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Polymers
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Polymers and Nanogels for Gene Therapy
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Polymers and Nanogels for Gene Therapy

A special issue of Polymers (ISSN 2073-4360).

Deadline for manuscript submissions: closed (15 March 2017) | Viewed by 60072

Special Issue Editor

Prof. Dr. Ravin Narain

E-Mail Website
Guest Editor
Department of Chemical and Materials Engineering, Donadeo Innovation Centre for Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB T6G 1H9, Canada
Interests: polymer science and engineering; materials science; drug delivery; gene therapy; biomaterials bio-nanotechnology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Gene therapy has attracted significant attention over the past few decades for the treatment of inherited and acquired diseases. Even with substantial effort in recent years, delivery of genes to the target cells remains a significant challenge and the successful clinical translation of these technologies are still very slim. Current research efforts are focused on designing and synthesizing proper vectors that can efficiently compact and protect oligonucleotides. However, due to the hydrophilic and negatively charged nature of DNA or RNA and their low stability in the physiological environment (free oligonucleotides and plasmid DNA are rapidly degraded by serum nucleases in the blood when injected intravenously), the development of suitable carriers has been a daunting task for researchers working in this area. In addition, since both the genes and cell surfaces are negatively charged; entry of free DNA or RNA inside cells is a difficult task. So, the clinical translation of gene therapy is heavily dependent on the development of safe and efficient gene delivery systems. Research initially focused on viral vectors as these vectors exhibited high efficiency at delivering both DNA and RNA to numerous cell lines. However, several problems such as toxicity, immunogenicity and limitations with respect to scale-up procedures associated with viral vector systems have encouraged the investigation of synthetic DNA or RNA carriers into targeted tissue. Non-viral vector systems, including cationic lipids, polymers, dendrimers, peptides and nanoparticles, are the preferred means for compacting DNA for systemic delivery, but, unlike viral analogues, non-viral gene carriers reliably exhibit significant reduced transfection efficiency due to numerous extra- and intracellular obstacles, and the challenges are significant in vivo. However, their tunable biocompatibility and facilitated production make them potentially useful and attractive for gene therapy. As a result, major research efforts have focused on designing cationic systems that can form complexes with DNA, and avoid both in vitro and in vivo barriers.

This Special Issue entitled “Polymers and Nanogels for Gene Therapy” will cover recent developments in the use of precisely engineered polymers, nanoparticles and nanogels that can efficiently condense DNA and RNA and that demonstrate excellent gene expression or gene knock down efficacies. Special efforts in the design of new materials that are safe and efficient will be highlighted. Manuscripts on modification of polymers and nanoparticles to improve the gene expression or gene knock down efficacies as well as topics on mechanistic studies are also welcome. Contributions from both original research studies and comprehensive reviews will be considered.

Prof. Dr. Ravin Narain
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Polymers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Synthetic polymers
  • Natural polymers
  • Peptides
  • Nanogels
  • Polymer nanoparticles
  • Stimuli responsive polymers
  • Degradable polymers
  • DNA delivery
  • RNA delivery
  • In vitro and in vivo studies

Published Papers (8 papers)

