The Development and Mechanism Studies of Cationic Chitosan-Modified Biodegradable PLGA Nanoparticles for Efficient siRNA Drug Delivery

Yuan, Xudong; Shah, Bruhal A.; Kotadia, Naimesh; Li, Jian; Gu, Hua; Wu, Zhonghua

doi:10.1007/s11095-010-0103-0

Cited by 66 publications

(39 citation statements)

References 40 publications

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“…It has been reported that cationic polymers, such as polyethyleneimine and poly-L-lysine hydrobromide, can be used as candidate materials to modify PLGA nanoparticles for gene or drug delivery. [10][11][12][13] Among these, chitosan seems to be the most suitable adjuvant due to its biodegradable and biocompatible, mucoadhesive, and permeability-enhancing properties. 14,15 Mucus adhesion can prolong the duration of interaction between drugs and cells, while increased tissue permeability can allow dissemination of drugs through the paracellular transport pathway, via the opening of tight junctions between epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

Preparation, characterization, and in vitro and in vivo investigation of chitosan-coated poly (d,l-lactide-co-glycolide) nanoparticles for intestinal delivery of exendin-4

Wang

Zhang²,

Jiao³

et al. 2013

IJN

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Background: Exendin-4 is an incretin mimetic agent approved for type 2 diabetes treatment. However, the required frequent injections restrict its clinical application. Here, the potential use of chitosan-coated poly (d,l-lactide-co-glycolide) (CS-PLGA) nanoparticles was investigated for intestinal delivery of exendin-4. Methods and results: Nanoparticles were prepared using a modified water-oil-water (w/o/w) emulsion solvent-evaporation method, followed by coating with chitosan. The physical properties, particle size, and cell toxicity of the nanoparticles were examined. The cellular uptake mechanism and transmembrane permeability were performed in Madin-Darby canine kidney-cell monolayers. Furthermore, in vivo intraduodenal administration of exendin-4-loaded nanoparticles was carried out in rats. The PLGA nanoparticle coating with chitosan led to a significant change in zeta potential, from negative to positive, accompanied by an increase in particle size of ∼30 nm. Increases in both the molecular weight and degree of deacetylation of chitosan resulted in an observable increase in zeta potential but no apparent change in the particle size of ∼300 nm. Both unmodified PLGA and chitosan-coated nanoparticles showed only slight cytotoxicity. Use of different temperatures and energy depletion suggested that the cellular uptake of both types of nanoparticles was energy-dependent. Further investigation revealed that the uptake of PLGA nanoparticles occurred via caveolin-mediated endocytosis and that of CS-PLGA nanoparticles involved both macropinocytosis and clathrin-mediated endocytosis, as evidenced by using endocytic inhibitors. However, under all conditions, CS-PLGA nanoparticles showed a greater potential to be transported into cells, as shown by flow cytometry and confocal microscopy. Transmembrane permeability analysis showed that unmodified and modified PLGA nanoparticles could improve the transport of exendin-4 by up to 8.9-and 16.5-fold, respectively, consistent with the evaluation in rats. Conclusion:The chitosan-coated nanoparticles have a higher transport potential over both free drug and unmodified particles, providing support for their potential development as a candidate oral delivery agent for exendin-4.

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Section: Introductionmentioning

confidence: 99%

Preparation, characterization, and in vitro and in vivo investigation of chitosan-coated poly (d,l-lactide-co-glycolide) nanoparticles for intestinal delivery of exendin-4

Wang

Zhang²,

Jiao³

et al. 2013

IJN

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“…Unfortunately, PLGA has a negative charge, which limits its interaction with DNA/RNA, so cationic compounds have been combined with this polymer in order to condense genetic material efficiently. 17,18 For example, chitosan, a polysaccharide used widely in the pharmaceutical field because of its biocompatibility, biodegradability, safety, and mucoadhesive properties, 19,20 has been used in combination with PLGA in order to increase transfection efficiency. 21,22 In 2007, Nafee et al investigated the variation in physicochemical parameters of PLGA/high molecular weight chitosan nanoparticles (produced by the emulsion-diffusionevaporation technique) as a function of the proportions of compounds contained therein.…”

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confidence: 99%

Physicochemical features and transfection properties of chitosan/poloxamer 188/poly(D,L-lactide-co-glycolide) nanoplexes

