Biodegradable Gene Carriers Containing Rigid Aromatic Linkage with Enhanced DNA Binding and Cell Uptake

Zhang, Ju-Hui; Yang, Huizhen; Zhang, Ji; Liu, Yanhong; He, Xi; Xiao, Yaping; Yu, Xiao‐Qi

doi:10.3390/polym10101080

Cited by 7 publications

(9 citation statements)

References 43 publications

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“…Higher degrees of modification resulted in more zPEI being required to fully bind the DNA. For example, unmodified PEI required a bPEI/DNA ratio of 0.375 (w/w) in good agreement with prior literature . In contrast, to fully condense the DNA, zPEI 3, 6.5, 9, and 11.5 required polymer/DNA ratios of 0.625, 0.625, 0.75, and 1.125 (w:w), respectively.…”

Section: Resultssupporting

confidence: 81%

“…For example, unmodified PEI required a bPEI/ DNA ratio of 0.375 (w/w) in good agreement with prior literature. 48 In contrast, to fully condense the DNA, zPEI 3, 6.5, 9, and 11.5 required polymer/DNA ratios of 0.625, 0.625, 0.75, and 1.125 (w:w), respectively. No significant difference in DNA binding between the PEI and zPEI 2 was observed.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Enhanced Gene Delivery and CRISPR/Cas9 Homology-Directed Repair in Serum by Minimally Succinylated Polyethylenimine

et al. 2021

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Gene therapy aims to treat patients by altering or controlling gene expression. The field of gene therapy has had increasing success in recent years primarily using viral-based approaches; however, there is still significant interest toward the use of polymeric materials due to their potential as flexible, low-cost scaffolds for gene delivery that do not suffer the mutagenesis and immunogenicity concerns of viral vectors. To address the challenges of efficiency and biocompatibility, a series of zwitterion-like polyethylenimine derivatives (zPEIs) were produced via the succinylation of 2–11.5% of polyethylenimine (PEI) amines. With increasing modification, zPEI polyplexes exhibited decreased serum-protein aggregation and dissociated more easily in the presence of a competitor polyanion when compared to unmodified PEI. Surprisingly, the gene delivery mediated in the presence of serum showed that succinylation of as few as 2% of PEI amines resulted in transgene expression 260- to 480-fold higher than that of unmodified PEI and 50- to 65-fold higher than that of commercial PEI-PEG2k in HEK293 and HeLa cells, respectively. Remarkably, the same zPEIs also produced 16-fold greater efficiency of CRISPR/Cas9 gene knock-in compared to unmodified PEI in the presence of serum. In addition, we show that 2% succinylation does not significantly decrease polymer/DNA binding ability or serum protein interaction to a significant extent, yet this small modification is still sufficient to provide a remarkable increase in transgene expression and gene knock-in in the presence of serum.

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Section: Resultssupporting

confidence: 81%

Section: ■ Results and Discussionmentioning

confidence: 99%

Enhanced Gene Delivery and CRISPR/Cas9 Homology-Directed Repair in Serum by Minimally Succinylated Polyethylenimine

et al. 2021

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“…Further modification of this polymer with substance P (SP) as the targeting ligand through PEG produced a conjugated polymer that had excellent biocompatibility, ROS cleavability ad transfection efficacy and gene silencing activity in vitro and satisfactory antitumor activity in vivo. A recent study shows that linking of 600 Da PEI with biodegradable bridges of aromatic rings could enhance the DNA binding ability of low MW PEI and increase its stability and transfection efficacy [118].…”

Section: Synthetic Polymers For Gene Deliverymentioning

confidence: 99%

Biodegradable Polymers for Gene Delivery

2019

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The cellular transport process of DNA is hampered by cell membrane barriers, and hence, a delivery vehicle is essential for realizing the potential benefits of gene therapy to combat a variety of genetic diseases. Virus-based vehicles are effective, although immunogenicity, toxicity and cancer formation are among the major limitations of this approach. Cationic polymers, such as polyethyleneimine are capable of condensing DNA to nanoparticles and facilitate gene delivery. Lack of biodegradation of polymeric gene delivery vehicles poses significant toxicity because of the accumulation of polymers in the tissue. Many attempts have been made to develop biodegradable polymers for gene delivery by modifying existing polymers and/or using natural biodegradable polymers. This review summarizes mechanistic aspects of gene delivery and the development of biodegradable polymers for gene delivery.

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“…Alongside several synthetic methods ( 16 – 19 ), the administration of the antimalarial drug chloroquine during transfection has been commonly employed to promote intracellular plasmid DNA (pDNA) unpackaging ( 20 ). In addition to promoting endosomal escape ( 21 – 23 ), chloroquine has been shown to facilitate unpackaging of pDNA by competitive binding ( 24 , 25 ).…”

mentioning

confidence: 99%

Quinine copolymer reporters promote efficient intracellular DNA delivery and illuminate a protein-induced unpackaging mechanism

Bruggen

Punihaole

Keith

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Polymeric vehicles that efficiently package and controllably release nucleic acids enable the development of safer and more efficacious strategies in genetic and polynucleotide therapies. Developing delivery platforms that endogenously monitor the molecular interactions, which facilitate binding and release of nucleic acids in cells, would aid in the rational design of more effective vectors for clinical applications. Here, we report the facile synthesis of a copolymer containing quinine and 2-hydroxyethyl acrylate that effectively compacts plasmid DNA (pDNA) through electrostatic binding and intercalation. This polymer system poly(quinine-co-HEA) packages pDNA and shows exceptional cellular internalization, transgene expression, and low cytotoxicity compared to commercial controls for several human cell lines, including HeLa, HEK 293T, K562, and keratinocytes (N/TERTs). Using quinine as an endogenous reporter for pDNA intercalation, Raman imaging revealed that proteins inside cells facilitate the unpackaging of polymer–DNA complexes (polyplexes) and the release of their cargo. Our work showcases the ability of this quinine copolymer reporter to not only facilitate effective gene delivery but also enable diagnostic monitoring of polymer–pDNA binding interactions on the molecular scale via Raman imaging. The use of Raman chemical imaging in the field of gene delivery yields unprecedented insight into the unpackaging behavior of polyplexes in cells and provides a methodology to assess and design more efficient delivery vehicles for gene-based therapies.

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Biodegradable Gene Carriers Containing Rigid Aromatic Linkage with Enhanced DNA Binding and Cell Uptake

Cited by 7 publications

References 43 publications

Enhanced Gene Delivery and CRISPR/Cas9 Homology-Directed Repair in Serum by Minimally Succinylated Polyethylenimine

Enhanced Gene Delivery and CRISPR/Cas9 Homology-Directed Repair in Serum by Minimally Succinylated Polyethylenimine

Biodegradable Polymers for Gene Delivery

Quinine copolymer reporters promote efficient intracellular DNA delivery and illuminate a protein-induced unpackaging mechanism

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