmacokinetics, distribution, and efficacy in vivo

被引:46
作者
Biscans, Annabelle [1 ,2 ]
Coles, Andrew [1 ,2 ]
Echeverria, Dimas [1 ,2 ]
Khvorova, Anastasia [1 ,2 ]
机构
[1] Univ Massachusetts, Med Sch, RNA Therapeut Inst, Worcester, MA 01604 USA
[2] Univ Massachusetts, Med Sch, Program Mol Med, Worcester, MA 01604 USA
基金
美国国家卫生研究院;
关键词
Therapeutic oligonucleotides; RNA interference; Conjugated siRNAs; Branched lipid conjugate; Pharmacokinetics; siRNA delivery; Gene silencing in vivo; HIGH-THROUGHPUT METHOD; ANTISENSE OLIGONUCLEOTIDES; STRUCTURAL BASIS; GUIDE RNA; DELIVERY; GENE; POTENCY; THERAPEUTICS; HEPATOCYTES; RECOGNITION;
D O I
10.1016/j.jconrel.2019.03.028
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Lipid-conjugated small-interfering RNAs (siRNAs) exhibit accumulation and gene silencing in extrahepatic tissues, providing an opportunity to expand therapeutic siRNA utility beyond the liver. Chemically engineering lipids may further improve siRNA delivery and efficacy, but the relationship between lipid structure/configuration and siRNA pharmacodynamics is unclear. Here, we synthesized a panel of mono-, di-, and tri-meric fatty acid-conjugated siRNAs to systematically evaluate the impact of fatty acid structure and valency on siRNA clearance, distribution, and efficacy. Fatty acid valency significantly altered the physicochemical properties of conjugated siRNAs, including hydrophobicity and micelle formation, which affected distribution. Trivalent lipid-conjugated siRNAs were predominantly retained at the site of injection with minimal systemic exposure, whereas monovalent lipid-conjugated siRNAs were quickly released into the circulation and accumulated primarily in kidney. Divalent lipid-conjugated siRNAs showed intermediate behavior, and preferentially accumulated in liver with functional distribution to lung, heart, and fat. The chemical structure of the conjugate, rather than overall physicochemical properties (i.e. hydrophobicity), predicted the degree of extrahepatic tissue accumulation necessary for productive gene silencing. Our findings will inform chemical engineering strategies for enhancing the extrahepatic delivery of lipophilic siRNAs.
引用
收藏
页码:116 / 125
页数:10
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