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

Mol Pharm. 2017 Oct 2;14(10):3290-3298. doi: 10.1021/acs.molpharmaceut.7b00362. Epub 2017 Aug 25.


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.

Keywords: active targeting; cancer; liposome; nonstandard macrocyclic peptide; siRNA delivery.

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides
  • Cell Line, Tumor
  • Drug Delivery Systems*
  • Epithelial Cell Adhesion Molecule / genetics*
  • Epithelial Cell Adhesion Molecule / metabolism
  • Fish Proteins
  • Gene Knockdown Techniques
  • Humans
  • Lipids / chemistry
  • Liposomes
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred ICR
  • Nanoparticles / chemistry
  • Particle Size
  • Polyethylene Glycols / chemistry
  • RNA, Small Interfering / pharmacology*
  • Tissue Distribution
  • Xenograft Model Antitumor Assays


  • Antimicrobial Cationic Peptides
  • EPCAM protein, human
  • Epithelial Cell Adhesion Molecule
  • Fish Proteins
  • Lipids
  • Liposomes
  • RNA, Small Interfering
  • epinecidin-1, Epinephelus coioides
  • Polyethylene Glycols