Linda Waldherr1, Maria Seitanidou2, Marie Jakešová3, Tobias Abrahamsson2, Verena Handl1, Tamara Tomin4, Meysam Karami Rad2, Nassim Ghaffari Tabrizi-Wizsy5, Silke Patz6, Daniel Simon2, Rainer Schindl1

1Gottfried Schatz Research Center – Biophysics, Medical University of Graz, 8010 Graz, Austria; 2Laboratory of Organic Electronics, Department of Science and Technology, Linköping University, 60174 Norrköping, Sweden; 3CEITEC – Central European Institute of Technology, 601 77 Brno, Czech Republic; 4Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; 5Otto Loewi Research Center – Division of Immunology and Pathophysiology, Medical University of Graz, 8010 Graz, Austria; 6University Clinic of Neurosurgery, Medical University of Graz, 8010 Graz, Austria;

Aggressively growing brain tumors, such as glioblastoma multiforme (GBM) remain incurable due to limited surgical resection possibilities and hindrance of promising chemotherapeutics that are shielded by the blood brain barrier (BBB). We present an electrically-driven device able to deliver selected chemotherapeutics, such as Gemcitabine (Gem). We observed Gem as drug in different cell cultures (GBM, neurons, astrocytes) and analyze the effect of the drug via cell-based assays (apoptosis, necrosis, viability) and via mass spectrometry (whole proteome analysis). Furthermore, we engineered Gemcitabine Ion Pumps (GemIPs), and monitored their performance via voltage-current measurements. The functionality of GemIPs was further tested in different cell culture models and vascularized tumor models and effects were observed via flow cytometry analyzing induced apoptosis. We show that Gem is a potent chemotherapeutic with special properties suitable for the application in the brain. We can state that Gem effectively kills GBM cells, is more potent than the gold standard temozolomide, but is at the same time harmless to neurons and astrocytes and does not alter protein expression in neurons after presentation of high Gem concentrations over 72 h. The engineered GemIPs are able to administer Gem with pmol*min-1 delivery precision at currents in the nano-ampere range. The further application of this electrical and temporal control was shown in the cell monolayer and 3D cell culture, triggering the disintegration of targeted GBM tumor spheroids among GemIP treatment. Additionally, we show preliminary results indicating that GemIP treatment significantly reduces the tumor size of vascularized GBM tumors cultivated in the chick chorioallantoic membrane (CAM) assay. The here exemplified electrically-driven chemotherapy has the potential to increase the efficacy of GBM treatment and represent a highly-targeted and locally-controlled drug delivery tool that is independent from BBB permeability of potent chemotherapeutics.

Acknowledgements: This project is supported by the FWF (TAI 245 1000 Ideas Project) and an ÖAW DOC fellowship assigned to Linda Waldherr.

Presenting author e-mail address: linda.waldherr@medunigraz.at