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.
Antibodies, Monoclonal, Antineoplastic Agents, Aromatase Inhibitors, Brain Neoplasms, Cell Line, Tumor, Cell Movement, Cell Proliferation, Gangliosides, Glioblastoma, HeLa Cells, Humans, Immunotoxins, Lactic Acid, Nanoparticles, Nitriles, Polyglycolic Acid, Transfection, Triazoles
This work was supported by the Irish Cancer Society Research Fellowship CRF13TIV, supported by Tesco Charity of the Year (AT). TH was funded by the www.impactjournals.com/oncotarget 16617 Oncotarget ERASMUS+ program. JHMP receives support from Science Foundation Ireland (14/IA/2582) and Brain Tumor Ireland. BWS, BWD and AWB are members of the Brain Cancer Discovery Collaborative, which is supported by the Cure Brain Cancer Foundation. Work by JNS and JLP was supported by the Mayo SPORE in Brain Cancer (CA108961) and the Mayo Clinic.
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.
Physics | Physiology
Tivnan A, Heilinger T, Ramsey JM, O'Connor G, Pokorny JL, Sarkaria JN, Stringer BW, Day BW, Boyd AW, Kim EL, Lode HN, Cryan SA, Prehn JH. 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. Oncotarget. 2017;8(10):16605-16620
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