Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patient-derived GBM tumor cells

// Amanda Tivnan 1 , Tatjana Heilinger 1, 2 , Joanne M. Ramsey 3 , Gemma O’Connor 3 , Jenny L. Pokorny 4, 5 , Jann N. Sarkaria 4 , Brett W. Stringer 6 , Bryan W. Day 6 , Andrew W. Boyd 6 , Ella L. Kim 7 , Holger N. Lode 8 , Sally-Ann Cryan 3 , Jochen H.M. Prehn 1 1 Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, Dublin 2, Ireland 2 IMC Fachhochschule Krems, University of Applied Sciences, Krems, Austria 3 School of Pharmacy, Royal College of Surgeons in Ireland, York House, Dublin 2, Ireland & Tissue Engineering Research Group, Department of Anatomy, RCSI and Centre for Research in Medical Devices (CURAM), NUIG, Ireland 4 Department of Radiation Oncology, Mayo Clinic, Rochester, MN, United States of America 5 Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA 6 Brain Cancer Research Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia 7 Laboratory of Neurooncology, Department of Neurosurgery, Johannes Gutenberg University Medical Center, Mainz, Germany 8 Department of Paediatrics and Paediatric Haematology/Oncology, University of Greifswald, Greifswald, Germany Correspondence to: Amanda Tivnan, email: amandativnan@rcsi.ie Keywords: glioblastoma, nanoparticles, aromatase inhibitor, miRNA-191, brain Received: November 02, 2016      Accepted: January 16, 2017      Published: February 03, 2017 ABSTRACT Aromatase is a critical enzyme in the irreversible conversion of androgens to oestrogens, with inhibition used clinically in hormone-dependent malignancies. We tested the hypothesis that targeted aromatase inhibition in an aggressive brain cancer called glioblastoma (GBM) may represent a new treatment strategy. In this study, aromatase inhibition was achieved using third generation inhibitor, Letrozole, encapsulated within the core of biodegradable poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs). PLGA-NPs were conjugated to human/mouse chimeric anti-GD2 antibody ch14.18/CHO, enabling specific targeting of GD2-positive GBM cells. Treatment of primary and recurrent patient-derived GBM cells with free-Letrozole (0.1 μM) led to significant decrease in cell proliferation and migration; in addition to reduced spheroid formation. Anti-GD2-ch14.18/CHO-NPs displayed specific targeting of GBM cells in colorectal-glioblastoma co-culture, with subsequent reduction in GBM cell numbers when treated with anti-GD2-ch14.18-PLGA-Let-NPs in combination with temozolomide. As miR-191 is an estrogen responsive microRNA, its expression, fluctuation and role in Letrozole treated GBM cells was evaluated, where treatment with premiR-191 was capable of rescuing the reduced proliferative phenotype induced by aromatase inhibitor. The repurposing and targeted delivery of Letrozole for the treatment of GBM, with the potential role of miR-191 identified, provides novel avenues for target assessment in this aggressive brain cancer.