Secretin-Mediated Gene Delivery, a Specific Targeting Mechanism with Potential for Treatment of Biliary and Pancreatic Disease in Cystic Fibrosis

McKay, Tristan R.; Reynolds, Paul N.; Jezzard, S; Curiel, David T.; Coutelle, Charles

doi:10.1006/mthe.2002.0560

Cited by 14 publications

(7 citation statements)

References 42 publications

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“…They can form highly condensed structures that allow internalization and protection of the packaged DNA from the effects of nucleases. Many different ligands such as asialoglycoprotein [6], tranferrin [7], lactose [8], mannose [9], monoclonal antibody fragments [10], insulin [11], nerve growth factor [12], vasoactive intestinal peptide [13], neurotensin [14], secretin [15] and folate [16] have been employed for targeting, while DNA-binding moiety usually uses high-molecular-weight poly-L-lysine, but occasionally polyethyleneimine, protamine, histone, non-histone and cyclodextrin polymers [17][18][19][20]. One obvious advantage of these non-viral gene delivery systems is their lack of packaging-related size constraints that limit the insert size of viral vectors [21].…”

Section: Discussionmentioning

confidence: 99%

A novel synthetic peptide vector system for optimal gene delivery to bone marrow stromal cells

Pan¹,

Zheng²,

Guo³

2006

Journal of Peptide Science

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A 23-amino acid, bifunctional, integrin-targeted synthetic peptide was evaluated for ex vivo gene delivery to rabbit bone marrow stromal cells (BMSCs). The peptide (K)(16)GRGDSPC consists of an amino terminal domain of 16 lysines for electrostatic binding of DNA, and a 7-amino acid integrin-binding domain at the carboxyl terminal. PcDNA3-EGFP plasmids were transfected into BMSCs by (K)(16)GRGDSPC and the positive cells gave out a bright green fluorescence. High levels of gene delivery of pcDNA3-TGF-beta1 plasmids were obtained with 2 to 4 microg/ml DNA concentration, with (K)(16)GRGDSPC at an optimal peptide: DNA w/w ratio of 3:1, with a required exposure time of more than 4 h but shorter than 24 h for BMSC exposure to the peptide/DNA complexes with completely absent serum in the initial stage; with 100 microM chloroquine and at least 8 h exposure for BMSC exposure to chloroquine; with a fusogenic peptide at an optimal (K)(16)GRGDSPC/DNA/fusogenic peptide w/w ratio of 3:1:5; and with Lipofectamine 2000 at an optimal (K)(16)GRGDSPC/DNA/Lipofectamine 2000 w/w ratio of 3:1:2 at a constant DNA concentration of 2 microg/ml. Chloroquine, the fusogenic peptide and Lipofectamine 2000 all significantly promoted gene delivery, but chloroquine was more effective than the fusogenic peptide and had obvious synergistic effects with Lipofectamine 2000. Under optimal conditions, TGF-beta1 gene was transfected into BMSCs without observable toxicity, and the stable expression was examined by RT-PCR and Western blot analysis. The stable transgenic cells showed obvious bands. This novel synthetic peptide, providing a new way for the use of polylysine and RGD motif in DNA vector system, is potentially well suited to ex vivo gene delivery to BMSCs for experimental and clinical applications in the field of bone tissue engineering.

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Section: Discussionmentioning

confidence: 99%

A novel synthetic peptide vector system for optimal gene delivery to bone marrow stromal cells

Pan¹,

Zheng²,

Guo³

2006

Journal of Peptide Science

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“…Another feature of this targeting system attractive for gene delivery is the rapid internalization of the secretin-SR complex into endosomes. 140 The C-and N-termini of secretin have no secondary structure and the N-terminus is responsible for the high SR affinity, leaving the C-terminus free for manipulation and conjugation. 141 McKay et al used full length secretin with a GGC spacer at the C-terminus where the neutral glycines act as a physical spacer between the bioactive sequence and the charged DNA binding region, and the cysteine was required to form a disulde linkage with linear PEI (HSDGTFTSELSRLRDSARLQRLLQGLVGGC-PEI).…”

