2. Academic Validation
  3. Improvement of DNA Vector Delivery of DOTAP Lipoplexes by Short-Chain Aminolipids

Improvement of DNA Vector Delivery of DOTAP Lipoplexes by Short-Chain Aminolipids

  • ACS Omega. 2020 Sep 15;5(38):24724-24732. doi: 10.1021/acsomega.0c03303.
Jonas Buck 1,  Dennis Mueller 2,  Ute Mettal 2 3,  Miriam Ackermann 2,  Hiu Man Grisch-Chan 4,  Beat Thöny 4,  Andreas Zumbuehl 2 5,  Jörg Huwyler 1,  Dominik Witzigmann 1 6
Affiliations

Affiliations

  • 1 Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
  • 2 Department of Chemistry, University of Fribourg, 1700 Fribourg, Switzerland.
  • 3 Department of Bioresources of the Fraunhofer Institute for Molecular Biology and Applied Ecology, Institute for Insect Biotechnology, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
  • 4 Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, 8032 Zürich, Switzerland.
  • 5 Acthera Therapeutics Ltd., Peter Merian-Strasse 45, 4052 Basel, Switzerland.
  • 6 Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
PMID: 33015490 DOI: 10.1021/acsomega.0c03303
Abstract

Cellular delivery of DNA vectors for the expression of therapeutic proteins is a promising approach to treat monogenic disorders or Cancer. Significant efforts in a preclinical and clinical setting have been made to develop potent nonviral gene delivery systems based on lipoplexes composed of permanently Cationic Lipids. However, transfection efficiency and tolerability of such systems are in most cases not satisfactory. Here, we present a one-pot combinatorial method based on double-reductive amination for the synthesis of short-chain aminolipids. These lipids can be used to maximize the DNA vector delivery when combined with the cationic lipid 1,2-dioleoyl-3-trimethylammonium propane (DOTAP). We incorporated various aminolipids into such lipoplexes to complex minicircle DNA and screened these systems in a human liver-derived cell line (HuH7) for gene expression and cytotoxicity. The lead aminolipid AL-A12 showed twofold enhanced gene delivery and reduced toxicity compared to the native DOTAP:cholesterol lipoplexes. Moreover, AL-A12-containing lipoplexes enabled enhanced transgene expression in vivo in the zebrafish embryo model.

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  • HY-166997
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