Rational design of cationic lipids for siRNA delivery View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2010-02

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

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. More... »

PAGES

172

Journal

TITLE

Nature Biotechnology

ISSUE

2

VOLUME

28

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nbt.1602

    DOI

    http://dx.doi.org/10.1038/nbt.1602

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1051671503

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/20081866


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