Cellular Internalization and Inhibition Capacity of New Anti-Glioma Peptide Conjugates: Physicochemical Characterization and Evaluation on Various Monolayer- and 3D-Spheroid-Based in Vitro Platforms

J Med Chem. 2021 Mar 25;64(6):2982-3005. doi: 10.1021/acs.jmedchem.0c01399. Epub 2021 Mar 15.


Most therapeutic agents used for treating brain malignancies face hindered transport through the blood-brain barrier (BBB) and poor tissue penetration. To overcome these problems, we developed peptide conjugates of conventional and experimental anticancer agents. SynB3 cell-penetrating peptide derivatives were applied that can cross the BBB. Tuftsin derivatives were used to target the neuropilin-1 transport system for selectivity and better tumor penetration. Moreover, SynB3-tuftsin tandem compounds were synthesized to combine the beneficial properties of these peptides. Most of the conjugates showed high and selective efficacy against glioblastoma cells. SynB3 and tandem derivatives demonstrated superior cellular internalization. The penetration profile of the conjugates was determined on a lipid monolayer and Transwell co-culture system with noncontact HUVEC-U87 monolayers as simple ex vivo and in vitro BBB models. Importantly, in 3D spheroids, daunomycin-peptide conjugates possessed a better tumor penetration ability than daunomycin. These conjugates are promising tools for the delivery systems with tunable features.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology
  • Blood-Brain Barrier / metabolism*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell-Penetrating Peptides / chemistry
  • Cell-Penetrating Peptides / pharmacokinetics*
  • Cell-Penetrating Peptides / pharmacology
  • Drug Carriers / chemistry
  • Drug Carriers / pharmacokinetics
  • Drug Carriers / pharmacology
  • Drug Delivery Systems
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Neuropilin-1 / metabolism
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacokinetics*
  • Oligopeptides / pharmacology
  • Rats
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / metabolism
  • Tuftsin / analogs & derivatives
  • Tuftsin / pharmacokinetics*
  • Tuftsin / pharmacology
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Cell-Penetrating Peptides
  • Drug Carriers
  • Oligopeptides
  • SynB3 peptide
  • Neuropilin-1
  • Tuftsin