1. Anti-miR delivery strategies to bypass the blood-brain barrier in glioblastoma therapy
- Author
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Eric G. Marcusson, Kang Ho Kim, Hye Won Lee, Kyoungmin Lee, Do Hyun Nam, Eunju Son, Heekyoung Yang, Jason K. Sa, Yun Jee Seo, and Donggeon Kim
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Mice, Nude ,Antineoplastic Agents ,Blood–brain barrier ,Metastasis ,03 medical and health sciences ,Mice ,Bolus (medicine) ,anti-miR ,Internal medicine ,medicine ,Animals ,Humans ,intraventricular injection ,Injections, Spinal ,Injections, Intraventricular ,Mice, Inbred BALB C ,delivery efficiency ,business.industry ,Brain Neoplasms ,Therapeutic effect ,intratumoral injection ,glioblastoma ,Antagomirs ,medicine.disease ,Xenograft Model Antitumor Assays ,Surgery ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Blood-Brain Barrier ,Delivery efficiency ,Neurosurgery ,business ,Biomedical sciences ,Glioblastoma ,Research Paper - Abstract
// Dong Geon Kim 1, 2 , Kang Ho Kim 2 , Yun Jee Seo 2 , Heekyoung Yang 2, 3 , Eric G. Marcusson 6 , Eunju Son 2, 4 , Kyoungmin Lee 1, 2 , Jason K. Sa 1, 2 , Hye Won Lee 1, 2, 5 , Do-Hyun Nam 1, 2, 3 1 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea 2 Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea 3 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea 5 Department of Urology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea 6 Providence Therapeutics, Calgary, Canada Correspondence to: Do-Hyun Nam, email: nsnam@skku.edu Keywords: anti-miR, glioblastoma, intratumoral injection, intraventricular injection, delivery efficiency Received: December 03, 2015 Accepted: March 28, 2016 Published: April 19, 2016 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.
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- 2016