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

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.

DNA repair genes in astrocytoma tumorigenesis, progression and therapy resistance

“…However, several variables were found among the studies, including light dose and delivery method, photosensitizer utilized, and sensitivity of different tumor types, evidencing the requirement of standardized clinical trials to effectively evaluate PDT as a treatment option for GBM patients (Quirk et al, 2015). Other modern attempts under study include the use of gamma knife surgery (Skeie et al, 2013), gene therapy (Wilson et al, 2014), modulation of the immune system (Garris and Pittet, 2013), molecular imaging (Jarzabek et al, 2013) and nanoparticles (Tivnan et al, 2017).…”

Functionalizing PLGA and PLGA Derivatives for Drug Delivery and Tissue Regeneration Applications

“…Glioblastoma [177] Trastuzumab Doxorubicin Trastuzumab, a monoclonal antibody, was used as a ligand to functionalize PLGA nanoparticles, aiming the HER2 antigen targeting in human breast cancer cell lines. Cellular uptake of conjugated nanoparticles was higher than unconjugated nanoparticles for MCF-7 and SK-BR-3 cell lines.…”

Disialoganglioside GD2 Expression in Solid Tumors and Role as a Target for Cancer Therapy

“…Conjugation, or fusion, of cytokines to mAbs (immunocytokines) may avoid this issue, as, for example, Hu14.18-IL-2 anti-GD2 immunocytokine ( 116 , 117 ). Other novel anti-GD2 therapies include targeted nanoparticles (presenting anticancer drugs at a sustained rate directly to tumor cells) ( 118 ), antibody–drug conjugates (allowing chemotherapeutic agents and other toxic drugs to be released into the microenvironment of the tumor via antibody targeting) ( 119 ), T-cell engaging bispecific antibodies (binding to two different antigens) ( 120 ), radiolabeled antibodies (delivering radiotherapy directly to the tumor environment) ( 121 ), and cell surface expression of chimeric antigen receptors (merging specific antigen binding with T-cell effector functions) ( 122 ). Barry et al determined that the combination of dinutuximab and adoptively transferred ex vivo -activated human NK cells significantly improved the survival of immunodeficient mice following resection of neuroblastoma xenografts compared with dinutuximab or activated NK cells alone ( 123 ).…”