Synthesis of high functionality and quality mannose-grafted lipids to produce macrophage-targeted liposomes

Eur J Pharm Sci. 2018 Oct 15:123:153-161. doi: 10.1016/j.ejps.2018.07.036. Epub 2018 Jul 18.

Abstract

The mannose receptor, which is responsible for tumor invasion, proliferation, and metastasis in the tumor microenvironment, is overexpressed in tumor-associated macrophages. Mannose is commonly applied to PEGylated liposomes in macrophage-targeted cancer therapy. To develop a high functionality and quality (HFQ) lipid for macrophage-targeted liposomes, we designed a novel mannosylated lipid with improved mannose receptor binding affinity using serine-glycine repeats (SG)n. We synthesized Man(S)-(SG)5-SSK-K(Pal)2 using only a fluorenylmethyloxycarbonyl (Fmoc) protecting group solid-phase peptide synthesis method, which produced a high-quality lipid at a moderately good yield. We then prepared Man-(SG)5/PEGylated liposomes using a post-insertion technique to insert Man(S)-(SG)5-SSK-K(Pal)2 into the PEGylated liposomes. In vitro cell investigations revealed that the Man-(SG)5/PEGylated liposomes effectively associated with mouse peritoneal macrophages by interacting with the mannose receptors. The results suggest that we produced a novel high-quality, highly functional mannosylated lipid that is suitable for clinical drug delivery applications.

Keywords: Lipid; Liposome; Macrophage; Mannose; Serine–glycine repeat spacer.

MeSH terms

  • Animals
  • Drug Delivery Systems
  • Lectins, C-Type / metabolism
  • Lipids* / chemical synthesis
  • Lipids* / chemistry
  • Liposomes* / chemistry
  • Liposomes* / metabolism
  • Macrophages* / metabolism
  • Male
  • Mannose Receptor
  • Mannose*
  • Mannose-Binding Lectins / metabolism
  • Mice, Inbred ICR
  • Organ Specificity
  • Receptors, Cell Surface / metabolism
  • Solid-Phase Synthesis Techniques

Substances

  • Lectins, C-Type
  • Lipids
  • Liposomes
  • Mannose Receptor
  • Mannose-Binding Lectins
  • Receptors, Cell Surface
  • Mannose