The Nuclear Pore Complex: The Gateway to Successful Nonviral Gene Delivery

Aa, Marieke A. E. M. van der; Mastrobattista, Enrico; Oosting, Ronald S.; Hennink, Wim E.; Koning, Gerben A.; Crommelin, Daan J.A.

doi:10.1007/s11095-005-9445-4

Cited by 133 publications

(106 citation statements)

References 143 publications

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“…NLSs to bring pDNA into the nucleus is not within the scope of this review and has been reviewed elsewhere [1,21]. As described above, when cells undergo mitosis the NE is temporary disassembled, to reappear at the end of mitosis, when a new NE forms around the segregated sister chromatids.…”

Section: Reflections On Therapeutic Strategies For the Improvement Ofmentioning

confidence: 99%

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Intracellular partitioning of cell organelles and extraneous nanoparticles during mitosis

Symens

Soenen

Rejman

et al. 2012

Advanced Drug Delivery Reviews

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Section: Reflections On Therapeutic Strategies For the Improvement Ofmentioning

confidence: 99%

“…These 125 kDa large multi-protein complexes contain an aqueous channel that permits passive transport of molecules up to 10 nm in size. Larger molecules require a nuclear localization signal (NLS) that can enlarge the central channel of the NPCs up to 40 nm [21].…”

Section: General Introductionmentioning

confidence: 99%

Intracellular partitioning of cell organelles and extraneous nanoparticles during mitosis

Symens

Soenen

Rejman

et al. 2012

Advanced Drug Delivery Reviews

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“…This tightly regulated association of nucleoporins contains a central channel of +-9 nm width through which translocation of cargo from the cytoplasmic sight to the nucleoplasm should take place. Upon the presence of so-called nuclear localization signals (NLS), the central channel can widen up to 40 nm, increasing the permeability of the NPCs to a certain extent [1]. Several strategies to increase the translocation of pDNA through NPCs have been evaluated, such as targeting with NLSs or dilation of the NPCs with corticosteroids [2][3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Cell division responsive peptides for optimized plasmid DNA delivery: The mitotic window of opportunity?

Remaut

Symens

Lucas

et al. 2014

Journal of Controlled Release

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The delivery of plasmid DNA remains hard to achieve, especially due to the presence of the nuclear membrane barrier. During cell division, however, the nuclear membrane is temporarily disassembled. We evaluated two different strategies to optimize plasmid DNA delivery in dividing cells: 1) phosphorylation responsive peptides that release plasmid DNA preferentially during mitosis and 2) chromatin targeting peptides to anchor plasmid DNA in newly formed nuclei upon cell division. Peptide/DNA particles alone were not efficient in penetrating cells. Upon co-delivery with lipid-based carriers, however, transfection efficiency drastically improved when compared to controls. For the phosphorylation responsive peptides, the presence of the phosphorylation sequence slightly increased transfection efficiency. For the chromatin targeting peptides, however, the chromatin targeting sequence did not seem to be the main reason for the improvement of transfection efficiency when applied in living cells. In conclusion, the pre-condensation of plasmid DNA with peptides improves lipid based delivery, but the nature of the peptides (cell responsive or not) does not seem to be the main reason for the improvement. It seems that the nuclear entry of foreign plasmid DNA is still under tight control, even during the mitotic window of opportunity.

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“…This process usually requires the assistance of a nuclear localization signal (NLS), which facilitates the active transport of macromolecules into the nucleus from the cytoplasm through binding to nuclear transport proteins. 8 Different types of NLS have been reported to enhance the nuclear uptake of macromolecules. In general, NLS can be categorized as classical and non-classical.…”

Section: Introductionmentioning

confidence: 99%

“…The former typically contains a series of basic, positively charged amino acid sequence while the latter does not, and they differ in binding affinity to different nuclear transport receptors. 6,8 The most widely studied classical NLS is the Simian Virus 40 (SV40) large T-antigen-derived NLS, 9-11 a monopartite NLS that contains a single stretch of basic amino acids. It is also the most commonly investigated NLS for the delivery of macromolecules with a well-defined nuclear import pathway.…”

Section: Introductionmentioning

confidence: 99%

Incorporation of a Nuclear Localization Signal in pH Responsive LAH4-L1 Peptide Enhances Transfection and Nuclear Uptake of Plasmid DNA

Liang

Qiu

et al. 2016

Mol. Pharmaceutics

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The major intracellular barriers associated with DNA delivery using non-viral vectors are inefficient endosomal/lysosomal escape and poor nuclear uptake. LAH4-L1, a pH responsive cationic amphipathic peptide, is an efficient DNA delivery vector that promotes the release of nucleic acid into cytoplasm through endosomal escape. Here we further enhance the DNA transfection efficiency of LAH4-L1 by incorporating nuclear localizing signal (NLS) to promote nuclear importation. Four NLSs were investigated: Simian virus 40 (SV40) large T-antigen derived NLS, nucleoplasmin targeting signal, M9 sequence and the reverse SV40 derived NLS.All peptides tested were able to form positively charged nano-sized complexes with DNA.Significant improvement in DNA transfection was observed in slow-dividing epithelial cancer cells (Calu-3), macrophages (RAW264.7), dendritic cells (JAWSII), as well as thymidine-induced growth-arrested cells, but not in rapidly dividing cells (A549). Among the four NLS-modified peptides, PK1 (modified with SV40 derived NLS) and PK2 (modified with reverse SV40 derived NLS) were the most consistent in improving DNA transfection; up to a 10-fold increase in gene expression was observed for PK1 and PK2 over the unmodified LAH4-L1. Additionally PK1 and PK2 were shown to enhance cellular uptake as well as nuclear entry of DNA. Overall, we show that the incorporation of SV40 derived NLS, in particular, to LAH4-L1 is a promising strategy to improve DNA delivery efficiency in slow-dividing cells and dendritic cells, with development potential for in vivo applications and as a DNA vaccine carrier.

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The Nuclear Pore Complex: The Gateway to Successful Nonviral Gene Delivery

Cited by 133 publications

References 143 publications

Intracellular partitioning of cell organelles and extraneous nanoparticles during mitosis

Intracellular partitioning of cell organelles and extraneous nanoparticles during mitosis

Cell division responsive peptides for optimized plasmid DNA delivery: The mitotic window of opportunity?

Incorporation of a Nuclear Localization Signal in pH Responsive LAH4-L1 Peptide Enhances Transfection and Nuclear Uptake of Plasmid DNA

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