Systemic delivery of microRNA-21 antisense oligonucleotides to the brain using T7-peptide decorated exosomes

Antisense miRNA oligonucleotides against miR-21 (AMO-21) have a therapeutic potential for treatment of glioblastoma. However, glioblastoma-targeted delivery through systemic injection requires development of an efficient targeting carrier. For this purpose, a glioblastoma-targeting carrier was devel...

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Bibliographic Details
Published in:Journal of controlled release Vol. 317; pp. 273 - 281
Main Authors: Kim, Gyeungyun, Kim, Minkyung, Lee, Youngki, Byun, Jung Woo, Hwang, Do Won, Lee, Minhyung
Format: Journal Article
Language:English
Published: Netherlands Elsevier B.V 10.01.2020
Subjects:
animal models
Anti-microRNA oligonucleotide
brain
caudal vein
electroporation
exosomes
Glioblastoma
glycoproteins
in vitro studies
intravenous injection
microRNA
microRNA-21
neurons
oligonucleotides
peptides
Rabies lyssavirus
T7 peptide
transferrin
Transferrin receptor
transferrin receptors
T7 peptide
microRNA-21
Transferrin receptor
Glioblastoma
Anti-microRNA oligonucleotide
ISSN:0168-3659, 1873-4995, 1873-4995
Online Access:Get full text
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Summary:Antisense miRNA oligonucleotides against miR-21 (AMO-21) have a therapeutic potential for treatment of glioblastoma. However, glioblastoma-targeted delivery through systemic injection requires development of an efficient targeting carrier. For this purpose, a glioblastoma-targeting carrier was developed using the T7 peptide and exosomes. The transferrin receptor is overexpressed on the surface of glioblastoma cells, and T7 is a transferrin receptor-binding peptide. A T7 peptide-decorated exosome (T7-exo) was produced by incorporation of T7 into the exosome membrane as a fusion protein of T7 and Lamp2b. As a control, rabies virus glycoprotein (RVG) peptide targeting brain neuron cells was incorporated into the exosome membrane. AMO-21 was loaded into the exosomes by electroporation. In vitro studies of AMO-21 delivery showed that T7-exo had a higher delivery efficiency to C6 glioblastoma cells than unmodified exosome (Unmod-exo) and RVG-decorated exosome (RVG-exo). For in vivo delivery studies, T7-exo with AMO-21 was delivered into intracranial glioblastoma rat models by intravenous injection through the tail vein. The results showed that T7-exo delivered AMO-21 into the brain more efficiently than Unmod-exo and RVG-exo. In addition, delivery of AMO-21 using T7-exo reduced the miR-21 level in the glioblastoma efficiently. Reduction of miR-21 by AMO-21 induced the expression of PDCD4 and PTEN in tumors, resulting in reduction of tumor sizes. Taken together, these findings indicate that T7-exo is an efficient carrier of AMO-21 into the glioblastoma and may be useful in development of glioblastoma therapy. [Display omitted]
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ISSN:0168-3659
1873-4995
1873-4995
DOI:10.1016/j.jconrel.2019.11.009