Anti-miR delivery strategies to bypass the blood-brain barrier in glioblastoma therapy.
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.
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
Dong Geon
DG
Kim
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
Kang Ho
KH
Kim
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
Yun Jee
YJ
Seo
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.|Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Heekyoung
H
Yang
Providence Therapeutics, Calgary, Canada.
Eric G
EG
Marcusson
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.|Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea.
Eunju
E
Son
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
Kyoungmin
K
Lee
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
Jason K
JK
Sa
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.|Department of Urology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea.
Hye Won
HW
Lee
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.|Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Do-Hyun
DH
Nam
D000818:Animals; D000070416:Antagomirs / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000188:drug therapy*; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D000070416:Antagomirs; D000970:Antineoplastic Agents; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human
anti-miR; delivery efficiency; glioblastoma; intratumoral injection; intraventricular injection