Polymers in Gene Delivery

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

Deadline for manuscript submissions: closed (15 December 2018) | Viewed by 43264

Special Issue Editor

College of Pharmacy and Nutrition, University of Saskatchewan, 107 Wiggins Road, Health Sciences Building, Room 3D01.5, Box 3D01-13, Saskatoon, SK S7N 5E5, Canada
Interests: nucleic acid delivery; nanodiamonds; cationic gemini lipids; self-assembling nanoparticles; small angle X-ray scattering; flow cytometry; radiopharmaceuticals
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Special Issue Information

Dear Colleagues,

Gene therapy has been at the forefront of drug delivery research for the past three decades. To overcome the barriers of gene delivery, different types of non-viral delivery systems, including polymers, have been developed and advanced to clinical trials.

Manuscripts addressing the design, synthesis, and characterization of polymer-based gene delivery systems are solicited. Novel characterization techniques for polymers and hybrid materials, their assembly with the genetic material into complex systems, and fundamental understanding of their morphology and thermodynamic properties are fields of interest. Submission of work regarding interaction of the polymer/nucleic acid complexes with biological systems, as well as their fate in biological environments is encouraged.

Dr. Ildiko Badea
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

  • polyplex
  • genetic material
  • surface properties
  • self-assembly
  • structure–activity relationship
  • gene expression
  • cellular internalization
  • toxicity

Published Papers (8 papers)

