Inhibition of neuroblastoma tumor growth by targeted delivery of microRNA-34a using anti-disialoganglioside GD2 coated nanoparticles.
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 (GD(2)), providing a target for tumor-specific delivery.


RESULTS
Nanoparticles encapsulating miR-34a and conjugated to a GD(2) 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.


CONCLUSIONS
These novel findings highlight the potential of anti-GD(2)-nanoparticle-mediated targeted delivery of miR-34a for both the treatment of GD(2)-expressing tumors, and as a basic discovery tool for elucidating biological effects of novel miRNAs on tumor growth.
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Amanda
A
Tivnan
Wayne Shannon
WS
Orr
Vladimir
V
Gubala
Robert
R
Nooney
David E
DE
Williams
Colette
C
McDonagh
Suzanne
S
Prenter
Harry
H
Harvey
Raquel
R
Domingo-Fernández
Isabella M
IM
Bray
Olga
O
Piskareva
Catherine Y
CY
Ng
Holger N
HN
Lode
Andrew M
AM
Davidoff
Raymond L
RL
Stallings
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D005732:Gangliosides / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D000071447:N-Myc Proto-Oncogene Protein; D058726:Nanoconjugates / Q000008:administration & dosage*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D005732:Gangliosides; C522425:MIRN34 microRNA, human; C459801:MYCN protein, human; D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D058726:Nanoconjugates; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C019403:ganglioside, GD2