Section: Gene Delivery With Peptides Targeting Integrinsmentioning

confidence: 99%

“…141 McKay et al used full length secretin with a GGC spacer at the C-terminus where the neutral glycines act as a physical spacer between the bioactive sequence and the charged DNA binding region, and the cysteine was required to form a disulde linkage with linear PEI (HSDGTFTSELSRLRDSARLQRLLQGLVGGC-PEI). 140 When compared to plasmid DNA transfection with nontargeted linear PEI, the secretin-conjugated PEI improved transfection in cells expressing the secretin receptor, and actually inhibited transfection in cells not expressing the secretin receptor, causing 10 fold transfection efficiency improvement in SR expressing cells over the control cell line. 140 This suggests that specic targeting could be achieved when delivered in vivo.…”

Section: Gene Delivery With Peptides Targeting Integrinsmentioning

confidence: 99%

“…140 When compared to plasmid DNA transfection with nontargeted linear PEI, the secretin-conjugated PEI improved transfection in cells expressing the secretin receptor, and actually inhibited transfection in cells not expressing the secretin receptor, causing 10 fold transfection efficiency improvement in SR expressing cells over the control cell line. 140 This suggests that specic targeting could be achieved when delivered in vivo.…”

Section: Gene Delivery With Peptides Targeting Integrinsmentioning

confidence: 99%

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Peptide functionalized nanoparticles for nonviral gene delivery

2013

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Much attention has been directed toward improving nonviral gene delivery in order to replace viral vectors and overcome the barriers to clinical gene therapy. Specifically targeting nonviral gene delivery vehicles to the disease tissue can significantly improve their delivery efficiency. Targeting peptides have been developed for growth factor receptors, integrins and tumor vasculature to target cancer, neurotrophin or neurotoxin receptors aiming to give specificity for neurodegenerative disease, airway epithelial cells to target cystic fibrosis and other tissue specific cells and receptors in bone tissue, cornea and dendritic cells.These highly specific, high-affinity peptides were identified using phage display or through rational design, and were evaluated within this review for their potential and ability to improve transfection, highlighting the successful applications of this technology and discussing the features of the design that contribute to this success. It was found that effective peptide targeting of gene delivery relied both on peptide ligand performance and on nonviral vectors that exploit the appropriate intracellular trafficking mechanisms.

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“…Many peptides have been described in the literature as receptor-specific ligands so any of them can be added to the multifunctional proteins in order to confer them cell specificity. [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] The most natural specific ligands that can also be used for cell targeting are monoclonal antibodies. 32,[63][64][65] In addition, if no specific peptides are available for an intended target, new specific binding peptides can be found by using phage display 66 or combinatorial chemistry.…”

Section: Cell Binding and Internalizationmentioning

confidence: 99%

Engineered Biological Entities for Drug Delivery and Gene Therapy

Domingo-Espín

Unzueta

Saccardo

et al. 2011

Progress in Molecular Biology and Translational Science

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The development of genetic engineering techniques has speeded up the growth of the biotechnological industry, resulting in a significant increase in the number of recombinant protein products on the market. The deep knowledge of protein function, structure, biological interactions, and the possibility to design new polypeptides with desired biological activities have been the main factors involved in the increase of intensive research and preclinical and clinical approaches. Consequently, new biological entities with added value for innovative medicines such as increased stability, improved targeting, and reduced toxicity, among others have been obtained. Proteins are complex nanoparticles with sizes ranging from a few nanometers to a few hundred nanometers when complex supramolecular interactions occur, as for example, in viral capsids. However, even though protein production is a delicate process that imposes the use of sophisticated analytical methods and negative secondary effects have been detected in some cases as immune and inflammatory reactions, the great potential of biodegradable and tunable protein nanoparticles indicates that protein-based biotechnological products are expected to increase in the years to come.

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Secretin-Mediated Gene Delivery, a Specific Targeting Mechanism with Potential for Treatment of Biliary and Pancreatic Disease in Cystic Fibrosis

Cited by 14 publications

References 42 publications

A novel synthetic peptide vector system for optimal gene delivery to bone marrow stromal cells

A novel synthetic peptide vector system for optimal gene delivery to bone marrow stromal cells

Peptide functionalized nanoparticles for nonviral gene delivery

Engineered Biological Entities for Drug Delivery and Gene Therapy

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