Circumventing Drug Treatment? Intrinsic Lethal Effects of Polyethyleneimine (PEI)-Functionalized Nanoparticles on Glioblastoma Cells Cultured in Stem Cell Conditions

Neeraj Prabhakar, Joni Merisaari, Vadim Le Joncour, Markus Peurla, Didem Şen Karaman, Eudald Casals, Pirjo Laakkonen, Jukka Westermarck, Jessica M. Rosenholm

Research output: Contribution to journalArticleScientificpeer-review

1 Citation (Scopus)

Abstract

Glioblastoma (GB) is the most frequent malignant tumor originating from the central nervous system. Despite breakthroughs in treatment modalities for other cancer types, GB remains largely irremediable due to the high degree of intratumoral heterogeneity, infiltrative growth, and intrinsic resistance towards multiple treatments. A sub-population of GB cells, glioblastoma stem cells (GSCs), act as a reservoir of cancer-initiating cells and consequently, constitute a significant challenge for successful therapy. In this study, we discovered that PEI surface-functionalized mesoporous silica nanoparticles (PEI-MSNs), without any anti-cancer drug, very potently kill multiple GSC lines cultured in stem cell conditions. Very importantly, PEI-MSNs did not affect the survival of established GB cells, nor other types of cancer cells cultured in serum-containing medium, even at 25 times higher doses. PEI-MSNs did not induce any signs of apoptosis or autophagy. Instead, as a potential explanation for their lethality under stem cell culture conditions, we demonstrate that the internalized PEI-MSNs accumulated inside lysosomes, subsequently causing a rupture of the lysosomal membranes. We also demonstrate blood–brain-barrier (BBB) permeability of the PEI-MSNs in vitro and in vivo. Taking together the recent indications for the vulnerability of GSCs for lysosomal targeting and the lethality of the PEI-MSNs on GSCs cultured under stem cell culture conditions, the results enforce in vivo testing of the therapeutic impact of PEI-functionalized nanoparticles in faithful preclinical GB models.
Original languageEnglish
Article number2631
JournalCancers
Volume13
Issue number11
DOIs
Publication statusPublished - 27 May 2021
MoE publication typeA1 Journal article-refereed

Keywords

  • glioblastoma multiforme
  • brain cancer
  • therapy resistance
  • mesoporous silica nanoparticles
  • polyethyleneimine (PEI)
  • proton-sponge effect

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