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Research

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20 pages, 3449 KiB  
Article
Amphiphilic Peptides for Efficient siRNA Delivery
by Saghar Mozaffari, Emira Bousoik, Farideh Amirrad, Robert Lamboy, Melissa Coyle, Ryley Hall, Abdulaziz Alasmari, Parvin Mahdipoor, Keykavous Parang and Hamidreza Montazeri Aliabadi
Polymers 2019, 11(4), 703; https://doi.org/10.3390/polym11040703 - 17 Apr 2019
Cited by 19 | Viewed by 4091
Abstract
A number of amphiphilic cyclic peptides—[FR]4, [WR]5, and [WK]5—containing hydrophobic and positively-charged amino acids were synthesized by Fmoc/tBu solid-phase peptide methods and evaluated for their efficiency in intracellular delivery of siRNA to triple-negative breast cancer cell lines, [...] Read more.
A number of amphiphilic cyclic peptides—[FR]4, [WR]5, and [WK]5—containing hydrophobic and positively-charged amino acids were synthesized by Fmoc/tBu solid-phase peptide methods and evaluated for their efficiency in intracellular delivery of siRNA to triple-negative breast cancer cell lines, MDA-MB-231 and MDA-MB-468, in the presence and absence of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Among the peptides, [WR]5, which contains alternate tryptophan (W) and arginine (R) residues, was found to be the most efficient in the delivery of siRNA by improving the delivery by more than 3-fold when compared to other synthesized cyclic peptides that were not efficient. The data also showed that co-formulation of [WR]5 with lipid DOPE significantly enhanced the efficiency of siRNA delivery by up to ~2-fold compared to peptide alone. Based on the data indicating the efficiency of [WR]5 in siRNA delivery, peptides containing arginine residues on the ring and tryptophan residues on the side chain, [R6K]W6 and [R5K]W5, were also evaluated, and demonstrated improved delivery of siRNA. The presence of DOPE again enhanced the siRNA delivery in most cases. [WR]5, [R5K]W5, and [R6K]W6 did not show any significant toxicity in MDA-MB-231, MDA-MB-468, and AU565 WT cells at N/P ratios of 20:1 or less, in the presence and absence of DOPE. Silencing of kinesin spindle protein (KSP) and Janus kinase 2 (JAK2) was evaluated in MDA-MB-231 cells in the presence of the peptides. The addition of DOPE significantly enhanced the silencing efficiency for all selected peptides. In conclusion, peptides containing tryptophan and arginine residues were found to enhance siRNA delivery and to generate silencing of targeted proteins in the presence of DOPE. Full article
(This article belongs to the Special Issue Polymers in Gene Delivery)
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16 pages, 6292 KiB  
Article
Polyplexes of Functional PAMAM Dendrimer/Apoptin Gene Induce Apoptosis of Human Primary Glioma Cells In Vitro
by Yoonhee Bae, Le Thi Thuy, Young Hwa Lee, Kyung Soo Ko, Jin Han and Joon Sig Choi
Polymers 2019, 11(2), 296; https://doi.org/10.3390/polym11020296 - 10 Feb 2019
Cited by 20 | Viewed by 4073
Abstract
Highly efficient and safe gene delivery has become an important aspect of neuronal gene therapy. We evaluated the ability of polyamidoamine (PAMAM) dendrimer grafted with phenylalanine, histidine, and arginine (PAMAM-FHR), a nonviral gene delivery vector, to deliver a therapeutic, tumor cell-specific killer gene, [...] Read more.
Highly efficient and safe gene delivery has become an important aspect of neuronal gene therapy. We evaluated the ability of polyamidoamine (PAMAM) dendrimer grafted with phenylalanine, histidine, and arginine (PAMAM-FHR), a nonviral gene delivery vector, to deliver a therapeutic, tumor cell-specific killer gene, apoptin, into the human primary glioma cell line GBL-14 and human dermal fibroblasts. We performed a transfection assay using plasmids of luciferase and enhanced green fluorescent protein (EGFP) and assessed cell viability. Both cell lines were treated with complexes of PAMAM-FHR and apoptin after which their intracellular uptake and localization were examined by fluorescence-activated cell sorting (FACS)analysis and confocal laser scanning microscopy. Confocal microscopy showed that the PAMAM-FHR escaped from the endo-lysosome into the cytosol. Cell cycle phase distribution analysis, annexin V staining, and a tetramethylrhodamine ethyl ester (TMRE) assay established that apoptin triggered apoptosis in the GBL-14 cell line but not in normal fibroblasts. These results indicated that the PAMAM-FHR/apoptin complex is an effective gene vehicle for cancer therapy in vitro. Full article
(This article belongs to the Special Issue Polymers in Gene Delivery)
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9 pages, 2917 KiB  
Communication
Glycosylated Artificial Virus-Like Hybrid Vectors for Advanced Gene Delivery
by Shashank Reddy Pinnapireddy, Mohamed Raafat El Assy, Patrick Schlote and Udo Bakowsky
Polymers 2019, 11(2), 243; https://doi.org/10.3390/polym11020243 - 01 Feb 2019
Cited by 9 | Viewed by 3999
Abstract
The major obstacle facing efficient gene therapy is the development of reliable delivery vehicles, which are both nontoxic and biocompatible and possess efficient cell-specific gene delivery. Previously, hybrid delivery vehicles comprising anionic liposomes and cationic polymers have been used successfully for gene therapy. [...] Read more.
The major obstacle facing efficient gene therapy is the development of reliable delivery vehicles, which are both nontoxic and biocompatible and possess efficient cell-specific gene delivery. Previously, hybrid delivery vehicles comprising anionic liposomes and cationic polymers have been used successfully for gene therapy. In this study, hybrid vectors based on glycosylated artificial viral envelopes (including two novel compositions mimicking HIV and HSV envelopes) and polyethylenimine were morphologically and physiologically characterised. Transfection studies showed that the hybrid vectors based on the control liposomes, and their glycosylated modifications, had significantly higher transfection rates compared to the polyplexes. Improvement in the transfection efficiency was observed with the glycosylated HIV- and HSV-mimicking hybrid vectors, which also showed a safe biocompatibility profile based on the cytotoxicity and haemocompatibility assays. These glycosylated artificial viral envelope-based hybrid vectors could be used as safe gene delivery systems with potential to become new compositions for efficient nonviral gene therapy. Full article
(This article belongs to the Special Issue Polymers in Gene Delivery)
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9 pages, 2089 KiB  
Article
A Polycationic Brush Mediated Co-Delivery of Doxorubicin and Gene for Combination Therapy
by Wenjuan Chen, Mingming Zhang, Wei Shen, Bo Du, Jing Yang and Qiqing Zhang
Polymers 2019, 11(1), 60; https://doi.org/10.3390/polym11010060 - 03 Jan 2019
Cited by 14 | Viewed by 3656
Abstract
