Chitosan-DNA/siRNA Nanoparticles for Gene Therapy

Shi, Qin; Tiera, Márcio José; Xiao-ling, Zhang; Dai, Kerong; Benderdour, Mohamed; Fernandes, Julio C.

doi:10.5772/21903

Cited by 4 publications

(7 citation statements)

References 147 publications

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“…The amine groups of chitosan confer weakly basic properties that enable binding of nucleic acids through electrostatic interaction. Chitosan itself is not efficiently endosomolytic, and PEI has been conjugated to the polymer to improve entry into the cytoplasm [67]. PEG has been coupled to these residues to enhance stability and limit unintended interaction with circulating proteins [68,69].…”

Section: Polymer Vectorsmentioning

confidence: 99%

Delivery of Antiviral Nucleic Acids with Nonviral Vectors

Arbuthnot

2015

Gene Therapy for Viral Infections

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Section: Polymer Vectorsmentioning

confidence: 99%

Delivery of Antiviral Nucleic Acids with Nonviral Vectors

Arbuthnot

2015

Gene Therapy for Viral Infections

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“…2 CH, a natural polymer composed of glucosamine units, showed good biocompatibility and biodegradability properties. 3 Its versatility allows it to be used in several fields, including wastewater treatment, agriculture, textiles, food protection and cosmetics. 4 It has a tremendous potential for biomedical and pharmaceutical applications as a drug delivery vehicle, 5 in vaccine systems, 6 tissue engineering, wound dressing, diagnosis, 7 and gene therapy, 8 among others.…”

Section: Introductionmentioning

confidence: 99%

<p>Evidence Supporting the Safety of Pegylated Diethylaminoethyl-Chitosan Polymer as a Nanovector for Gene Therapy Applications</p>

Rondon¹,

Benabdoun²,

Vallières³

et al. 2020

IJN

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Purpose: Diethylaminoethyl-chitosan (DEAE-CH) is a derivative with excellent potential as a delivery vector for gene therapy applications. The aim of this study is to evaluate its toxicological profile for potential future clinical applications. Methods: An endotoxin-free chitosan (CH) modified with DEAE, folic acid (FA) and polyethylene glycol (PEG) was used to complex small interfering RNA (siRNA) and form nanoparticles (DEAE 12-CH-PEG-FA 2 /siRNA). Based on the guidelines from the International Organization for Standardization (ISO), the American Society for Testing and Materials (ASTM), and the Nanotechnology Characterization Laboratory (NCL), we evaluated the effects of the interaction between these nanoparticles and blood components. In vitro screening assays such as hemolysis, hemagglutination, complement activation, platelet aggregation, coagulation times, cytokine production, and reactive species, such as nitric oxide (NO) and reactive oxygen species (ROS), were performed on erythrocytes, plasma, platelets, peripheral blood mononuclear cells (PBMC) and Raw 264.7 macrophages. Moreover, MTS and LDH assays on Raw 264.7 macrophages, PBMC and MG-63 cells were performed. Results: Our results show that a targeted theoretical plasma concentration (TPC) of DEAE 12-CH-PEG-FA 2 /siRNA nanoparticles falls within the guidelines' thresholds: <1% hemolysis, 2.9% platelet aggregation, no complement activation, and no effect on coagulation times. ROS and NO production levels were comparable to controls. Cytokine secretion (TNF-α, IL-6, IL-4, and IL-10) was not affected by nanoparticles except for IL-1β and IL-8. Nanoparticles showed a slight agglutination. Cell viability was >70% for TPC in all cell types, although LDH levels were statistically significant in Raw 264.7 macrophages and PBMC after 24 and 48 h of incubation. Conclusion: These DEAE 12-CH-PEG-FA 2 /siRNA nanoparticles fulfill the existing ISO, ASTM and NCL guidelines' threshold criteria, and their low toxicity and blood biocompatibility warrant further investigation for potential clinical applications.

