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.
Grade C PF: (i) accounts for 15% of fistulae following PD and has an associated mortality rate of 35%; (ii) occurs most commonly in pathology associated with a soft remnant, and (iii) requires reoperation in approximately one half of patients. The published literature incompletely describes grade C PF.
Introduction
The anti-tumor activity of angiogenesis inhibitors is often limited by the development of resistance to these drugs. Here we establish HIF-1α as a major factor in the development of this resistance in neuroblastoma xenografts.
Methods
Neuroblastoma xenografts were established by injecting unmodified SKNAS or NB-1691 cells (2×106 cells), or cells in which HIF-1α expression had been knocked down with shRNA, into the retroperitoneal space of SCID mice. Treatment of established tumors included bevacizumab (5mg/kg q2wk), sunitinib (40mg/kg qd), or topotecan (0.5mg/kg qd) alone or in combination for a total of two weeks.
Results
NB-1691 xenografts showed no difference in relative growth in HIF-1α knockdowns compared to control tumors (73.33±7.90 vs 79.94±6.15, p=0.528). However, HIF-1α knockdowns demonstrated relative final volumes that were significantly lower than unmodified tumors when both were treated with bevacizumab (35.88±4.24 vs 53.57±6.61, p=0.0544) or sunitinib (12.46±2.59 vs 36.36±4.82, p=0.0024). Monotherapy of unmodified xenografts with bevacizumab, sunitinib, or topotecan was largely ineffective. Relative final volumes of NB-1691 xenografts were significantly less in cohorts treated with sunitinib+topotecan (4.78±0.77 vs 39.17±2.44 [sunitinib alone], p=0.011) and bevacizumab+topotecan (13.63±1.55 vs 48.16±9.94 [bevacizumab alone], p=0.014).
Conclusion
Upregulation of HIF-1α appears to be a significant mechanism of resistance to antiangiogenic therapies in neuroblastoma. Suppressing HIF-1α with low-dose topotecan potentiates the effects of the antiangiogenic drugs in a mouse model.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.