Working Paper
Authors
- Mickaël Marloye Université Libre de Bruxelles ,
- Inam Haider Pennsylvania State University ,
- Connor J. Moore Pennsylvania State University ,
- Tyler R. Mertens University of Kentucky ,
- Aude Ingels Université Libre de Bruxelles ,
- Marilin Koch Harvard Medical School ,
- Michal O. Nowicki Harvard Medical School ,
- Véronique Mathieu Université Libre de Bruxelles ,
- Justin Pritchard Pennsylvania State University ,
- Samuel Awuah University of Kentucky ,
- Sean E. Lawler Harvard Medical School & Brown University ,
- Franck Meyer Université Libre de Bruxelles ,
- François Dufrasne Université Libre de Bruxelles ,
- Gilles Berger
Université Libre de Bruxelles & Harvard Medical School
Abstract
We disclose novel amphiphilic ruthenium and osmium complexes that auto-assemble into nanomedicines with potent antiproliferative activity by inhibition of mitochondrial respiration. The self-assembling units were rationally designed from the [M(p-cymene)(1,10-phenanthroline)Cl]PF6 motif (where M is either RuII or OsII) with an appended C16 fatty chain to achieve high cellular activity, nano-assembling and mitochondrial targeting. These amphiphilic complexes block cell proliferation at the sub-micromolar range and are particularly potent towards glioblastoma neurospheres made from patient-derived cancer stem cells. A subcutaneous mouse model using these glioblastoma stem cells highlights one of our C16 OsII nanomedicines as highly successful in vivo. Mechanistically, we show that they act as metabolic poisons, strongly impairing mitochondrial respiration, corroborated by morphological changes and damage to the mitochondria. A genetic strategy based on RNAi gave further insight on the potential involvement of microtubules as part of the induced cell death. In parallel, we present a careful examination of the structural properties of these new amphiphilic metal-based constructs, their reactivity and mechanism.
Content

Supplementary material

Supplementary Information
The SI contains all protocols and characterization data, and added experimental data.