Anti-tumor activity of nanomicelles encapsulating CXCR4 peptide antagonist E5

PLoS One. 2017 Aug 9;12(8):e0182697. doi: 10.1371/journal.pone.0182697. eCollection 2017.

Abstract

Cancer is the leading cause of death worldwide, and metastasis is the main attribute to cancer death. CXCR4 and its natural ligand CXCL12 have been known to play a critical role in tumorigenesis, angiogenesis and metastasis. Therefore, designing a new CXCR4 antagonist to prevent tumor metastasis will be of great significance. Herein, a novel chemically synthesized peptide (E5) that has an ability to target CXCR4/CXCL12 axis was loaded in micelle glycol-phosphatidylethanolamine (PEG-PE) block copolymer to form micelle-encapsulated E5 (M-E5). We demonstrated that M-E5 exhibited higher affinity for CXCR4-overexpressing MCF-7 and HepG2 tumor cells as compared to free E5, and efficiently inhibited the tumor cells migration. Mechanistic studies implied that PEG-PE micelle can encapsulate E5 and improve E5 targeting efficiency for CXCR4 by accumulating E5 on the tumor cell membrane. Furthermore, through encapsulation of chemotherapeutic drug doxorubicin (Dox) in PEG-PE micelle, we proved that PEG-PE micelle could serve as a co-carrier for both E5 and Dox (M-E5-Dox). M-E5 enhanced the efficiency of Dox by down-regulating the phosphorylation level of Akt, Erk and p38/MAPK proteins. In conclusion, PEG-PE micelle demonstrated a promising delivery system for E5, and M-E5 is expected to be a potential therapeutic agent that will help to improve the clinical benefits in current therapies used for solid tumors.

MeSH terms

  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / therapeutic use
  • Blotting, Western
  • Doxorubicin / administration & dosage
  • Doxorubicin / therapeutic use
  • Drug Carriers*
  • Hep G2 Cells
  • Humans
  • MCF-7 Cells
  • Micelles*
  • Nanocapsules*
  • Peptides / administration & dosage*
  • Peptides / therapeutic use
  • Phosphatidylethanolamines
  • Polyethylene Glycols
  • Real-Time Polymerase Chain Reaction
  • Receptors, CXCR4 / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • CXCR4 protein, human
  • Drug Carriers
  • E5 CXCR4-targeting peptide
  • Micelles
  • Nanocapsules
  • Peptides
  • Phosphatidylethanolamines
  • Receptors, CXCR4
  • dioleoyl-N-(monomethoxypolyethylene glycol succinyl)phosphatidylethanolamine
  • Polyethylene Glycols
  • Doxorubicin

Grants and funding

This work was financially supported by the Strategic Priority Research Program of Chinese Academy of Sciences (Grant No. XDA09030306, recipient:Y.Y., and XDA09040300, recipient:C.W.) and the Chinese Postdoctoral Science Foundation (Y6791Z11GJ, recipient:X.F.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.