Cosco

Federico

Maiuolo

et al. 2014

IJN

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The aim of this study was the evaluation of the effects of two emulsifiers on the physicochemical and technological properties of low molecular weight chitosan/poly (D,L-lactide-co-glycolide) (PLGA) nanoplexes and their transfection efficiency. Nanospheres were prepared using the nanoprecipitation method of the preformed polymer. The mean diameter and surface charge of the nanospheres were investigated by photocorrelation spectroscopy. The degree of binding of the plasmid with the nanoplexes was qualitatively and quantitatively determined. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) testing was performed using HeLa, RPMI8226, and SKMM1 cell lines. Flow cytometry and confocal laser scanning microscopy were used to determine the degree of cellular transfection and internalization of the nanoplexes into cells, respectively. The nanoplexes had a positive zeta potential, and low amounts of PLGA and poloxamer 188 showed a mean colloidal size of ~200 nm with a polydispersity index of ~0.14. The nanoplexes had suitable entrapment efficiency (80%). In vitro experiments showed that the colloidal nanodevices did not induce significant cytotoxicity. The nanoplexes investigated in this study could represent efficient and useful nonviral devices for gene delivery. Use of low amounts of PLGA and poloxamer 188 enabled development of a nanosphere able to transfect cells efficiently. These nanosystems are a helpful platform for delivery of genetic material while preserving therapeutic efficacy.

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“…Therefore, a considerable amount of work has been documented on the loading efficiency of siRNA on polymers but very few have loaded siRNA on chitosan nanoparticles as a bioadhesive, biocompatible, and biodegradable polymer with unique gene delivery properties [2]. The efficacy of siRNA loaded carriers (i.e., gene silencing) has been reported to significantly increase with increasing the siRNA loading [3].…”

mentioning

confidence: 99%

“…The salt form of chitosan [4], concentration of chitosan in chitosan-poly(lactic-co-glycolic acid) nanoparticles [3] and insertion of 1,2-dioleoyl-3-trimethylammonium-propane [5] and tripolyphosphate [6] as ionic agents, have been reported to affect the loading efficiency of chitosan nanoparticles as carriers of siRNA. However, the above-mentioned studies have only reported a very limited number of experiments without providing a comprehensive understanding about factors influencing the loading efficacy in an siRNA/polymer system.…”

mentioning

confidence: 99%

Chitosan Nanoparticles for siRNA Delivery: Optimization of Processing/Formulation Parameters

Gharehdaghi

Amani²,

Khoshayand³

et al. 2014

Nucleic Acid Therapeutics

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Chitosan nanoparticles were prepared using ultrasonication methodology at specific amplitudes and times of sonication. Subsequently, small interfering RNA (siRNA) was added to the solution at predetermined values of nitrogen to phosphorous ratio (N/P), and stirring time. Employing response surfaces generated from a statistical model, the effect of sonication time and amplitude, stirring time, and N/P ratio was studied on the particle size, polydispersity, and loading efficiency of prepared siRNA/chitosan nanoparticles. It was found that to obtain the smallest size, amplitude and time of sonication as well as stirring time should be kept at *45%, 165 seconds, and 50 minutes, respectively. Minimum polydispersity values were also obtained at similar values of sonication time/ amplitude and stirring time in addition to N/P values of *28. Also, the maximum proportion of siRNA loading was observed at approximate values of 300 seconds, 80% and 280 for sonication time, amplitude, and N/P ratio, respectively. The optimum conditions (i.e., to prepare a sample with minimum values of particle size and polydispersity index and maximum values of loading efficiency) were determined as 60.6, 30.0 (seconds), 28.0, and 12.5 (minutes) for amplitude, time of sonication, N/P, and stirring time, respectively. In this scrutiny, the predicted values of optimum formulation were 456 nm size, 89.6% loading efficiency, and 0.4 polydispersity index.

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The Development and Mechanism Studies of Cationic Chitosan-Modified Biodegradable PLGA Nanoparticles for Efficient siRNA Drug Delivery

Abstract: This study suggests that biodegradable cationic CHT-PLGA nanoparticles possess great potential for efficient and safer siRNA delivery in future clinical applications.

Cited by 66 publications

References 40 publications

Preparation, characterization, and in vitro and in vivo investigation of chitosan-coated poly (d,l-lactide-co-glycolide) nanoparticles for intestinal delivery of exendin-4

Preparation, characterization, and in vitro and in vivo investigation of chitosan-coated poly (d,l-lactide-co-glycolide) nanoparticles for intestinal delivery of exendin-4

Physicochemical features and transfection properties of chitosan/poloxamer 188/poly(D,L-lactide-co-glycolide) nanoplexes

Chitosan Nanoparticles for siRNA Delivery: Optimization of Processing/Formulation Parameters

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