Cargando…

Tween 85-Modified Low Molecular Weight PEI Enhances Exon-Skipping of Antisense Morpholino Oligomer In Vitro and in mdx Mice

We investigated a series of Tween 85 modified low molecular weight polyethylenimine (LPEI, 0.8k/1.2k/2.0k)-copolymers (Zs) through simple formulation and covalent conjugation with phosphorodiamidate morpholino oligomer (PMO) for their potential to enhance delivery in vitro and in dystrophic mdx mice...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Mingxing, Wu, Bo, Tucker, Jason D., Shah, Sapana N., Lu, Peijuan, Bollinger, Lauren E., Lu, Qilong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633364/
https://www.ncbi.nlm.nih.gov/pubmed/29246291
http://dx.doi.org/10.1016/j.omtn.2017.09.006
_version_ 1783269880371347456
author Wang, Mingxing
Wu, Bo
Tucker, Jason D.
Shah, Sapana N.
Lu, Peijuan
Bollinger, Lauren E.
Lu, Qilong
author_facet Wang, Mingxing
Wu, Bo
Tucker, Jason D.
Shah, Sapana N.
Lu, Peijuan
Bollinger, Lauren E.
Lu, Qilong
author_sort Wang, Mingxing
collection PubMed
description We investigated a series of Tween 85 modified low molecular weight polyethylenimine (LPEI, 0.8k/1.2k/2.0k)-copolymers (Zs) through simple formulation and covalent conjugation with phosphorodiamidate morpholino oligomer (PMO) for their potential to enhance delivery in vitro and in dystrophic mdx mice. Z polymers significantly enhanced PMO-induced exon-skipping in a GFP reporter-based cell culture system. Application of optimized formulations of Zs with PMO targeted to dystrophin exon 23 demonstrated a significant increase in exon-skipping efficiency in mdx mice. Consistent with our observations in vitro, optimization of molecular size and hydropholic-lipopholic balance (HLB) of polymers are important factors to achieve enhanced PMO delivery in vivo. The best formulation of Zs enhanced PMO delivery with 20- and 6-fold over PMO alone in vitro and in vivo, respectively. Further, chemical conjugation of the polymer and PMO exhibits greater benefit than polymer/PMO simple formulation in PMO delivery efficiency. Observed cytotoxicity of the Zs was lower than Endo-porter and PEI 25k in vitro, and no tissue toxicity was clearly detected with the Zs at the dosage tested. These results indicate the potential of the Zs as effective and safe PMO delivery carriers for treating diseases such as muscular dystrophy.
format Online
Article
Text
id pubmed-5633364
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher American Society of Gene & Cell Therapy
record_format MEDLINE/PubMed
spelling pubmed-56333642017-10-13 Tween 85-Modified Low Molecular Weight PEI Enhances Exon-Skipping of Antisense Morpholino Oligomer In Vitro and in mdx Mice Wang, Mingxing Wu, Bo Tucker, Jason D. Shah, Sapana N. Lu, Peijuan Bollinger, Lauren E. Lu, Qilong Mol Ther Nucleic Acids Article We investigated a series of Tween 85 modified low molecular weight polyethylenimine (LPEI, 0.8k/1.2k/2.0k)-copolymers (Zs) through simple formulation and covalent conjugation with phosphorodiamidate morpholino oligomer (PMO) for their potential to enhance delivery in vitro and in dystrophic mdx mice. Z polymers significantly enhanced PMO-induced exon-skipping in a GFP reporter-based cell culture system. Application of optimized formulations of Zs with PMO targeted to dystrophin exon 23 demonstrated a significant increase in exon-skipping efficiency in mdx mice. Consistent with our observations in vitro, optimization of molecular size and hydropholic-lipopholic balance (HLB) of polymers are important factors to achieve enhanced PMO delivery in vivo. The best formulation of Zs enhanced PMO delivery with 20- and 6-fold over PMO alone in vitro and in vivo, respectively. Further, chemical conjugation of the polymer and PMO exhibits greater benefit than polymer/PMO simple formulation in PMO delivery efficiency. Observed cytotoxicity of the Zs was lower than Endo-porter and PEI 25k in vitro, and no tissue toxicity was clearly detected with the Zs at the dosage tested. These results indicate the potential of the Zs as effective and safe PMO delivery carriers for treating diseases such as muscular dystrophy. American Society of Gene & Cell Therapy 2017-09-20 /pmc/articles/PMC5633364/ /pubmed/29246291 http://dx.doi.org/10.1016/j.omtn.2017.09.006 Text en © 2017 The Authors http://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 Article
Wang, Mingxing
Wu, Bo
Tucker, Jason D.
Shah, Sapana N.
Lu, Peijuan
Bollinger, Lauren E.
Lu, Qilong
Tween 85-Modified Low Molecular Weight PEI Enhances Exon-Skipping of Antisense Morpholino Oligomer In Vitro and in mdx Mice
title Tween 85-Modified Low Molecular Weight PEI Enhances Exon-Skipping of Antisense Morpholino Oligomer In Vitro and in mdx Mice
title_full Tween 85-Modified Low Molecular Weight PEI Enhances Exon-Skipping of Antisense Morpholino Oligomer In Vitro and in mdx Mice
title_fullStr Tween 85-Modified Low Molecular Weight PEI Enhances Exon-Skipping of Antisense Morpholino Oligomer In Vitro and in mdx Mice
title_full_unstemmed Tween 85-Modified Low Molecular Weight PEI Enhances Exon-Skipping of Antisense Morpholino Oligomer In Vitro and in mdx Mice
title_short Tween 85-Modified Low Molecular Weight PEI Enhances Exon-Skipping of Antisense Morpholino Oligomer In Vitro and in mdx Mice
title_sort tween 85-modified low molecular weight pei enhances exon-skipping of antisense morpholino oligomer in vitro and in mdx mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633364/
https://www.ncbi.nlm.nih.gov/pubmed/29246291
http://dx.doi.org/10.1016/j.omtn.2017.09.006
work_keys_str_mv AT wangmingxing tween85modifiedlowmolecularweightpeienhancesexonskippingofantisensemorpholinooligomerinvitroandinmdxmice
AT wubo tween85modifiedlowmolecularweightpeienhancesexonskippingofantisensemorpholinooligomerinvitroandinmdxmice
AT tuckerjasond tween85modifiedlowmolecularweightpeienhancesexonskippingofantisensemorpholinooligomerinvitroandinmdxmice
AT shahsapanan tween85modifiedlowmolecularweightpeienhancesexonskippingofantisensemorpholinooligomerinvitroandinmdxmice
AT lupeijuan tween85modifiedlowmolecularweightpeienhancesexonskippingofantisensemorpholinooligomerinvitroandinmdxmice
AT bollingerlaurene tween85modifiedlowmolecularweightpeienhancesexonskippingofantisensemorpholinooligomerinvitroandinmdxmice
AT luqilong tween85modifiedlowmolecularweightpeienhancesexonskippingofantisensemorpholinooligomerinvitroandinmdxmice