Highly branched  poly(β-amino ester) delivery of minicircle DNA for transfection of neurodegenerative disease related cells

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Abstract

Current therapies for most neurodegenerative disorders are only symptomatic in nature and do not change the course of the disease. Gene therapy plays an important role in disease modifying therapeutic strategies. Herein, we have designed and optimized a series of highly branched poly(β-amino ester)s (HPAEs) containing biodegradable disulfide units in the HPAE backbone (HPAESS) and guanidine moieties (HPAESG) at the extremities. The optimized polymers are used to deliver minicircle DNA to multipotent adipose derived stem cells (ADSCs) and astrocytes, and high transfection efficiency is achieved (77% in human ADSCs and 52% in primary astrocytes) whilst preserving over 90% cell viability. Furthermore, the top-performing candidate mediates high levels of nerve growth factor (NGF) secretion from astrocytes, causing neurite outgrowth from a model neuron cell line. This synergistic gene delivery system provides a viable method for highly efficient non-viral transfection of ADSCs and astrocytes.

Abstract

Therapeutics delivery by using non-viral vectors presents several challenges in the design of an appropriate polymeric structure. Here, the authors report a series of highly branched, biodegradable polymers which show high transfection efficiency in human multipotent adipose derived stem cells and primary astrocytes.

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Most cited references 63

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The lack of safe and efficient gene-delivery methods is a limiting obstacle to human gene therapy. Synthetic gene-delivery agents, although safer than recombinant viruses, generally do not possess the required efficacy. In recent years, a variety of effective polymers have been designed specifically for gene delivery, and much has been learned about their structure-function relationships. With the growing understanding of polymer gene-delivery mechanisms and continued efforts of creative polymer chemists, it is likely that polymer-based gene-delivery systems will become an important tool for human gene therapy.

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The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters.

P A Wender, D J Mitchell, K Pattabiraman … (2000)

Certain proteins contain subunits that enable their active translocation across the plasma membrane into cells. In the specific case of HIV-1, this subunit is the basic domain Tat(49-57) (RKKRRQRRR). To establish the optimal structural requirements for this translocation process, and thereby to develop improved molecular transporters that could deliver agents into cells, a series of analogues of Tat(49-57) were prepared and their cellular uptake into Jurkat cells was determined by flow cytometry. All truncated and alanine-substituted analogues exhibited diminished cellular uptake, suggesting that the cationic residues of Tat(49-57) play a principal role in its uptake. Charge alone, however, is insufficient for transport as oligomers of several cationic amino acids (histidine, lysine, and ornithine) are less effective than Tat(49-57) in cellular uptake. In contrast, a 9-mer of l-arginine (R9) was 20-fold more efficient than Tat(49-57) at cellular uptake as determined by Michaelis-Menton kinetic analysis. The d-arginine oligomer (r9) exhibited an even greater uptake rate enhancement (>100-fold). Collectively, these studies suggest that the guanidinium groups of Tat(49-57) play a greater role in facilitating cellular uptake than either charge or backbone structure. Based on this analysis, we designed and synthesized a class of polyguanidine peptoid derivatives. Remarkably, the subset of peptoid analogues containing a six-methylene spacer between the guanidine head group and backbone (N-hxg), exhibited significantly enhanced cellular uptake compared to Tat(49-57) and even to r9. Overall, a transporter has been developed that is superior to Tat(49-57), protease resistant, and more readily and economically prepared.

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Author and article information

Contributors

Dezhong Zhou: dezhong.zhou@ucd.ie

Tianying Guo:

ORCID: http://orcid.org/0000-0001-6587-6466

tyguo@nankai.edu.cn

Wenxin Wang:

ORCID: http://orcid.org/0000-0002-5053-0611

wenxin.wang@ucd.ie

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 24 July 2019

Publication date PMC-release: 24 July 2019

Publication date Collection: 2019

Volume: 10

Electronic Location Identifier: 3307

Affiliations

[1 ]ISNI 0000 0001 0768 2743, GRID grid.7886.1, Charles Institute of Dermatology, School of Medicine, , University College Dublin, ; Belfield, 4 Dublin, Ireland

[2 ]ISNI 0000 0000 9878 7032, GRID grid.216938.7, Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, , Nankai University, ; 300071 Tianjin, China

[3 ]ISNI 0000 0001 0599 1243, GRID grid.43169.39, School of Chemical Engineering and Technology, , Xiʹan Jiaotong University, ; 710049 Xiʹan, China

[4 ]ISNI 0000 0001 0807 5670, GRID grid.5600.3, School of Pharmacy and Pharmaceutical Sciences, , Cardiff University, ; CF103AT Cardiff, UK

[5 ]ISNI 0000 0004 1761 325X, GRID grid.469325.f, School of Pharmaceutical Science, , Zhejiang University of Technology, ; 310014 Hangzhou, China

[6 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Department of Polymer Science and Engineering, , Zhejiang University, ; 310027 Hangzhou, China

Author information

Shuai Liu http://orcid.org/0000-0002-8405-6743

Tianying Guo http://orcid.org/0000-0001-6587-6466

Wenxin Wang http://orcid.org/0000-0002-5053-0611

Article

Publisher ID: 11190

DOI: 10.1038/s41467-019-11190-0

PMC ID: 6656726

PubMed ID: 31341171

SO-VID: 3e706c0a-48cc-4000-bbf4-e8ca5920210f

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 11 November 2016

Date accepted : 24 June 2019

Funding

Funded by: FundRef https://doi.org/10.13039/501100001602, Science Foundation Ireland (SFI);

Award ID: 13/IA/1962

Award Recipient : Wenxin Wang

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 51873179

Award Recipient : Wenxin Wang

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ScienceOpen disciplines: Uncategorized

Keywords: biomaterials,drug delivery,polymer synthesis

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ScienceOpen disciplines: Uncategorized

Keywords: biomaterials, drug delivery, polymer synthesis

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Highly branched poly(β-amino ester) delivery of minicircle DNA for transfection of neurodegenerative disease related cells

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RNA drug delivery

Most cited references 63

Design and development of polymers for gene delivery.

Nonviral vectors for gene delivery.

The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters.

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Cited by 35

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