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Inhibition of neuroblastoma tumor growth by targeted delivery of microRNA-34a using anti-disialoganglioside GD2 coated nanoparticles

Tivnan, A., Orr, W.S., Gubala, V., Nooney, R., Williams, D.E., McDonagh, C., Prenter, S., Harvey, H., Domingo-Fernández, R., Bray, I.M., and others. (2012) Inhibition of neuroblastoma tumor growth by targeted delivery of microRNA-34a using anti-disialoganglioside GD2 coated nanoparticles. PloS one, 7 (5). ISSN 1932-6203. (doi:10.1371/journal.pone.0038129) (KAR id:45222)

Abstract

Background: Neuroblastoma 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 Findings: Nanoparticles 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. Significance: These 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. © 2012 Tivnan et al.

Item Type: Article
DOI/Identification number: 10.1371/journal.pone.0038129
Additional information: Unmapped bibliographic data: C7 - e38129 [EPrints field already has value set] LA - English [Field not mapped to EPrints] J2 - PLoS ONE [Field not mapped to EPrints] C2 - 22662276 [Field not mapped to EPrints] AD - Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland [Field not mapped to EPrints] AD - National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland [Field not mapped to EPrints] AD - Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, United States [Field not mapped to EPrints] AD - Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, United States [Field not mapped to EPrints] AD - Biomedical Diagnostics Institute, Dublin City University, Dublin, Ireland [Field not mapped to EPrints] AD - Department of Paediatrics and Paediatric Haematology/Oncology, University of Greifswald, Greifswald, Germany [Field not mapped to EPrints] DB - Scopus [Field not mapped to EPrints]
Uncontrolled keywords: disialoganglioside GD2 antibody, ganglioside antibody, ganglioside GD2, microRNA 34a, nanoparticle, silicon dioxide, tissue inhibitor of metalloproteinase 2, unclassified drug, animal experiment, animal model, antiangiogenic activity, apoptosis, article, cancer inhibition, controlled study, drug coating, drug conjugation, drug delivery system, drug targeting, embryo, human, human cell, molecular mechanics, mouse, nanoencapsulation, neuroblastoma, nonhuman, tumor vascularization, tumor xenograft, Animals, Apoptosis, Cell Line, Tumor, Gangliosides, Gene Expression, Gene Expression Profiling, Humans, Mice, Mice, SCID, MicroRNAs, Nanoconjugates, Neovascularization, Pathologic, Neuroblastoma, Nuclear Proteins, Oncogene Proteins, Xenograft Model Antitumor Assays, Murinae, Mus
Divisions: Divisions > Division of Natural Sciences > Medway School of Pharmacy
Depositing User: Vladimir Gubala
Date Deposited: 14 Dec 2017 19:11 UTC
Last Modified: 16 Nov 2021 10:18 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/45222 (The current URI for this page, for reference purposes)

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