The difficulty involved in the treatment of many tumours due to their recurrence and resistance to chemotherapy is tightly linked to the presence of cancer stem cells (CSCs). This CSC sub-population is distinct from the majority of cancer cells of the tumour bulk. Indeed, CSCs have increased mitochondrial mass that has been linked to increased sensitivity to mitochondrial targeting compounds. Thus, a platinum-based polyethylenimine (PEI) polymer–drug conjugate (PDC) was assessed as a potential anti-CSC therapeutic since it has previously displayed mitochondrial accumulation. Our results show that CSCs have increased specific sensitivity to the PEI carrier and to the PDC. The mechanism of cell death seems to be necrotic in nature, with an absence of apoptotic markers. Cell death is accompanied by the induction of a protective autophagy. The interference in the balance of this pathway, which is highly important for CSCs, may be responsible for a partial reversion of the stem-like phenotype observed with prolonged PEI and PDC treatment. Several markers also indicate the cell death mode to be capable of inducing an anti-cancer immune response. This study thus indicates the potential therapeutic perspectives of polycations against CSCs.

Cationic polymers such as polyethylenimine (PEI) have found a pervasive place in laboratories across the world as gene delivery agents. However, their applications are not limited to this role, having found a place as delivery agents for drugs, in complexes known as polymer-drug conjugates (PDCs). Yet a potentially underexplored domain of research is in their inherent potential as anti-cancer therapeutic agents, which has been indicated by several studies. Even more interesting is the recent observation that certain polycations may present a significantly greater toxicity towards the clinically important cancer stem cell (CSC) niche than towards more differentiated bulk tumour cells. These cells, which possess the stem-like characteristics of self-renewal and differentiation, are highly implicated in cancer drug resistance, tumour recurrence and poor clinical prognosis. The search for compounds which may target and eliminate these cells is thus of great research interest. As such, the observation in our previous study on a PEI-based PDC which showed a considerably higher toxicity of PEI towards glioblastoma CSCs (GSCs) than on more differentiated glioma (U87) cells led us to investigate other cationic polymers for a similar effect. The evaluation of the toxicity of a range of different types of polycations, and an investigation into the potential source of GSC’s sensitivity to such compounds is thus described.

Des polymères cationiques et des complexes N-hétérocycliques métalliques pour tuer des cellules souches cancéreuses: Ce travail se concentre sur l’évaluation du potentiel de nouvelles composées en tant que chimiothérapies anti-cellule souches cancéreuses (CSC). Ces cellules constituent une sous-population dans les tumeurs qui possèdent des caractéristiques semblables à celles des cel-lules souches, ce qui les rendent résistantes à la chimiothérapie actuelle, et donc respon-sable pour la récurrence des tumeurs. Le développement de nouvelles chimiothérapies qui peuvent éliminer ces cellules est donc intéressant. Des nouvelles composées NHC-Ir(III) et NHC-Pt(II), ainsi que le polymère cationique, PEI, ont été évalué pour leur potentiel en tant qu’agents anti-CSC. L’étude a démontré un effet anti-CSC prometteur du composée NHC-Ir(III), qui induisait une mortalité dont l’activation des caspases était redondante. Le PEI a démontré une toxicité contre les CSC qui était plusieurs fois plus important que celle contre les cellules cancéreuses non-souches. Les propriétés anti-inflammatoires du PEI ont aussi été évalué.