Delivery of Oligonucleotides Using a Self-Degradable Lipid-Like Material
Hiroki Tanaka,
Nae Takata,
Yu Sakurai,
Tokuyuki Yoshida,
Takao Inoue,
Shinya Tamagawa,
Yuta Nakai,
Kota Tange,
Hiroki Yoshioka,
Masatoshi Maeki,
Manabu Tokeshi,
Hidetaka Akita
Affiliations
Hiroki Tanaka
Laboratory of DDS Design and Drug Disposition, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-0856, Japan
Nae Takata
Laboratory of DDS Design and Drug Disposition, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-0856, Japan
Yu Sakurai
Laboratory of DDS Design and Drug Disposition, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-0856, Japan
Tokuyuki Yoshida
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan
Takao Inoue
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan
Shinya Tamagawa
DDS Research Laboratory, NOF CORPORATION, 3-3 Chidori-cho, Kawasaki-ku, Kawasaki City, Kanagawa 210-0865, Japan
Yuta Nakai
DDS Research Laboratory, NOF CORPORATION, 3-3 Chidori-cho, Kawasaki-ku, Kawasaki City, Kanagawa 210-0865, Japan
Kota Tange
DDS Research Laboratory, NOF CORPORATION, 3-3 Chidori-cho, Kawasaki-ku, Kawasaki City, Kanagawa 210-0865, Japan
Hiroki Yoshioka
DDS Research Laboratory, NOF CORPORATION, 3-3 Chidori-cho, Kawasaki-ku, Kawasaki City, Kanagawa 210-0865, Japan
Masatoshi Maeki
Division of Applied Chemistry, Faculty of Engineering, Hokkaido University, Kita 13, Nishi 8, Kita-ku, Sapporo, Hokkaido 060-8628, Japan
Manabu Tokeshi
Division of Applied Chemistry, Faculty of Engineering, Hokkaido University, Kita 13, Nishi 8, Kita-ku, Sapporo, Hokkaido 060-8628, Japan
Hidetaka Akita
Laboratory of DDS Design and Drug Disposition, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-0856, Japan
The world-first success of lipid nanoparticle (LNP)-based siRNA therapeutics (ONPATTRO®) promises to accelerate developments in siRNA therapeutics/gene therapy using LNP-type drug delivery systems (DDS). In this study, we explore the optimal composition of an LNP containing a self-degradable material (ssPalmO-Phe) for the delivery of oligonucleotides. siRNA or antisense oligonucleotides (ASO) were encapsulated in LNP with different lipid compositions. The hepatic knockdown efficiency of the target genes and liver toxicity were evaluated. The optimal compositions for the siRNA were different from those for ASO, and different from those for mRNA that were reported in a previous study. Extracellular stability, endosomal escape and cellular uptake appear to be the key processes for the successful delivery of mRNA, siRNA and ASO, respectively. Moreover, the compositions of the LNPs likely contribute to their toxicity. The lipid composition of the LNP needs to be optimized depending on the type of nucleic acids under consideration if the applications of LNPs are to be further expanded.
