Dexamethasone‐Loaded Reconstitutable Charged Polymeric (PLGA)n‐b‐bPEI Micelles for Enhanced Nuclear Delivery of Gene Therapeutics

Kang, Han Chang; Cho, Hanna; Bae, You Han

doi:10.1002/mabi.201300432

Cited by 19 publications

(11 citation statements)

References 45 publications

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“…Dexamethasone is a corticosteroid that is known to dilate nuclear pores. ,, To investigate an alternative method of nuclear membrane disruption, we utilized dexamethasone to perturb the permeability of the nucleus in cultures of HDFs and iPSCs during transfection. Cells were prepared as described previously in the GFP expression section.…”

Section: Resultsmentioning

confidence: 99%

Molecular Additives Significantly Enhance Glycopolymer-Mediated Transfection of Large Plasmids and Functional CRISPR-Cas9 Transcription Activation Ex Vivo in Primary Human Fibroblasts and Induced Pluripotent Stem Cells

et al. 2018

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Fast, efficient, and inexpensive methods for delivering functional nucleic acids to primary human cell types are needed to advance regenerative medicine and cell therapies. Plasmid-based gene editing (such as with CRISPR-Cas9) can require the delivery of plasmids that are large (∼9.5–13 kbp) in comparison to common reporter plasmids (∼5–8 kbp). To develop more efficient plasmid delivery vehicles, we investigated the effect of plasmid size on the transfection of primary human dermal fibroblasts (HDFs) and induced pluripotent stem cells (iPSCs) using a heparin-treated trehalose-containing polycation (Tr4-heparin). Transfections with 4.7 kbp to 10 kbp plasmids exhibited high rates of polyplex internalization with both plasmid sizes. However, transfection with the large plasmid was nearly eliminated in HDFs and significantly reduced in iPSCs. Molecular additives were used to probe intracellular barriers to transfection. Chloroquine treatments were used to destabilize endosomes, and dexamethasone and thymidine were used to destabilize the nuclear envelope. Destabilizing the nuclear envelope resulted in significantly increased large-plasmid-transfection, indicating that nuclear localization may be more difficult for large plasmids. To demonstrate the potential clinical utility of this formulation, HDFs and iPSCs were treated with to dexamethasone-Tr4-heparin polyplexes encoding dCas9-VP64, synthetic transcription activator, targeted to collagen type VII. These transfections enhanced collagen expression in HDFs and iPSCs by 5- and 20-fold, respectively, compared to an untransfected control and were the more effective than the Lipofectamine 2000 control. Functional plasmid transfection efficiency can be significantly improved by nuclear destabilization, which could lead to improved development of nonviral vehicles for ex vivo CRISPR-Cas9 gene editing.

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Section: Resultsmentioning

confidence: 99%

Molecular Additives Significantly Enhance Glycopolymer-Mediated Transfection of Large Plasmids and Functional CRISPR-Cas9 Transcription Activation Ex Vivo in Primary Human Fibroblasts and Induced Pluripotent Stem Cells

et al. 2018

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“…The GFP expression induced by PCA/Dex/ GFP DNA was slightly higher than that induced by PCA/ GFP DNA. Since we measured GFP levels using FACS, it is difficult to compare our results with those of Mishra et al, 29 who investigated DNA uptake levels in the nucleus. Further study is needed to confirm the effect of Dex on gene delivery via nanoparticles.…”

mentioning

confidence: 88%

“…Dex has been reported as a nuclear pore dilatory factor, and the polyplexes containing Dex showed a 3-to 13-fold higher DNA uptake efficiency in the nucleus, compared with Dex-free polyplexes. 29 Therefore, the GFP gene expression level was compared among the PCA/Dex/GFP DNA, PCA/GFP DNA and Lipofectamine groups in Figure 8. The GFP expression level induced by PCA/Dex/GFP DNA Figure 11 Functional application of Pca/Dex compared with lipofectamine ® 3000 (lipo) in heI-Oc1 cells.…”

Section: Effect Of Dex On Gene Transfectionmentioning

confidence: 99%

The effect of dexamethasone/cell-penetrating peptide nanoparticles on gene delivery for inner ear therapy

Yoon¹,

Yang²,

Park³

et al. 2016

IJN

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“…Dexamethasone (Dex) has been reported as a useful molecule for nuclear targeted drug delivery . In the cytosol, Dex can bind to glucocorticoid receptors and eventually translocate to the nucleus .…”

Section: Introductionmentioning

confidence: 99%

Reduction‐responsive poly (ethylene glycol)‐dexamethasone biarm conjugate and its self‐assembled nanomicelles: Preparation, physicochemical characterization, and thiol‐triggered drug release

Thi

Hwang

Kim

et al. 2019

Polymers for Advanced Techs

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In this study, a reduction-responsive poly (ethylene glycol)-dexamethasone biarm conjugate was synthesized as intracellular targeted drug delivery carriers. The hydroxyl end group of methoxy poly (ethylene glycol) (mPEG) was modified to introduce a biarm structure with bioreducible disulfide bond and amine end groups. Dexamethasone (Dex) as a nuclear targeting moiety was conjugated to the amine end groups of mPEG biarm derivatives, mPEG-(NH 2 ) 2 or mPEG-(ss-NH 2 ) 2 , with or without bioreducible disulfide bonds. The bioreducible and nonreducible mPEG-Dex biarm conjugates, R-mPEG-Dex and N-mPEG-Dex, were synthesized and characterized by various analytical methods, proton nuclear magnetic resonance ( 1 H-NMR), Fourier transform infraredspectroscopy (FT-IR), dynamic light scattering (DLS), and fluorescence measurements. Amphiphilic mPEG-Dex conjugates self-assembled in aqueous solutions to form nanoparticles (NPs) with a size range of 130 to 150 nm, and their critical micelle concentrations (CMCs) were determined to be 12.4 and 15.3 mg/L, respectively, for bioreducible and nonreducible ones. The R-mPEG-Dex NPs maintained good colloidal stability in the presence of bovine serum albumin (BSA) for more than 1 week but demonstrated a significant change in colloidal stability in the presence of dithiothreitol (DTT). In DTT-containing phosphate-buffered saline (PBS), the bioreducible NPs showed not only reduction-responsive destabilization with PEG shedding but also thiol-dependent drug release profile. Our observations indicated that the R-mPEG-Dex NPs have a promising prospective as an efficient nanocarrier for intracellular targeted delivery of various anticancer drugs.

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Dexamethasone‐Loaded Reconstitutable Charged Polymeric (PLGA)_n‐b‐bPEI Micelles for Enhanced Nuclear Delivery of Gene Therapeutics

Cited by 19 publications

References 45 publications

Molecular Additives Significantly Enhance Glycopolymer-Mediated Transfection of Large Plasmids and Functional CRISPR-Cas9 Transcription Activation Ex Vivo in Primary Human Fibroblasts and Induced Pluripotent Stem Cells

Molecular Additives Significantly Enhance Glycopolymer-Mediated Transfection of Large Plasmids and Functional CRISPR-Cas9 Transcription Activation Ex Vivo in Primary Human Fibroblasts and Induced Pluripotent Stem Cells

The effect of dexamethasone/cell-penetrating peptide nanoparticles on gene delivery for inner ear therapy

Reduction‐responsive poly (ethylene glycol)‐dexamethasone biarm conjugate and its self‐assembled nanomicelles: Preparation, physicochemical characterization, and thiol‐triggered drug release

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