Rational Design of Cationic Lipids for SiRNA Delivery

Overview

Journal Nat Biotechnol

Specialty Biotechnology

Date 2010 Jan 19

PMID 20081866

Citations 626

Authors

Sean C Semple

Akin Akinc

Jianxin Chen

Ammen P Sandhu

Barbara L Mui

Connie K Cho

Dinah W Y Sah

Derrick Stebbing

Erin J Crosley

Ed Yaworski

Ismail M Hafez

J Robert Dorkin

June Qin

Kieu Lam

Kallanthottathil G Rajeev

Kim F Wong

Lloyd B Jeffs

Lubomir Nechev

Merete L Eisenhardt

Muthusamy Jayaraman

Mikameh Kazem

Martin A Maier

Masuna Srinivasulu

Michael J Weinstein

Qingmin Chen

Rene Alvarez

Scott A Barros

Soma De

Sandra K Klimuk

Todd Borland

Verbena Kosovrasti

William L Cantley

Ying K Tam

Muthiah Manoharan

Marco A Ciufolini

Mark A Tracy

Antonin De Fougerolles

Ian MacLachlan

Pieter R Cullis

Thomas D Madden

Michael J Hope

Affiliations

Soon will be listed here.

Abstract

We adopted a rational approach to design cationic lipids for use in formulations to deliver small interfering RNA (siRNA). Starting with the ionizable cationic lipid 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA), a key lipid component of stable nucleic acid lipid particles (SNALP) as a benchmark, we used the proposed in vivo mechanism of action of ionizable cationic lipids to guide the design of DLinDMA-based lipids with superior delivery capacity. The best-performing lipid recovered after screening (DLin-KC2-DMA) was formulated and characterized in SNALP and demonstrated to have in vivo activity at siRNA doses as low as 0.01 mg/kg in rodents and 0.1 mg/kg in nonhuman primates. To our knowledge, this represents a substantial improvement over previous reports of in vivo endogenous hepatic gene silencing.

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