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

Abstract

Glioblastoma (GB) is the most frequent malignant tumor originating from the centralnervous system. Despite breakthroughs in treatment modalities for other cancer types, GB remainslargely irremediable due to the high degree of intratumoral heterogeneity, infiltrative growth, andintrinsic 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 challengefor successful therapy. In this study, we discovered that PEI surface-functionalized mesoporoussilica nanoparticles (PEI-MSNs), without any anti-cancer drug, very potently kill multiple GSClines cultured in stem cell conditions. Very importantly, PEI-MSNs did not affect the survival ofestablished GB cells, nor other types of cancer cells cultured in serum-containing medium, even at25 times higher doses. PEI-MSNs did not induce any signs of apoptosis or autophagy. Instead, asa potential explanation for their lethality under stem cell culture conditions, we demonstrate thatthe internalized PEI-MSNs accumulated inside lysosomes, subsequently causing a rupture of thelysosomal membranes. We also demonstrate blood–brain-barrier (BBB) permeability of the PEI-MSNs in vitroandin vivo. Taking together the recent indications for the vulnerability of GSCs for lysosomaltargeting and the lethality of the PEI-MSNs on GSCs cultured under stem cell culture conditions,the results enforcein vivotesting of the therapeutic impact of PEI-functionalized nanoparticles infaithful preclinical GB models.