Details

Autor(en) / Beteiligte

• Semple, Sean C
• Akinc, Akin
• Chen, Jianxin
• Sandhu, Ammen P
• Mui, Barbara L
• Cho, Connie K
• Sah, Dinah W Y
• Stebbing, Derrick
• Crosley, Erin J
• Yaworski, Ed
• Hafez, Ismail M
• Dorkin, J Robert
• Qin, June
• Lam, Kieu
• Rajeev, Kallanthottathil G
• Wong, Kim F
• Jeffs, Lloyd B
• Nechev, Lubomir
• Eisenhardt, Merete L
• Jayaraman, Muthusamy
• Kazem, Mikameh
• Maier, Martin A
• Srinivasulu, Masuna
• Weinstein, Michael J
• Chen, Qingmin
• Alvarez, Rene
• Barros, Scott A
• De, Soma
• Klimuk, Sandra K
• Borland, Todd
• Kosovrasti, Verbena
• Cantley, William L
• Tam, Ying K
• Manoharan, Muthiah
• Ciufolini, Marco A
• Tracy, Mark A
• de Fougerolles, Antonin
• MacLachlan, Ian
• Cullis, Pieter R
• Madden, Thomas D
• Hope, Michael J

Titel

Rational design of cationic lipids for siRNA delivery

Ist Teil von

• Nature biotechnology, 2010-02, Vol.28 (2), p.172-176

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2010

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.