Abstract
BackgroundNeuroblastoma is one of the most challenging malignancies of childhood, being associated with the highest death rate in paediatric oncology, underlining the need for novel therapeutic approaches. Typically, patients with high risk disease undergo an initial remission in response to treatment, followed by disease recurrence that has become refractory to further treatment. Here, we demonstrate the first silica nanoparticle-based targeted delivery of a tumor suppressive, pro-apoptotic microRNA, miR-34a, to neuroblastoma tumors in a murine orthotopic xenograft model. These tumors express high levels of the cell surface antigen disialoganglioside GD2 (GD2), providing a target for tumor-specific delivery.Principal FindingsNanoparticles encapsulating miR-34a and conjugated to a GD2 antibody facilitated tumor-specific delivery following systemic administration into tumor bearing mice, resulted in significantly decreased tumor growth, increased apoptosis and a reduction in vascularisation. We further demonstrate a novel, multi-step molecular mechanism by which miR-34a leads to increased levels of the tissue inhibitor metallopeptidase 2 precursor (TIMP2) protein, accounting for the highly reduced vascularisation noted in miR-34a-treated tumors.SignificanceThese novel findings highlight the potential of anti-GD2-nanoparticle-mediated targeted delivery of miR-34a for both the treatment of GD2-expressing tumors, and as a basic discovery tool for elucidating biological effects of novel miRNAs on tumor growth.
Highlights
Neuroblastoma is a childhood cancer derived from precursor cells of the sympathetic nervous system, occurring primarily in children under the age of 5 years
Patients with high risk neuroblastoma treated with intensive multi-modal chemotherapy often show an initial remission, disease recurrence that is refractory to further treatment is common
GD2 expression in neuroblastoma tumour samples is substantial [7] and uniform [8] and recent immunotherapy studies with a human/ mouse chimeric disialoganglioside GD2 (GD2) antibody combined with cytokine administration resulted in a significant improvement in neuroblastoma patient outcome [9] suggesting that the development of therapeutics directed to GD2 is a promising concept [10,11,12]
Summary
Neuroblastoma is a childhood cancer derived from precursor cells of the sympathetic nervous system, occurring primarily in children under the age of 5 years. Patients with high risk neuroblastoma treated with intensive multi-modal chemotherapy often show an initial remission, disease recurrence that is refractory to further treatment is common. GD2 is a glycolipid highly expressed on the cell surface of neuroblastoma and several other cancers [2], providing a potential target for immunotherapy and therapeutic targeting [3,4,5,6]. We demonstrate the first silica nanoparticle-based targeted delivery of a tumor suppressive, proapoptotic microRNA, miR-34a, to neuroblastoma tumors in a murine orthotopic xenograft model. These tumors express high levels of the cell surface antigen disialoganglioside GD2 (GD2), providing a target for tumor-specific delivery
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