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.
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.
Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, Dublin 2, Ireland.
Amanda
A
Tivnan
Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, Dublin 2, Ireland.|IMC Fachhochschule Krems, University of Applied Sciences, Krems, Austria.
Tatjana
T
Heilinger
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.
Joanne M
JM
Ramsey
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.
Gemma
G
O'Connor
Department of Radiation Oncology, Mayo Clinic, Rochester, MN, United States of America.|Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
Jenny L
JL
Pokorny
Department of Radiation Oncology, Mayo Clinic, Rochester, MN, United States of America.
Jann N
JN
Sarkaria
Brain Cancer Research Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Brett W
BW
Stringer
Brain Cancer Research Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Bryan W
BW
Day
Brain Cancer Research Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Andrew W
AW
Boyd
Laboratory of Neurooncology, Department of Neurosurgery, Johannes Gutenberg University Medical Center, Mainz, Germany.
Ella L
EL
Kim
Department of Paediatrics and Paediatric Haematology/Oncology, University of Greifswald, Greifswald, Germany.
Holger N
HN
Lode
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.
Sally-Ann
SA
Cryan
Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, Dublin 2, Ireland.
Jochen H M
JH
Prehn
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D047072:Aromatase Inhibitors / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005732:Gangliosides / Q000276:immunology; D005909:Glioblastoma / Q000188:drug therapy*; D006367:HeLa Cells; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage*; D019344:Lactic Acid / Q000008:administration & dosage; D000077289:Letrozole; D053758:Nanoparticles / Q000008:administration & dosage*; D009570:Nitriles / Q000008:administration & dosage*; D011100:Polyglycolic Acid / Q000008:administration & dosage; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D014162:Transfection; D014230:Triazoles / Q000008:administration & dosage*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D005732:Gangliosides; D000922:Immunotoxins; D009570:Nitriles; D014230:Triazoles; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C019403:ganglioside, GD2; D000077289:Letrozole
aromatase inhibitor; brain; glioblastoma; miRNA-191; nanoparticles