The combination of drug and gene strategies for cancer therapy, has exhibited greater effectiveness than drug or gene therapy alone. In this paper, a coil-comb shaped polycationic brush was used as a multifunctional carrier for co-delivery of drug and gene. The side chains [...] Read more.
The combination of drug and gene strategies for cancer therapy, has exhibited greater effectiveness than drug or gene therapy alone. In this paper, a coil-comb shaped polycationic brush was used as a multifunctional carrier for co-delivery of drug and gene. The side chains of the comb block of the brush were composed of cyclodextrin (CD)-containing cationic star polymers, with a super-high density of positive charge. Doxorubicin (DOX) could be loaded into the cavity of CD polymers to form DOX-loaded nanoparticles (DOX-NPs) and the p53 gene could be subsequently condensed by DOX-NPs. The obtained DOX-NPs/pDNA complexes were less than 150 nm in size, and so could transport DOX and the gene into the same cell. The complexes performed well with regards to their transfection efficiency on MCF-7 cancer cells. As a result, enhanced cell growth inhibition, with decreased DOX dosage was achieved due to the synergistic effect of co-delivery of DOX and the p53 gene. This finding provides an efficient approach for the development of a co-delivery system in combination therapy. Full article
(This article belongs to the Special Issue Polymers in Gene Delivery)
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16 pages, 5921 KiB  
Article
Biodegradable Gene Carriers Containing Rigid Aromatic Linkage with Enhanced DNA Binding and Cell Uptake
by Ju-Hui Zhang, Hui-Zhen Yang, Ji Zhang, Yan-Hong Liu, Xi He, Ya-Ping Xiao and Xiao-Qi Yu
Polymers 2018, 10(10), 1080; https://doi.org/10.3390/polym10101080 - 29 Sep 2018
Cited by 7 | Viewed by 2695
Abstract
The linking and modification of low molecular weight cationic polymers (oligomers) has become an attracted strategy to construct non-viral gene carriers with good transfection efficiency and much reduced cytotoxicity. In this study, PEI 600 Da was linked by biodegradable bridges containing rigid aromatic [...] Read more.
The linking and modification of low molecular weight cationic polymers (oligomers) has become an attracted strategy to construct non-viral gene carriers with good transfection efficiency and much reduced cytotoxicity. In this study, PEI 600 Da was linked by biodegradable bridges containing rigid aromatic rings. The introduction of aromatic rings enhanced the DNA-binding ability of the target polymers and also improved the stability of the formed polymer/DNA complexes. The biodegradable property and resulted DNA release were verified by enzyme stimulated gel electrophoresis experiment. These materials have lower molecular weights compared to PEI 25 kDa, but exhibited higher transfection efficiency, especially in the presence of serum. Flow cytometry and confocal laser scanning microscopy results indicate that the polymers with aromatic rings could induce higher cellular uptake. This strategy for the construction of non-viral gene vectors may be applied as an efficient and promising method for gene delivery. Full article
(This article belongs to the Special Issue Polymers in Gene Delivery)
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11 pages, 4612 KiB  
Article
Sugar Functionalized Synergistic Dendrimers for Biocompatible Delivery of Nucleic Acid Therapeutics
by Shuqin Han, Tsogzolmaa Ganbold, Qingming Bao, Takashi Yoshida and Huricha Baigude
Polymers 2018, 10(9), 1034; https://doi.org/10.3390/polym10091034 - 18 Sep 2018
Cited by 8 | Viewed by 3179
Abstract
Sugars containing cationic polymers are potential carriers for in vitro and in vivo nucleic acid delivery. Monosaccharides such as glucose and galactose have been chemically conjugated to various materials of synergistic poly-lysine dendrimer systems for efficient and biocompatible delivery of short interfering RNA [...] Read more.
Sugars containing cationic polymers are potential carriers for in vitro and in vivo nucleic acid delivery. Monosaccharides such as glucose and galactose have been chemically conjugated to various materials of synergistic poly-lysine dendrimer systems for efficient and biocompatible delivery of short interfering RNA (siRNA). The synergistic dendrimers, which contain lipid conjugated glucose terminalized lysine dendrimers, have significantly lower adverse impact on cells while maintaining efficient cellular entry. Moreover, the synergistic dendrimers complexed to siRNA induced RNA interference (RNAi) in the cells and profoundly knocked down green fluorescence protein (GFP) as well as the endogenously expressing disease related gene Plk1. The new synergic dendrimers may be promising system for biocompatible and efficient siRNA delivery. Full article
(This article belongs to the Special Issue Polymers in Gene Delivery)
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14 pages, 2147 KiB  
Article
Modular Synthesis of Bioreducible Gene Vectors through Polyaddition of N,N′-Dimethylcystamine and Diglycidyl Ethers
by Guoying Si, M. Rachèl Elzes, Johan F. J. Engbersen and Jos M. J. Paulusse
Polymers 2018, 10(6), 687; https://doi.org/10.3390/polym10060687 - 20 Jun 2018
Cited by 7 | Viewed by 3988
Abstract
Bioreducible, cationic linear poly(amino ether)s (PAEs) were designed as promising gene vectors. These polymers were synthesized by the reaction of a disulfide-functional monomer, N,N′-dimethylcystamine (DMC), and several different diglycidyl ethers. The resulting PAEs displayed a substantial buffer capacity (up to [...] Read more.
Bioreducible, cationic linear poly(amino ether)s (PAEs) were designed as promising gene vectors. These polymers were synthesized by the reaction of a disulfide-functional monomer, N,N′-dimethylcystamine (DMC), and several different diglycidyl ethers. The resulting PAEs displayed a substantial buffer capacity (up to 64%) in the endosomal acidification region of pH 7.4–5.1. The PAEs condense plasmid DNA into 80–200 nm sized polyplexes, and have surface charges ranging from +20 to +40 mV. The polyplexes readily release DNA upon exposure to reducing conditions (2.5 mM DTT) due to the cleavage of the disulfide groups that is present in the main chain of the polymers, as was demonstrated by agarose gel electrophoresis. Upon exposing COS-7 cells to polyplexes that were prepared at polymer/DNA w/w ratios below 48, cell viabilities between 80–100% were observed, even under serum-free conditions. These polyplexes show comparable or higher transfection efficiencies (up to 38%) compared to 25 kDa branched polyethylenimine (PEI) polyplexes (12% under serum-free conditions). Moreover, the PAE-based polyplexes yield transfection efficiencies as high as 32% in serum-containing medium, which makes these polymers interesting for gene delivery applications. Full article
(This article belongs to the Special Issue Polymers in Gene Delivery)
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Review

