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Antisense-oligonucleotide co-micelles with tumor targeting peptides elicit therapeutic effects by inhibiting microRNA-21 in the glioblastoma animal models
INTRODUCTION: miRNA-21 (miR-21) is highly expressed in glioblastoma, facilitating tumor growth by blocking the expression of apoptosis-related genes. Therefore, an antisense microRNA oligonucleotide (AMO) against miR-21 was suggested as a therapeutic nucleic acid for glioblastoma. OBJECTIVES: AMO21...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10658310/ https://www.ncbi.nlm.nih.gov/pubmed/36632887 http://dx.doi.org/10.1016/j.jare.2023.01.005 |
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author | Lee, Youngki Ha, Junkyu Kim, Minkyung Kang, Subin Kang, Minji Lee, Minhyung |
author_facet | Lee, Youngki Ha, Junkyu Kim, Minkyung Kang, Subin Kang, Minji Lee, Minhyung |
author_sort | Lee, Youngki |
collection | PubMed |
description | INTRODUCTION: miRNA-21 (miR-21) is highly expressed in glioblastoma, facilitating tumor growth by blocking the expression of apoptosis-related genes. Therefore, an antisense microRNA oligonucleotide (AMO) against miR-21 was suggested as a therapeutic nucleic acid for glioblastoma. OBJECTIVES: AMO21 co-micelles were developed with tumor-targeting T7 peptides as an AMO21 delivery system by intranasal administration. METHODS: Cholesterol-conjugated AMO21 (AMO21c) was mixed with cholesterol-conjugated T7 peptides (T7c) to produce tumor-targeted co-micelles. Physical characterization was performed by dynamic light scattering, gel retardation assay, scanning electron microscope and heparin competition assay. In vitro transfection efficiency to C6 glioblastoma cells was measured by flow cytometry. The AMO21c/T7c co-micelles were administered by intranasal instillation into the brain of intracranial glioblastoma rat models. Scrambled T7 (scrT7) and scrambled AMO21c (scrAMO21c) were used as a negative control. The therapeutic effects of the AMO21c/T7c co-micelles were evaluated by real time RT-PCR, immunohistochemistry, TUNEL assay, and Nissl staining. RESULTS: The formation of the AMO21c/T7c co-micelles was confirmed in gel retardation and heparin competition assays. The highest delivery efficiency in vitro was achieved at a 1:10 wt ratio of AMO21c/T7c. The AMO21c/T7c co-micelles had higher delivery efficiency into C6 glioblastoma cells than naked AMO21c or AMO21c/lipofectamine complexes. After intranasal administration into the intracranial glioblastoma models, the delivery efficiency of the co-micelles into the brain was also higher than those of naked AMO21c and AMO21c/scrambled T7c. Thanks to their enhanced delivery efficiency, the AMO21c/T7c co-micelles downregulated miR-21, inducing the production of the pro-apoptotic phosphatase and tensin homolog (PTEN) and programmed cell death 4 (PDCD4) proteins in the tumor tissues. The tumor size was reduced by the AMO21c/T7c co-micelles more effectively than naked AMO21c, AMO21c/lipofectamine, or scrAMO21c/T7c treatment. CONCLUSION: The results suggest that the co-micelles of AMO21c and T7c may be an efficient delivery system into a brain tumor through intranasal administration. |
format | Online Article Text |
id | pubmed-10658310 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-106583102023-01-09 Antisense-oligonucleotide co-micelles with tumor targeting peptides elicit therapeutic effects by inhibiting microRNA-21 in the glioblastoma animal models Lee, Youngki Ha, Junkyu Kim, Minkyung Kang, Subin Kang, Minji Lee, Minhyung J Adv Res Original Article INTRODUCTION: miRNA-21 (miR-21) is highly expressed in glioblastoma, facilitating tumor growth by blocking the expression of apoptosis-related genes. Therefore, an antisense microRNA oligonucleotide (AMO) against miR-21 was suggested as a therapeutic nucleic acid for glioblastoma. OBJECTIVES: AMO21 co-micelles were developed with tumor-targeting T7 peptides as an AMO21 delivery system by intranasal administration. METHODS: Cholesterol-conjugated AMO21 (AMO21c) was mixed with cholesterol-conjugated T7 peptides (T7c) to produce tumor-targeted co-micelles. Physical characterization was performed by dynamic light scattering, gel retardation assay, scanning electron microscope and heparin competition assay. In vitro transfection efficiency to C6 glioblastoma cells was measured by flow cytometry. The AMO21c/T7c co-micelles were administered by intranasal instillation into the brain of intracranial glioblastoma rat models. Scrambled T7 (scrT7) and scrambled AMO21c (scrAMO21c) were used as a negative control. The therapeutic effects of the AMO21c/T7c co-micelles were evaluated by real time RT-PCR, immunohistochemistry, TUNEL assay, and Nissl staining. RESULTS: The formation of the AMO21c/T7c co-micelles was confirmed in gel retardation and heparin competition assays. The highest delivery efficiency in vitro was achieved at a 1:10 wt ratio of AMO21c/T7c. The AMO21c/T7c co-micelles had higher delivery efficiency into C6 glioblastoma cells than naked AMO21c or AMO21c/lipofectamine complexes. After intranasal administration into the intracranial glioblastoma models, the delivery efficiency of the co-micelles into the brain was also higher than those of naked AMO21c and AMO21c/scrambled T7c. Thanks to their enhanced delivery efficiency, the AMO21c/T7c co-micelles downregulated miR-21, inducing the production of the pro-apoptotic phosphatase and tensin homolog (PTEN) and programmed cell death 4 (PDCD4) proteins in the tumor tissues. The tumor size was reduced by the AMO21c/T7c co-micelles more effectively than naked AMO21c, AMO21c/lipofectamine, or scrAMO21c/T7c treatment. CONCLUSION: The results suggest that the co-micelles of AMO21c and T7c may be an efficient delivery system into a brain tumor through intranasal administration. Elsevier 2023-01-09 /pmc/articles/PMC10658310/ /pubmed/36632887 http://dx.doi.org/10.1016/j.jare.2023.01.005 Text en © 2023 The Authors. Published by Elsevier B.V. on behalf of Cairo University. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Lee, Youngki Ha, Junkyu Kim, Minkyung Kang, Subin Kang, Minji Lee, Minhyung Antisense-oligonucleotide co-micelles with tumor targeting peptides elicit therapeutic effects by inhibiting microRNA-21 in the glioblastoma animal models |
title | Antisense-oligonucleotide co-micelles with tumor targeting peptides elicit therapeutic effects by inhibiting microRNA-21 in the glioblastoma animal models |
title_full | Antisense-oligonucleotide co-micelles with tumor targeting peptides elicit therapeutic effects by inhibiting microRNA-21 in the glioblastoma animal models |
title_fullStr | Antisense-oligonucleotide co-micelles with tumor targeting peptides elicit therapeutic effects by inhibiting microRNA-21 in the glioblastoma animal models |
title_full_unstemmed | Antisense-oligonucleotide co-micelles with tumor targeting peptides elicit therapeutic effects by inhibiting microRNA-21 in the glioblastoma animal models |
title_short | Antisense-oligonucleotide co-micelles with tumor targeting peptides elicit therapeutic effects by inhibiting microRNA-21 in the glioblastoma animal models |
title_sort | antisense-oligonucleotide co-micelles with tumor targeting peptides elicit therapeutic effects by inhibiting microrna-21 in the glioblastoma animal models |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10658310/ https://www.ncbi.nlm.nih.gov/pubmed/36632887 http://dx.doi.org/10.1016/j.jare.2023.01.005 |
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