Development of Cationic Quaternary Ammonium Sulfonamide Amino Lipids for Nucleic Acid Delivery

Jason B. Miller, Petra Kos, Victor Tieu, Kejin Zhou, Daniel J. Siegwart

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Lipid nanoparticles (LNPs) currently comprise the most effective carrier class for the delivery of small RNAs. Among lipid carriers, charge-unbalanced lipids are relatively unexplored synthetically. Herein, we developed and evaluated a novel collection of compounds for small interfering RNA (siRNA) delivery, termed cationic quaternary ammonium sulfonamide amino lipids (CSALs). The formulated CSAL LNPs containing cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine, and lipid poly(ethylene glycol) exhibited biophysical property trends directly related to the CSAL chemical structure. Lead CSAL LNPs were identified using an siRNA delivery screen. Further chemical synthesis using a rational structure-guided design showed that the head group structure could alter the pKa and other physical properties that modulated delivery efficacy. Shorter-chained dimethylamino head groups, acetate side chains, and higher tail carbon numbers were favorable for delivery. This led to a further study of A3-OAc-C2Me LNPs, which enabled in vivo delivery to normal mouse lungs and subcutaneous and orthotopic lung tumors. Incorporation of CSALs into liver-targeting formulations shifted the in vivo delivery of these carriers to the lungs. This study highlights the importance of the cationic lipid structure in LNPs and provides further design guidelines for nucleic acid carriers.

Original languageEnglish (US)
Pages (from-to)2302-2311
Number of pages10
JournalACS Applied Materials and Interfaces
Volume10
Issue number3
DOIs
Publication statusPublished - Jan 24 2018

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Keywords

  • cancer
  • lipid nanoparticles
  • lipid synthesis
  • lung delivery
  • siRNA

ASJC Scopus subject areas

  • Materials Science(all)

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