Backbone cationized highly branched poly(β-amino ester)s as enhanced delivery vectors in non-viral gene therapy
Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved..
Gene therapy holds great potential for treating Lung Cystic Fibrosis (CF) which is a fatal hereditary condition arising from mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in dysfunctional CFTR protein. However, the advancement and clinical application of CF gene therapy systems have been hindered due to the absence of a highly efficient delivery vector. In this work, we introduce a new generation of highly branched poly(β-amino ester) (HPAE) gene delivery vectors for CF treatment. Building upon the classical chemical composition of HPAE, a novel backbone cationization strategy was developed to incorporate additional functional amine groups into HPAE without altering their branching degree. By carefully adjusting the type, proportion, and backbone distribution of the added cationic groups, a series of highly effective HPAE gene delivery vectors were successfully constructed for CF disease gene therapy. In vitro assessment results showed that the backbone cationized HPAEs with randomly distributed 10% proportion of 1-(3-aminopropyl)-4-methylpiperazine (E7) amine groups exhibited superior transfection performance than their counterparts. Furthermore, the top-performed backbone cationized HPAEs, when loaded with therapeutic plasmids, successfully reinstated CFTR protein expression in the CFBE41o- disease model, achieving levels 20-23 times higher than that of normal human bronchial epithelial (HBE) cells. Their therapeutic effectiveness significantly surpassed that of the currently advanced commercial vectors, Xfect and Lipofectamine 3000.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:367 |
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| Enthalten in: |
Journal of controlled release : official journal of the Controlled Release Society - 367(2024) vom: 31. März, Seite 327-338 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Yinghao [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.03.2024 Date Revised 25.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jconrel.2024.01.046 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Backbone cationized highly branched poly(β-amino ester)s as enhanced delivery vectors in non-viral gene therapy |
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| 520 | |a Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a Gene therapy holds great potential for treating Lung Cystic Fibrosis (CF) which is a fatal hereditary condition arising from mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in dysfunctional CFTR protein. However, the advancement and clinical application of CF gene therapy systems have been hindered due to the absence of a highly efficient delivery vector. In this work, we introduce a new generation of highly branched poly(β-amino ester) (HPAE) gene delivery vectors for CF treatment. Building upon the classical chemical composition of HPAE, a novel backbone cationization strategy was developed to incorporate additional functional amine groups into HPAE without altering their branching degree. By carefully adjusting the type, proportion, and backbone distribution of the added cationic groups, a series of highly effective HPAE gene delivery vectors were successfully constructed for CF disease gene therapy. In vitro assessment results showed that the backbone cationized HPAEs with randomly distributed 10% proportion of 1-(3-aminopropyl)-4-methylpiperazine (E7) amine groups exhibited superior transfection performance than their counterparts. Furthermore, the top-performed backbone cationized HPAEs, when loaded with therapeutic plasmids, successfully reinstated CFTR protein expression in the CFBE41o- disease model, achieving levels 20-23 times higher than that of normal human bronchial epithelial (HBE) cells. Their therapeutic effectiveness significantly surpassed that of the currently advanced commercial vectors, Xfect and Lipofectamine 3000 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Backbone cationization | |
| 650 | 4 | |a Cystic fibrosis | |
| 650 | 4 | |a Highly branched structure | |
| 650 | 4 | |a Non-viral gene delivery | |
| 650 | 4 | |a Poly(β-amino ester) | |
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| 650 | 7 | |a poly(beta-amino ester) |2 NLM | |
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| 700 | 1 | |a Qiu, Bei |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zishan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xianqing |e verfasserin |4 aut | |
| 700 | 1 | |a He, Zhonglei |e verfasserin |4 aut | |
| 700 | 1 | |a Sandoval, Darío Manzanares |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Rijian |e verfasserin |4 aut | |
| 700 | 1 | |a Sigen, A |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Chunyu |e verfasserin |4 aut | |
| 700 | 1 | |a Johnson, Melissa |e verfasserin |4 aut | |
| 700 | 1 | |a Lyu, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Lara-Sáez, Irene |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Wenxin |e verfasserin |4 aut | |
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