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Research

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4002 KiB  
Article
Polyamidoamine (PAMAM) Dendrimers Modified with Cathepsin-B Cleavable Oligopeptides for Enhanced Gene Delivery
by Seulgi Lee, Sang Jae Son, Su Jeong Song, Tai Hwan Ha and Joon Sig Choi
Polymers 2017, 9(6), 224; https://doi.org/10.3390/polym9060224 - 14 Jun 2017
Cited by 24 | Viewed by 9113
Abstract
Because of the complex mechanisms mediating cancer onset, prognosis, and metastatic behavior, different therapeutic approaches targeting these mechanisms have been investigated. Recent advancements in nanocarrier-based drug and gene delivery methods have encouraged scientific groups to investigate various novel therapeutic techniques. In this study, [...] Read more.
Because of the complex mechanisms mediating cancer onset, prognosis, and metastatic behavior, different therapeutic approaches targeting these mechanisms have been investigated. Recent advancements in nanocarrier-based drug and gene delivery methods have encouraged scientific groups to investigate various novel therapeutic techniques. In this study, a poly(amidoamine) (PAMAM) polymer-based gene carrier containing the cathepsin B-enzyme sensitive sequence (glycine-phenylalanine-leucine-glycine, GFLG) was evaluated to determine transfection efficiency. Following the GFLG sequence, the surface of PAMAM generation 4 (G4) was conjugated with histidine (H) and arginine (R) for improved endosomal escape and cellular uptake, respectively. The successful synthesis of G4-GLFG-H-R was confirmed by 1H-nuclear magnetic resonance spectroscopy. The polyplex composed of G4-GLFG-H-R and pDNA was simulated by the enzyme cathepsin B and induced endosomal escape of pDNA, which was confirmed by gel electrophoresis. Compared with the G4 control, enzyme-sensitive G4-GLFG-H-R showed higher transfection efficiency and lower cytotoxicity in HeLa cells. These results demonstrated that G4-GLFG-H-R may be a highly potent and efficient carrier for gene therapy applications. Full article
(This article belongs to the Special Issue Polymers and Nanogels for Gene Therapy)
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5585 KiB  
Article
Apoptin Gene Delivery by the Functionalized Polyamidoamine (PAMAM) Dendrimer Modified with Ornithine Induces Cell Death of HepG2 Cells
by Yoonhee Bae, Su Jeong Song, Ji Young Mun, Kyung Soo Ko, Jin Han and Joon Sig Choi
Polymers 2017, 9(6), 197; https://doi.org/10.3390/polym9060197 - 29 May 2017
Cited by 14 | Viewed by 10366
Abstract
The use of tumor-specific therapeutic agents is a promising option for efficient and safe nonviral gene transfer in gene therapy. In this study, we describe the efficacy of polyamidoamine (PAMAM)-based nonviral gene delivery carriers, namely, an ornithine conjugated PAMAM (PAMAM-O) dendrimer in delivering [...] Read more.
The use of tumor-specific therapeutic agents is a promising option for efficient and safe nonviral gene transfer in gene therapy. In this study, we describe the efficacy of polyamidoamine (PAMAM)-based nonviral gene delivery carriers, namely, an ornithine conjugated PAMAM (PAMAM-O) dendrimer in delivering apoptin, a tumor-specific killer gene, into human hepatocellular carcinoma (HepG2 cells) and dermal fibroblasts. We analyzed the transfection efficiency by the luciferase assay and assessed cell viability in both cell types. The transfection efficiency of the PAMAM-O dendrimer was found to be higher than that of the PAMAM dendrimer. Moreover, the cytotoxicity of the PAMAM-O dendrimer was very low. We treated both cell types with a polyplex of PAMAM-O dendrimer with apoptin, and analyzed its cellular uptake and localization by confocal microscopy. Cell cycle distribution, tetramethylrhodamine, ethyl ester (TMRE) analysis, and transmission electron microscopy imaging showed that apoptin induced cell death in HepG2 cells. We therefore demonstrated that a PAMAM-O/apoptin polyplex can be used as an effective therapeutic strategy in cancer owing to its effectiveness as a suitable nonviral gene vector for gene therapy. Full article
(This article belongs to the Special Issue Polymers and Nanogels for Gene Therapy)
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5027 KiB  
Article
Evaluation of Amphiphilic Peptide Modified Antisense Morpholino Oligonucleotides In Vitro and in Dystrophic mdx Mice
by Mingxing Wang, Bo Wu, Peijuan Lu, Sapana N. Shah, Jason D. Tucker, Lauren E. Bollinger and Qilong Lu
Polymers 2017, 9(5), 177; https://doi.org/10.3390/polym9050177 - 15 May 2017
Cited by 2 | Viewed by 5468
Abstract
A series of amphiphilic peptides modified PMO (Pt-PMO) were prepared, and their antisense effect and toxicity were evaluated both in vitro and in mdx mice. The results showed that the exon-skipping performance of Pt-PMO are relative to the structure of the conjugated peptide: [...] Read more.
