Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity

Kathryn A. Whitehead, J. Robert Dorkin, Arturo J. Vegas, Philip H. Chang, Omid Veiseh, Jonathan Matthews, Owen S. Fenton, Yunlong Zhang, Karsten T. Olejnik, Volkan Yesilyurt, Delai Chen, Scott Barros, Boris Klebanov, Tatiana Novobrantseva, Robert Langer and Daniel G. Anderson ()
Additional contact information
Kathryn A. Whitehead: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
J. Robert Dorkin: Massachusetts Institute of Technology
Arturo J. Vegas: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Philip H. Chang: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Omid Veiseh: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Jonathan Matthews: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Owen S. Fenton: Massachusetts Institute of Technology
Yunlong Zhang: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Karsten T. Olejnik: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Volkan Yesilyurt: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Delai Chen: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Scott Barros: Alnylam Pharmaceuticals
Boris Klebanov: Alnylam Pharmaceuticals
Tatiana Novobrantseva: Alnylam Pharmaceuticals
Robert Langer: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Daniel G. Anderson: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: Abstract One of the most significant challenges in the development of clinically viable delivery systems for RNA interference therapeutics is to understand how molecular structures influence delivery efficacy. Here, we have synthesized 1,400 degradable lipidoids and evaluate their transfection ability and structure–function activity. We show that lipidoid nanoparticles mediate potent gene knockdown in hepatocytes and immune cell populations on IV administration to mice (siRNA EC50 values as low as 0.01 mg kg−1). We identify four necessary and sufficient structural and pKa criteria that robustly predict the ability of nanoparticles to mediate greater than 95% protein silencing in vivo. Because these efficacy criteria can be dictated through chemical design, this discovery could eliminate our dependence on time-consuming and expensive cell culture assays and animal testing. Herein, we identify promising degradable lipidoids and describe new design criteria that reliably predict in vivo siRNA delivery efficacy without any prior biological testing.

Date: 2014
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DOI: 10.1038/ncomms5277

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