Abstract
Small non-coding RNAs called miRNAs are key regulators in various biological processes, including tumor initiation, propagation, and metastasis in glioblastoma as well as other cancers. Recent studies have shown the potential for oncogenic miRNAs as therapeutic targets in glioblastoma. However, the application of antisense oligomers, or anti-miRs, to the brain is limited due to the blood-brain barrier (BBB), when administered in the traditional systemic manner. To induce a therapeutic effect in glioblastoma, anti-miR therapy requires a robust and effective delivery system to overcome this obstacle. To bypass the BBB, different delivery administration methods for anti-miRs were evaluated. Stereotaxic surgery was performed to administer anti-Let-7 through intratumoral (ITu), intrathecal (ITh), and intraventricular (ICV) routes, and each method's efficacy was determined by changes in the expression of anti-Let-7 target genes as well as by immunohistochemical analysis. ITu administration of anti-miRs led to a high rate of anti-miR delivery to tumors in the brain by both bolus and continuous administration. In addition, ICV administration, compared with ITu administration, showed a greater distribution of the miR across entire brain tissues. This study suggests that local administration methods are a promising strategy for anti-miR treatment and may overcome current limitations in the treatment of glioblastoma in preclinical animal models.
Highlights
In accordance with the patient’s informed consent and appropriate review by the IRB (Institutional Review Board), glioblastoma patient-derived cells were obtained from a patient undergoing surgery at the Samsung Medical Center (Seoul, Korea)
Before injection of the single cells into mice, glioblastoma patient-derived cells were briefly maintained in NBE (Neuronal Basal Medium) neurosphere culture medium consisting of Neurobasal-A medium (Invitrogen, Carlsbad, CA, USA) supplemented with glutamine (2 mM, Invitrogen, Carlsbad, CA, USA), penicillin
To evaluate intracellular transfer efficiency of antimiR in glioblastoma patient derived cell in vitro, GBM04T cell was plated at 1 × 105 cells/2 mL culture medium per well in a 6-well plate
Summary
In accordance with the patient’s informed consent and appropriate review by the IRB (Institutional Review Board), glioblastoma patient-derived cells were obtained from a patient undergoing surgery at the Samsung Medical Center (Seoul, Korea). Anti-miR delivery strategies to bypass the blood-brain barrier in glioblastoma therapy The tumor sample was classified as glioblastoma based on the pathologist’s examination and according to the World Health Organization criteria.
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