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  2. Effect of Cholesterol Content of Lipid Composition in mRNA-LNPs on the Protein Expression in the Injected Site and Liver after Local Administration in Mice

Effect of Cholesterol Content of Lipid Composition in mRNA-LNPs on the Protein Expression in the Injected Site and Liver after Local Administration in Mice

  • J Pharm Sci. 2022 Dec 31;S0022-3549(22)00617-7. doi: 10.1016/j.xphs.2022.12.026.
Maho Kawaguchi 1 Marin Noda 1 Akari Ono 2 Mariko Kamiya 1 Makoto Matsumoto 2 Masako Tsurumaru 3 Shusaku Mizukami 4 Hidefumi Mukai 1 Shigeru Kawakami 5
Affiliations

Affiliations

  • 1 Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki-shi, Nagasaki 852-8588, Japan.
  • 2 Under Graduate School of Pharmaceutical Sciences, Nagasaki University, 1-14 Bunkyo, Nagasaki-shi, Nagasaki 852-8521, Japan.
  • 3 Department of Hospital Pharmacy, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki-shi, Nagasaki 852-8501, Japan.
  • 4 Department of Immune Regulation, Shionogi Global Infectious Diseases Division, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki-shi, Nagasaki 852-8523, Japan.
  • 5 Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki-shi, Nagasaki 852-8588, Japan. Electronic address: skawakam@nagasaki-u.ac.jp.
Abstract

Delivery of messenger RNA (mRNA) by using lipid nanoparticles (LNPs) is expected to be applied to various diseases after the successful clinical use of the mRNA COVID-19 vaccines. This study aimed to evaluate the effect of the Cholesterol molar percentage of mRNA-LNPs on protein expression in hepatocellular carcinoma-derived cells and in the liver after intramuscular or subcutaneous administration of mRNA-LNPs in mice. For mRNA-LNPs with Cholesterol molar percentages reduced to 10 mol% and 20 mol%, we formulated neutral charge particles of approximately 100 nm diameter and polydispersity index (PDI) < 0.25. After the intramuscular or subcutaneous administration of mRNA-LNPs with different Cholesterol molar percentages in mice, protein expression in the liver decreased as the Cholesterol molar percentage in mRNA-LNPs decreased from 40 mol% to 20 mol% and 10 mol%, suggesting that reducing the Cholesterol molar percentage in mRNA-LNPs decreases protein expression in the liver. Furthermore, in HepG2 cells, protein expression decreased as Cholesterol in mRNA-LNPs was reduced by 40 mol%, 20 mol%, and 10 mol%. These results suggest that the downregulated expression of mRNA-LNPs with low Cholesterol content in the liver involves degradation in systemic circulating blood and decreased protein expression after hepatocyte distribution.

Keywords

Drug delivery systems; Lipid nanoparticles (LNPs); Messenger ribonucleic acid (mRNA), Intramuscular administration.

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