A series of amphiphilic peptides modified PMO (Pt-PMO) were prepared, and their antisense effect and toxicity were evaluated both in vitro and in mdx mice. The results showed that the exon-skipping performance of Pt-PMO are relative to the structure of the conjugated peptide: the Pt3/Pt4 composed of six/seven arginines and one myristoylation modified PMO showed more efficacy and with less toxicity as compared to others, confirming that appropriate hydrophilic-lipophilic balance (HLB) and cationic sequence numbers play a crucial role in improving cell uptake and corresponding exon-skipping efficiency. This was observed particularly in enhanced delivery efficiency of PMO comparable to B-PMO in vitro, while 6-fold improved exon-skipping was achieved against naked PMO in vivo. The multi-PMO modified Pt8-PMO also showed improved exon-skipping both in vitro and in vivo, though there is lower efficiency in systemic delivery as compared to Pt4-PMO. These data suggest that with optimization of peptide in component, charge density has clear potential for exploration towards achieving higher efficiency of antisense oligonucleotide systemic delivery, and thus is more applicable for clinical application. Full article
(This article belongs to the Special Issue Polymers and Nanogels for Gene Therapy)
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1237 KiB  
Article
Highly Branched poly(5-amino-1-pentanol-co-1,4-butanediol diacrylate) for High Performance Gene Transfection
by Ming Zeng, Dezhong Zhou, Singwei Ng, Jonathan O′Keeffe Ahern, Fatma Alshehri, Yongsheng Gao, Luca Pierucci, Udo Greiser and Wenxin Wang
Polymers 2017, 9(5), 161; https://doi.org/10.3390/polym9050161 - 01 May 2017
Cited by 22 | Viewed by 7408
Abstract
The top-performing linear poly(β-amino ester) (LPAE), poly(5-amino-1-pentanol-co-1,4-butanediol diacrylate) (C32), has demonstrated gene transfection efficiency comparable to viral-mediated gene delivery. Herein, we report the synthesis of a series of highly branched poly(5-amino-1-pentanol-co-1,4-butanediol diacrylate) (HC32) and explore how the branching structure influences the performance of [...] Read more.
The top-performing linear poly(β-amino ester) (LPAE), poly(5-amino-1-pentanol-co-1,4-butanediol diacrylate) (C32), has demonstrated gene transfection efficiency comparable to viral-mediated gene delivery. Herein, we report the synthesis of a series of highly branched poly(5-amino-1-pentanol-co-1,4-butanediol diacrylate) (HC32) and explore how the branching structure influences the performance of C32 in gene transfection. HC32 were synthesized by an “A2 + B3 + C2” Michal addition strategy. Gaussia luciferase (Gluciferase) and green fluorescent protein (GFP) coding plasmid DNA were used as reporter genes and the gene transfection efficiency was evaluated in human cervical cancer cell line (HeLa) and human recessive dystrophic epidermolysis bullosa keratinocyte (RDEBK) cells. We found that the optimal branching structure led to a much higher gene transfection efficiency in comparison to its linear counterpart and commercial reagents, while preserving high cell viability in both cell types. The branching strategy affected DNA binding, proton buffering capacity and degradation of polymers as well as size, zeta potential, stability, and DNA release rate of polyplexes significantly. Polymer degradation and DNA release rate played pivotal parts in achieving the high gene transfection efficiency of HC32-103 polymers, providing new insights for the development of poly(β-amino ester)s-based gene delivery vectors. Full article
(This article belongs to the Special Issue Polymers and Nanogels for Gene Therapy)
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6198 KiB  
Article
CAGW Peptide Modified Biodegradable Cationic Copolymer for Effective Gene Delivery
by Xinghong Duo, Jun Wang, Qian Li, Agnaldo Luis Neve, Mary Akpanyung, Abdelilah Nejjari, Zaidi Syed Saqib Ali, Yakai Feng, Wencheng Zhang and Changcan Shi
Polymers 2017, 9(5), 158; https://doi.org/10.3390/polym9050158 - 28 Apr 2017
Cited by 22 | Viewed by 6259
Abstract
In recent years, gene therapy has become a promising technology to enhance endothelialization of artificial vascular grafts. The ideal gene therapy requires a gene carrier with low cytotoxicity and high transfection efficiency. In this paper, we prepared a biodegradable cationic copolymer poly(d,l [...] Read more.
In recent years, gene therapy has become a promising technology to enhance endothelialization of artificial vascular grafts. The ideal gene therapy requires a gene carrier with low cytotoxicity and high transfection efficiency. In this paper, we prepared a biodegradable cationic copolymer poly(d,l-lactide-co-glycolide)-graft-PEI (PLGA-g-PEI), grafted Cys-Ala-Gly-Trp (CAGW) peptide onto this copolymer via the thiol-ene Click-reaction, and then prepared micelles by a self-assembly method. pEGFP-ZNF580 plasmids (pDNA) were condensed by these micelles via electrostatic interaction to form gene complexes. The CAGW peptide enables these gene complexes with special recognition for endothelial cells, which could enhance their transfection. As a gene carrier system, the PLGA-g-PEI-g-CAGW/pDNA gene complexes were evaluated and the results showed that they had suitable diameter and zeta potential for cellular uptake, and exhibited low cytotoxicity and high transfection efficiency for EA.hy926 cells. Full article
