Efficient siRNA Delivery by Lipid Nanoparticles Modified with a Nonstandard Macrocyclic Peptide for EpCAM-Targeting

DOI Web Site PubMed 被引用文献8件 参考文献40件
  • Yu Sakurai
    Faculty of Pharmaceutical Sciences, Hokkaido University, Hokkaido 060-0812, Japan
  • Wataru Mizumura
    Faculty of Pharmaceutical Sciences, Hokkaido University, Hokkaido 060-0812, Japan
  • Manami Murata
    Faculty of Pharmaceutical Sciences, Hokkaido University, Hokkaido 060-0812, Japan
  • Tomoya Hada
    Faculty of Pharmaceutical Sciences, Hokkaido University, Hokkaido 060-0812, Japan
  • Shoshiro Yamamoto
    Faculty of Pharmaceutical Sciences, Hokkaido University, Hokkaido 060-0812, Japan
  • Kenichiro Ito
    Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-0033, Japan
  • Kazuhiro Iwasaki
    Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8656, Japan
  • Takayuki Katoh
    Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-0033, Japan
  • Yuki Goto
    Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-0033, Japan
  • Asako Takagi
    Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
  • Michinori Kohara
    Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
  • Hiroaki Suga
    Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-0033, Japan
  • Hideyoshi Harashima
    Faculty of Pharmaceutical Sciences, Hokkaido University, Hokkaido 060-0812, Japan

書誌事項

公開日
2017-08-25
資源種別
journal article
DOI
  • 10.1021/acs.molpharmaceut.7b00362
公開者
American Chemical Society (ACS)

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説明

The development of a specific, effective method for the delivery of therapeutics including small molecules and nucleic acids to tumor tissue remains to be solved. Numerous types of lipid nanoparticles (LNPs) have been developed in attempts to achieve this goal. However, LNPs are probably not taken up by target cells because cancer-targeting LNPs are typically modified with poly(ethylene glycol) (PEG), which inhibits the cellular uptake of LNPs, to passively accumulate in tumor tissue via the enhanced permeability and retention (EPR) effect. It would clearly be important to develop a LNP with both a prolonged circulation and cancer-specific efficient uptake for use in an innovative nanodrug delivery system. Herein, we assessed the effect of nonstandard macrocyclic peptides against the epithelial cell adhesion molecule (EpCAM) Epi-1, which was discovered by a random nonstandard peptides integrated discovery (RaPID) system, on the cellular uptake and therapeutics delivery of LNPs. A liposomal siRNA delivery system (MEND) was modified with an Epi-1 lipid-derivative (EpCAM-targeting MEND; ET-MEND). The resulting ET-MEND showed a more than 27-fold increase in cellular uptake in EpCAM-positive cell lines. In the case of negative cells, cellular uptake and the efficiency of the ET-MEND for delivering therapeutics were comparable with those of nonmodified MEND. In addition, when systemically injected, the ET-MEND successfully inhibited gene expression in the tumor tissue at a dose of 0.5 mg siRNA/kg without any obvious toxicity. These results suggest that a combination of a specific peptide ligand can be used to identify a RaPID system and that the use of such a MEND for liposomal drug delivery has the potential for use in developing a system for the efficacious delivery of pharmaceuticals to various cancer cells.

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