Octa-arginine boosts the penetration of elastin-like polypeptide nanoparticles in 3D cancer models

Lisanne M.P.E. van Oppen, Jan Pille, Christiaan Stuut, Marleen van Stevendaal, Lisa N. van der Vorm, Jan A.M. Smeitink, Werner J.H. Koopman, Peter H.G.M. Willems, Jan C.M. van Hest, Roland Brock (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

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Elastin-like polypeptide (ELP) nanoparticles are a versatile platform for targeted drug delivery. As for any type of nanocarrier system, an important challenge remains the ability of deep (tumor) tissue penetration. In this study, ELP particles with controlled surface density of the cell-penetrating peptide (CPP) octa-arginine (R8) were created by temperature-induced co-assembly. ELPs formed micellar nanoparticles with a diameter of around 60 nm. Cellular uptake in human skin fibroblasts was directly dependent on the surface density of R8 as confirmed by flow cytometry and confocal laser scanning microscopy. Remarkably, next to promoting cellular uptake, the presence of the CPP also enhanced penetration into spheroids generated from human glioblastoma U-87 cells. After 24 h, uptake into cells was observed in multiple layers towards the spheroid core. ELP particles not carrying any CPP did not penetrate. Clearly, a high CPP density exerted a dual benefit on cellular uptake and tissue penetration. At low nanoparticle concentration, there was evidence of a binding site barrier as observed for the penetration of molecules binding with high affinity to cell surface receptors. In conclusion, R8-functionalized ELP nanoparticles form an excellent delivery vehicle that combines tunability of surface characteristics with small and well-defined size.

Original languageEnglish
Pages (from-to)175-184
Number of pages10
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Publication statusPublished - 1 Apr 2019


  • Binding site barrier
  • Elastin-like polypeptide nanoparticles
  • Octa-arginine
  • Penetration
  • Spheroid
  • Humans
  • Microscopy, Confocal/methods
  • Oligopeptides/chemistry
  • Elastin/chemistry
  • Drug Delivery Systems
  • Nanoparticles
  • Cell-Penetrating Peptides/chemistry
  • Flow Cytometry
  • Spheroids, Cellular/metabolism
  • Time Factors
  • Cell Line, Tumor
  • Chemistry, Pharmaceutical/methods
  • Binding Sites
  • Glioblastoma/metabolism


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