Recruiting Potent Membrane Penetrability in Tumor Cell-Targeted Protein-Only Nanoparticles

Nanotechnology. 2019 Mar 15;30(11):115101. doi: 10.1088/1361-6528/aaf959. Epub 2018 Dec 18.

Abstract

The membrane pore-forming activities of the antimicrobial peptide GWH1 have been evaluated in combination with the CXCR4-binding properties of the peptide T22, in self-assembling protein nanoparticles with high clinical potential. The resulting materials, of 25 nm in size and with regular morphologies, show a dramatically improved cell penetrability into CXCR4+ cells (more than 10-fold) and enhanced endosomal escape (the lysosomal degradation dropping from 90% to 50%), when compared with equivalent protein nanoparticles lacking GWH1. These data reveal that GWH1 retains its potent membrane activity in form of nanostructured protein complexes. On the other hand, the specificity of T22 in the CXCR4 receptor binding is subsequently minimized but, unexpectedly, not abolished by the presence of the antimicrobial peptide. The functional combination T22-GWH1 results in 30% of the nanoparticles entering cells via CXCR4 while also exploiting pore-based uptake. Such functional materials are capable to selectively deliver highly potent cytotoxic drugs upon chemical conjugation, promoting CXCR4-dependent cell death. These data support the further development of GWH1-empowered cell-targeted proteins as nanoscale drug carriers for precision medicines. This is a very promising approach to overcome lysosomal degradation of protein nanostructured materials with therapeutic value.

MeSH terms

  • Anti-Infective Agents / chemical synthesis
  • Anti-Infective Agents / chemistry*
  • Anti-Infective Agents / pharmacology
  • Antimicrobial Cationic Peptides / chemistry*
  • Antimicrobial Cationic Peptides / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Carriers / chemistry*
  • Drug Delivery Systems
  • Endocytosis
  • Endosomes / metabolism
  • Humans
  • Nanoparticles / chemistry*
  • Nanoparticles / ultrastructure
  • Peptides / chemistry*
  • Peptides / metabolism
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Receptors, CXCR4 / metabolism

Substances

  • Anti-Infective Agents
  • Antimicrobial Cationic Peptides
  • Drug Carriers
  • Peptides
  • Receptors, CXCR4
  • T22 peptide