(This article belongs to the Special Issue Polymers and Nanogels for Gene Therapy)
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3921 KiB  
Article
Systematic Study of a Library of PDMAEMA-Based, Superparamagnetic Nano-Stars for the Transfection of CHO-K1 Cells
by Ullrich Stahlschmidt, Valérie Jérôme, Alexander P. Majewski, Axel H.E. Müller and Ruth Freitag
Polymers 2017, 9(5), 156; https://doi.org/10.3390/polym9050156 - 28 Apr 2017
Cited by 6 | Viewed by 5475
Abstract
The introduction of the DNA into mammalian cells remains a challenge in gene delivery, particularly in vivo. Viral vectors are unmatched in their efficiency for gene delivery, but may trigger immune responses and cause severe side-reactions. Non-viral vectors are much less efficient. Recently, [...] Read more.
The introduction of the DNA into mammalian cells remains a challenge in gene delivery, particularly in vivo. Viral vectors are unmatched in their efficiency for gene delivery, but may trigger immune responses and cause severe side-reactions. Non-viral vectors are much less efficient. Recently, our group has suggested that a star-shaped structure improves and even transforms the gene delivery capability of synthetic polycations. In this contribution, this effect was systematically studied using a library of highly homogeneous, paramagnetic nano-star polycations with varied arm lengths and grafting densities. Gene delivery was conducted in CHO-K1 cells, using a plasmid encoding a green fluorescent reporter protein. Transfection efficiencies and cytotoxicities varied systematically with the nano-star architecture. The arm density was particularly important, with values of approximately 0.06 arms/nm2 yielding the best results. In addition, a certain fraction of the cells became magnetic during transfection. The gene delivery potential of a nano-star and its ability to render the cells magnetic did not have any correlations. End-capping the polycation arms with di(ethylene glycol) methyl ether methacrylate (PDEGMA) significantly improved serum compatibility under transfection conditions; such nano-stars are potential candidates for future in vivo testing. Full article
(This article belongs to the Special Issue Polymers and Nanogels for Gene Therapy)
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2680 KiB  
Article
Influence of Defined Hydrophilic Blocks within Oligoaminoamide Copolymers: Compaction versus Shielding of pDNA Nanoparticles
by Stephan Morys, Ana Krhac Levacic, Sarah Urnauer, Susanne Kempter, Sarah Kern, Joachim O. Rädler, Christine Spitzweg, Ulrich Lächelt and Ernst Wagner
Polymers 2017, 9(4), 142; https://doi.org/10.3390/polym9040142 - 19 Apr 2017
Cited by 17 | Viewed by 6514
Abstract
Cationic polymers are promising components of the versatile platform of non-viral nucleic acid (NA) delivery agents. For a successful gene delivery system, these NA vehicles need to comprise several functionalities. This work focuses on the modification of oligoaminoamide carriers with hydrophilic oligomer blocks [...] Read more.
Cationic polymers are promising components of the versatile platform of non-viral nucleic acid (NA) delivery agents. For a successful gene delivery system, these NA vehicles need to comprise several functionalities. This work focuses on the modification of oligoaminoamide carriers with hydrophilic oligomer blocks mediating nanoparticle shielding potential, which is necessary to prevent aggregation or dissociation of NA polyplexes in vitro, and hinder opsonization with blood components in vivo. Herein, the shielding agent polyethylene glycol (PEG) in three defined lengths (12, 24, or 48 oxyethylene repeats) is compared with two peptidic shielding blocks composed of four or eight repeats of sequential proline-alanine-serine (PAS). With both types of shielding agents, we found opposing effects of the length of hydrophilic segments on shielding and compaction of formed plasmid DNA (pDNA) nanoparticles. Two-arm oligoaminoamides with 37 cationizable nitrogens linked to 12 oxyethylene units or four PAS repeats resulted in very compact 40–50 nm pDNA nanoparticles, whereas longer shielding molecules destabilize the investigated polyplexes. Thus, the balance between sufficiently shielded but still compact and stable particles can be considered a critical optimization parameter for non-viral nucleic acid vehicles based on hydrophilic-cationic block oligomers. Full article
(This article belongs to the Special Issue Polymers and Nanogels for Gene Therapy)
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Review

