Anti-miR delivery strategies to bypass the blood-brain barrier in glioblastoma therapy
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Dong Geon Kim1,2, Kang Ho Kim2, Yun Jee Seo2, Heekyoung Yang2,3, Eric G. Marcusson6, Eunju Son2,4, Kyoungmin Lee1,2, Jason K. Sa1,2, Hye Won Lee1,2,5, Do-Hyun Nam1,2,3
1Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea
2Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea
3Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
4Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea
5Department of Urology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea
6Providence Therapeutics, Calgary, Canada
Do-Hyun Nam, email: [email protected]
Keywords: anti-miR, glioblastoma, intratumoral injection, intraventricular injection, delivery efficiency
Received: December 03, 2015 Accepted: March 28, 2016 Published: April 19, 2016
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.
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