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“…A wide variety of nonviral gene vectors have been proposed over the past few years, including chemical and structural modification of siRNAs, cationic liposomes and polymers, cell-penetrating peptides and targeted delivery. 14,[18][19][20] Chitosan (CH) and its derivatives are being tested in vitro and in vivo for siRNA delivery because of their good properties as nonviral plasmid DNA delivery systems. [21][22][23] CH is a widely used, biocompatible and biodegradable biomaterial, with low toxicity and immunogenicity.…”

mentioning

confidence: 99%

“…14,15 Different gene vectors, namely, viral 14 and nonviral systems, 16,17 have been studied for siRNA delivery inside the cytoplasm of targeted cells. A wide variety of nonviral gene vectors have been proposed over the past few years, including chemical and structural modification of siRNAs, cationic liposomes and polymers, cell-penetrating peptides and targeted delivery.…”

mentioning

confidence: 99%

“…[21][22][23] CH is a widely used, biocompatible and biodegradable biomaterial, with low toxicity and immunogenicity. 14,24 It has been modified with a folic acid ligand to enhance its performance as a gene carrier with transfection efficiency. 25 In vitro and in vivo transfection with folic acid ligands has been shown to assist DNA 26 and siRNA 27 uptake by folate receptor.…”

mentioning

confidence: 99%

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In vivo therapeutic efficacy of TNFα silencing by folate-PEG-chitosan-DEAE/siRNA nanoparticles in arthritic mice

Shi¹,

Rondon-Cavanzo²,

Picola³

et al. 2018

IJN

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Background Tumor necrosis factor-alpha (TNFα), a pro-inflammatory cytokine, has been shown to play a role in the pathophysiology of rheumatoid arthritis. Silencing TNFα expression with small interfering RNA (siRNA) is a promising approach to treatment of the condition. Methods Towards this end, our team has developed a modified chitosan (CH) nanocarrier, deploying folic acid, diethylethylamine (DEAE) and polyethylene glycol (PEG) (folate-PEG-CH-DEAE 15 ). The gene carrier protects siRNA against nuclease destruction, its ligands facilitate siRNA uptake via cell surface receptors, and it provides improved solubility at neutral pH with transport of its load into target cells. In the present study, nanoparticles were prepared with siRNA-TNFα, DEAE, and folic acid-CH derivative. Nanoparticle size and zeta potential were verified by dynamic light scattering. Their TNFα-knockdown effects were tested in a murine collagen antibody-induced arthritis model. TNFα expression was examined along with measurements of various cartilage and bone turnover markers by performing histology and microcomputed tomography analysis. Results We demonstrated that folate-PEG-CH-DEAE 15 /siRNA nanoparticles did not alter cell viability, and significantly decreased inflammation, as demonstrated by improved clinical scores and lower TNFα protein concentrations in target tissues. This siRNA nanocarrier also decreased articular cartilage destruction and bone loss. Conclusion The results indicate that folate-PEG-CH-DEAE 15 nanoparticles are a safe and effective platform for nonviral gene delivery of siRNA, and their potential clinical applications warrant further investigation.

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Chitosan-DNA/siRNA Nanoparticles for Gene Therapy

Cited by 4 publications

References 147 publications

Delivery of Antiviral Nucleic Acids with Nonviral Vectors

Delivery of Antiviral Nucleic Acids with Nonviral Vectors

<p>Evidence Supporting the Safety of Pegylated Diethylaminoethyl-Chitosan Polymer as a Nanovector for Gene Therapy Applications</p>

In vivo therapeutic efficacy of TNFα silencing by folate-PEG-chitosan-DEAE/siRNA nanoparticles in arthritic mice

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Chitosan-DNA/siRNA Nanoparticles for Gene Therapy

Cited by 4 publications

References 147 publications

Delivery of Antiviral Nucleic Acids with Nonviral Vectors

Delivery of Antiviral Nucleic Acids with Nonviral Vectors

<p>Evidence Supporting the Safety of Pegylated Diethylaminoethyl-Chitosan Polymer as a Nanovector for Gene Therapy Applications</p>

In vivo therapeutic efficacy of TNF&alpha; silencing by folate-PEG-chitosan-DEAE/siRNA nanoparticles in arthritic mice

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In vivo therapeutic efficacy of TNFα silencing by folate-PEG-chitosan-DEAE/siRNA nanoparticles in arthritic mice