PMID- 28178667 OWN - NLM STAT- MEDLINE DCOM- 20170823 LR - 20181202 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 8 IP - 10 DP - 2017 Mar 7 TI - 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. PG - 16605-16620 LID - 10.18632/oncotarget.15073 [doi] AB - 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 muM) 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. FAU - Tivnan, Amanda AU - Tivnan A AD - Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, Dublin 2, Ireland. FAU - Heilinger, Tatjana AU - Heilinger T AD - Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, Dublin 2, Ireland. AD - IMC Fachhochschule Krems, University of Applied Sciences, Krems, Austria. FAU - Ramsey, Joanne M AU - Ramsey JM AD - 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. FAU - O'Connor, Gemma AU - O'Connor G AD - 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. FAU - Pokorny, Jenny L AU - Pokorny JL AD - Department of Radiation Oncology, Mayo Clinic, Rochester, MN, United States of America. AD - Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA. FAU - Sarkaria, Jann N AU - Sarkaria JN AD - Department of Radiation Oncology, Mayo Clinic, Rochester, MN, United States of America. FAU - Stringer, Brett W AU - Stringer BW AD - Brain Cancer Research Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia. FAU - Day, Bryan W AU - Day BW AD - Brain Cancer Research Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia. FAU - Boyd, Andrew W AU - Boyd AW AD - Brain Cancer Research Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia. FAU - Kim, Ella L AU - Kim EL AD - Laboratory of Neurooncology, Department of Neurosurgery, Johannes Gutenberg University Medical Center, Mainz, Germany. FAU - Lode, Holger N AU - Lode HN AD - Department of Paediatrics and Paediatric Haematology/Oncology, University of Greifswald, Greifswald, Germany. FAU - Cryan, Sally-Ann AU - Cryan SA AD - 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. FAU - Prehn, Jochen H M AU - Prehn JH AD - Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, Dublin 2, Ireland. LA - eng GR - P50 CA108961/CA/NCI NIH HHS/United States PT - Journal Article PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (Aromatase Inhibitors) RN - 0 (Gangliosides) RN - 0 (Immunotoxins) RN - 0 (Nitriles) RN - 0 (Triazoles) RN - 1SIA8062RS (Polylactic Acid-Polyglycolic Acid Copolymer) RN - 26009-03-0 (Polyglycolic Acid) RN - 33X04XA5AT (Lactic Acid) RN - 65988-71-8 (ganglioside, GD2) RN - 7LKK855W8I (Letrozole) SB - IM MH - Antibodies, Monoclonal/administration & dosage/immunology MH - Antineoplastic Agents/*administration & dosage MH - Aromatase Inhibitors/*administration & dosage MH - Brain Neoplasms/*drug therapy MH - Cell Line, Tumor MH - Cell Movement/drug effects MH - Cell Proliferation/drug effects MH - Gangliosides/immunology MH - Glioblastoma/*drug therapy MH - HeLa Cells MH - Humans MH - Immunotoxins/*administration & dosage MH - Lactic Acid/administration & dosage MH - Letrozole MH - Nanoparticles/*administration & dosage MH - Nitriles/*administration & dosage MH - Polyglycolic Acid/administration & dosage MH - Polylactic Acid-Polyglycolic Acid Copolymer MH - Transfection MH - Triazoles/*administration & dosage PMC - PMC5369988 OTO - NOTNLM OT - aromatase inhibitor OT - brain OT - glioblastoma OT - miRNA-191 OT - nanoparticles COIS- CONFLICTS OF INTEREST The author(s) declare that they have no competing interests EDAT- 2017/02/09 06:00 MHDA- 2017/08/24 06:00 PMCR- 2017/03/07 CRDT- 2017/02/09 06:00 PHST- 2016/11/02 00:00 [received] PHST- 2017/01/16 00:00 [accepted] PHST- 2017/02/09 06:00 [pubmed] PHST- 2017/08/24 06:00 [medline] PHST- 2017/02/09 06:00 [entrez] PHST- 2017/03/07 00:00 [pmc-release] AID - 15073 [pii] AID - 10.18632/oncotarget.15073 [doi] PST - ppublish SO - Oncotarget. 2017 Mar 7;8(10):16605-16620. doi: 10.18632/oncotarget.15073.