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

Amanda Tivnan, Tatjana Heilinger, Joanne M. Ramsey, Gemma O'Connor, Jenny L. Pokorny, Jann N. Sarkaria, Brett W. Stringer, Bryan W. Day, Andrew W. Boyd, Ella L. Kim, Holger N. Lode, Sally Ann Cryan, Jochen H.M. Prehn

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)16605-16620
Number of pages16
JournalOncotarget
Volume8
Issue number10
DOIs
StatePublished - 2017

Keywords

  • Aromatase inhibitor
  • Brain
  • Glioblastoma
  • MiRNA-191
  • Nanoparticles

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patientderived GBM tumor cells'. Together they form a unique fingerprint.

  • Cite this

    Tivnan, A., Heilinger, T., Ramsey, J. M., O'Connor, G., Pokorny, J. L., Sarkaria, J. N., Stringer, B. W., Day, B. W., Boyd, A. W., Kim, E. L., Lode, H. N., Cryan, S. A., & Prehn, J. H. M. (2017). Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patientderived GBM tumor cells. Oncotarget, 8(10), 16605-16620. https://doi.org/10.18632/oncotarget.15073