Cell penetrating peptides improve tumor delivery of cargos through neuropilin-1-dependent extravasation

J Control Release. 2015 Mar 10;201:14-21. doi: 10.1016/j.jconrel.2015.01.011. Epub 2015 Jan 13.

Abstract

Cell-penetrating peptides (CPPs), also referred to as protein transduction domains (PTDs), can mediate the cellular uptake of a wide range of macromolecules including peptides, proteins, oligonucleotides, and nanoparticles, and thus have received considerable attention as a promising method for drug delivery in vivo. Here, we report that CPP/PTDs facilitate the extravasation of fused proteins by binding to neuropilin-1 (NRP1), a vascular endothelial growth factor (VEGF) co-receptor expressed on the surface of endothelial and some tumor cells. In this study, we examined the capacity of the amphipathic and cationic CPP/PTDs, PTD-3 and TAT-PTD, respectively, to bind cells in vitro and accumulate in xenograft tumors in vivo. Notably, these functions were significantly suppressed by pre-treatment with NRP1-neutralizing Ab. Furthermore, co-injection of iRGD, a cyclic peptide known to increase NRP1-dependent vascular permeability, significantly reduced CPP/PTD tumor delivery. This data demonstrates a mechanism by which NRP1 promotes the extravasation of CPP/PTDs that may open new avenues for the development of more efficient CPP/PTD delivery systems.

Keywords: Cell penetrating peptide; Drug delivery; Extravasation; Neuropilin-1; Protein transduction domain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell-Penetrating Peptides / administration & dosage*
  • Cell-Penetrating Peptides / chemistry
  • Drug Delivery Systems
  • Gene Products, tat / administration & dosage
  • Gene Products, tat / chemistry
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Neoplasms / metabolism*
  • Neuropilin-1 / metabolism*
  • Oligopeptides / administration & dosage
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / chemistry

Substances

  • Cell-Penetrating Peptides
  • Gene Products, tat
  • N-end cysteine peptide tumor-homing peptide
  • Oligopeptides
  • Recombinant Fusion Proteins
  • Neuropilin-1