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35 pages, 3663 KiB  
Review
Polymeric Nanoparticles in Gene Therapy: New Avenues of Design and Optimization for Delivery Applications
by Raj Rai, Saniya Alwani and Ildiko Badea
Polymers 2019, 11(4), 745; https://doi.org/10.3390/polym11040745 - 25 Apr 2019
Cited by 190 | Viewed by 16654
Abstract
The field of polymeric nanoparticles is quickly expanding and playing a pivotal role in a wide spectrum of areas ranging from electronics, photonics, conducting materials, and sensors to medicine, pollution control, and environmental technology. Among the applications of polymers in medicine, gene therapy [...] Read more.
The field of polymeric nanoparticles is quickly expanding and playing a pivotal role in a wide spectrum of areas ranging from electronics, photonics, conducting materials, and sensors to medicine, pollution control, and environmental technology. Among the applications of polymers in medicine, gene therapy has emerged as one of the most advanced, with the capability to tackle disorders from the modern era. However, there are several barriers associated with the delivery of genes in the living system that need to be mitigated by polymer engineering. One of the most crucial challenges is the effectiveness of the delivery vehicle or vector. In last few decades, non-viral delivery systems have gained attention because of their low toxicity, potential for targeted delivery, long-term stability, lack of immunogenicity, and relatively low production cost. In 1987, Felgner et al. used the cationic lipid based non-viral gene delivery system for the very first time. This breakthrough opened the opportunity for other non-viral vectors, such as polymers. Cationic polymers have emerged as promising candidates for non-viral gene delivery systems because of their facile synthesis and flexible properties. These polymers can be conjugated with genetic material via electrostatic attraction at physiological pH, thereby facilitating gene delivery. Many factors influence the gene transfection efficiency of cationic polymers, including their structure, molecular weight, and surface charge. Outstanding representatives of polymers that have emerged over the last decade to be used in gene therapy are synthetic polymers such as poly(l-lysine), poly(l-ornithine), linear and branched polyethyleneimine, diethylaminoethyl-dextran, poly(amidoamine) dendrimers, and poly(dimethylaminoethyl methacrylate). Natural polymers, such as chitosan, dextran, gelatin, pullulan, and synthetic analogs, with sophisticated features like guanidinylated bio-reducible polymers were also explored. This review outlines the introduction of polymers in medicine, discusses the methods of polymer synthesis, addressing top down and bottom up techniques. Evaluation of functionalization strategies for therapeutic and formulation stability are also highlighted. The overview of the properties, challenges, and functionalization approaches and, finally, the applications of the polymeric delivery systems in gene therapy marks this review as a unique one-stop summary of developments in this field. Full article
(This article belongs to the Special Issue Polymers in Gene Delivery)
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