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3874 KiB  
Review
Stimuli-Regulated Smart Polymeric Systems for Gene Therapy
by Ansuja Pulickal Mathew, Ki-Hyun Cho, Saji Uthaman, Chong-Su Cho and In-Kyu Park
Polymers 2017, 9(4), 152; https://doi.org/10.3390/polym9040152 - 24 Apr 2017
Cited by 29 | Viewed by 8637
Abstract
The physiological condition of the human body is a composite of different environments, each with its own parameters that may differ under normal, as well as diseased conditions. These environmental conditions include factors, such as pH, temperature and enzymes that are specific to [...] Read more.
The physiological condition of the human body is a composite of different environments, each with its own parameters that may differ under normal, as well as diseased conditions. These environmental conditions include factors, such as pH, temperature and enzymes that are specific to a type of cell, tissue or organ or a pathological state, such as inflammation, cancer or infection. These conditions can act as specific triggers or stimuli for the efficient release of therapeutics at their destination by overcoming many physiological and biological barriers. The efficacy of conventional treatment modalities can be enhanced, side effects decreased and patient compliance improved by using stimuli-responsive material that respond to these triggers at the target site. These stimuli or triggers can be physical, chemical or biological and can be internal or external in nature. Many smart/intelligent stimuli-responsive therapeutic gene carriers have been developed that can respond to either internal stimuli, which may be normally present, overexpressed or present in decreased levels, owing to a disease, or to stimuli that are applied externally, such as magnetic fields. This review focuses on the effects of various internal stimuli, such as temperature, pH, redox potential, enzymes, osmotic activity and other biomolecules that are present in the body, on modulating gene expression by using stimuli-regulated smart polymeric carriers. Full article
(This article belongs to the Special Issue Polymers and Nanogels for Gene Therapy)
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