DNA Nuclear Targeting Sequences for Non-Viral Gene Delivery

Gaal, Ethlinn V.B. van; Oosting, Ronald S.; Eijk, Roel van; Bakowska, Marta; Feyen, Dries; Kok, Robbert J.; Hennink, Wim E.; Crommelin, Daan J.A.; Mastrobattista, Enrico

doi:10.1007/s11095-011-0407-8

Cited by 48 publications

(32 citation statements)

References 61 publications

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“…Hence, there is a need for carriers that are able to protect the DNA through the in-vivo transportation process and play a certain role in enhancing the expression of encoded proteins. [46][47][48][49] Nanocarriers were designed first by Speiser and coworkers in the 1970s and were defined as solid colloidal particles with sizes less than 1 m that can interact with 50 Since that time, a considerable amount of work has been performed on nanoparticles worldwide, especially in fields of gene and drug delivery. Nanoparticles were initially designed as carriers for vaccines and anti-cancer drugs; however, they have been extensively applied in ophthalmic, oral drug delivery and various other therapeutic applications.…”

Section: Introductionmentioning

confidence: 99%

Polysaccharides as Nanocarriers for Therapeutic Applications

Singh¹,

Han²,

Shin³

2014

j biomed nanotechnol

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Nanocarriers have shown tremendous potential for the target-specific delivery of proteins, genes and drugs. Nanoparticles are fabricated using different natural and synthetic polymers. Natural polysaccharides are often used as building block for developing nano-sized drug delivery vehicles. The physicochemical properties of these materials, such as excellent biocompatibility, low cytotoxicity, surface charges that interact with DNA, protein and RNA, and cost effectiveness, make them exceptional base materials for nanocarrier fabrication. The mechanism for the complex formation of polysaccharides-DNA includes the electrostatic interactions between cationic polymers and anionic DNA to form polyplexes that offer unique possibilities for overcoming cellular barriers by escaping endosomal trafficking followed by cellular internalization and, consequently, enhancing the efficacy of drug and macromolecule delivery to targeted cells and tissue. Depending upon the cellular uptake and trafficking, nanocarriers are designed for different pharmacological and therapeutic applications. However, specific targeting that improves delivery remains an unsolved challenged. The process by which nanocarriers enter cells has important consequences not only for fate of these particles but also for biological systems and therapeutic applications.

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Section: Introductionmentioning

confidence: 99%

Polysaccharides as Nanocarriers for Therapeutic Applications

Singh¹,

Han²,

Shin³

2014

j biomed nanotechnol

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“…Another possibility or a combination of the two, for the observed differences in IC 50 reductions, could be the different INSM1-promoter activity levels in the three SCLC cell lines. In a recent study, van Gaal et al 27 hypothesized that one important bottleneck for the plasmid transgene expression could be the strength of the promoter used for the transgene expression and that a strong promoter, for example, the CMV promoter, could saturate the expression machinery, thereby masking any increase in nuclear translocation. In support of this hypothesis, we see the smallest effect of the NFkB-DTS insert in the NCI-H69 cell line that has the relatively highest INSM1-promoter activity; in contrast, we see the largest effect in the DMS53 cell line, which has the relatively lowest promoter activity of the three SCLC cell lines tested.…”

Section: Discussionmentioning

confidence: 99%

Insertion of a nuclear factor kappa B DNA nuclear-targeting sequence potentiates suicide gene therapy efficacy in lung cancer cell lines

et al. 2012

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Lung cancer currently causes the majority of cancer-related deaths worldwide and new treatments are in high demand. Gene therapy could be a promising treatment but currently lacks sufficient efficiency for clinical use, primarily due to limited cellular and nuclear DNA delivery. In the present study, we investigated whether it was possible to exploit the endogenous nuclear-shuttling activity by the nuclear factor kappa B (NFkB) system, which is highly prominent in many cancers as well as lung cancer. We observed that insertion of a DNA nuclear-targeting sequence (DTS) recognized by NFkB could improve plasmid nuclear delivery and enhance the therapeutic effect of a validated transcriptionally cancer-targeted suicide gene therapy system. A clear correlation between the number of inserted NFkB-binding sites and the therapeutic effect of the suicide system was observed in both small cell lung cancer (SCLC) and non-SCLC cell lines. The effect was observed to be due to elevated nuclear translocation of the suicide gene-encoding plasmids. The results show that a significant improvement of gene therapeutic efficiency can be obtained by increasing the intracellular trafficking of therapeutic DNA. This is to our knowledge the first time a DTS strategy has been implemented for suicide gene therapy.

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“…We used for all these genes the cytomegalovirus immediate early promoter (CMV) that is often employed for PEI-mediated transfection [33–35]. For experiments with plasmid DNA labeling with QD605 quantum dots, we used the phTERT-TK plasmid encoding HSV tk under human telomerase reverse transcriptase promoter as described earlier [16].…”

Section: Methodsmentioning

confidence: 99%

Subcellular trafficking and transfection efficacy of polyethylenimine–polyethylene glycol polyplex nanoparticles with a ligand to melanocortin receptor-1

Durymanov

Beletkaia

Ulasov

et al. 2012

Journal of Controlled Release

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We have synthesized and investigated properties of new PEI-PEG-based polyplexes containing MC1SP-peptide, a ligand specific for melanocortin receptor-1 (targeted polyplexes), and control polyplexes without this ligand peptide (non-targeted polyplexes). The targeted polyplexes demonstrated receptor-mediated transfection of Cloudman S91 (clone M-3) murine melanoma cells that was more efficient than with the non-targeted ones. Transfection with the targeted polyplexes was inhibited by chlorpromazine, an inhibitor of the clathrin-mediated endocytosis pathway, and, to a lesser extent, by filipin III or nystatin, inhibitors of the lipid-raft endocytosis pathway, whereas transfection with the non-targeted polyplexes was inhibited mainly by nystatin or filipin III. The targeted polyplexes caused significantly higher in vivo transfection of melanoma tumor cells after intratumoral administration compared to the non-targeted control. The targeted polyplexes carrying the HSVtk gene, after ganciclovir administration, more efficiently inhibited melanoma tumor growth and prolonged the lifespan of DBA/2 tumor-bearing mice compared to the non-targeted ones. Packed targeted polyplexes appeared and accumulated in the melanoma cells six hours earlier than the non-targeted ones. The targeted polyplexes enter into the nuclei of the melanoma cells more rapidly than the non-targeted control, and this difference may also be attributed to processes of receptor-mediated endocytosis. We believe that these data may be useful for the optimization of polyplex systems.

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DNA Nuclear Targeting Sequences for Non-Viral Gene Delivery

Cited by 48 publications

References 61 publications

Polysaccharides as Nanocarriers for Therapeutic Applications

Polysaccharides as Nanocarriers for Therapeutic Applications

Insertion of a nuclear factor kappa B DNA nuclear-targeting sequence potentiates suicide gene therapy efficacy in lung cancer cell lines

Subcellular trafficking and transfection efficacy of polyethylenimine–polyethylene glycol polyplex nanoparticles with a ligand to melanocortin receptor-1

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