Chitosan-based formulations for delivery of DNA and siRNA.

School of Pharmacy, Shenyang Pharmaceutical University, 110016 Shenyang, China.
Advanced drug delivery reviews (Impact Factor: 12.71). 09/2009; 62(1):12-27. DOI: 10.1016/j.addr.2009.08.004
Source: PubMed

ABSTRACT Among non-viral vectors, chitosan and chitosan derivatives have been developed in vitro and in vivo for DNA and siRNA delivery systems because of their cationic charge, biodegradability and biocompatibility, as well as their mucoadhesive and permeability-enhancing properties. However, the transfection efficiency of chitosan is too low for clinical application. Studies indicated that the transfection efficiency depends on a series of chitosan-based formulation parameters, such as the Mw of chitosan, its degree of deacetylation, the charge ratio of chitosan to DNA/siRNA (N/P ratio), the chitosan salt form used, the DNA/siRNA concentration, pH, serum, additives, preparation techniques of chitosan/nucleic acid particles and routes of administration. In this paper, chitosan-based formulations for the delivery of DNA and siRNA were reviewed to facilitate the process of chitosan vector development for clinical application. In addition to formulation optimization, chitosan structure modification or additive incorporation is an effective way to improve the stability of the polyplex in biological fluids, enhance targeted cell delivery and facilitate endo-lysosomal release of the complex. In summary, the transfection efficiency of chitosan-based delivery systems can be adjusted by changing formulation-related parameters.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Polyethylenimine-conjugated chitosan (CS-PEI) and arginine modified polyethylenimine-conjugated chitosan (CS-PEI-Arg) were prepared, and the copolymers were characterized by FTIR, (1)H NMR, and XRD. The properties of these copolymers like plasmid DNA (pDNA) binding capacity, complexes' size and zeta potential, cytotoxicity and transfection efficiency were also evaluated. The results show that CS-PEI-Arg derivatives can bind pDNA thoroughly, and form complexes with sizes about 170nm. Cytotoxicity assay in HepG2 and 293T cells show that CS-PEI-Arg has lower cytotoxicity compared with CS-PEI, which is similar to CS and far below that of PEI. In vitro luciferase assay show that CS-PEI-Arg has better transfection efficiency than CS-PEI, which is superior to that of PEI. The best transfection efficiency of CS-PEI-Arg (N/P=50) is 2.3-fold, 4.2-fold of those of CS-PEI (N/P=20) and PEI's (N/P=10) efficiency respectively. These results display that CS-PEI-Arg is a promising candidate as an efficient gene vector. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Carbohydrate Polymers 05/2015; 122. DOI:10.1016/j.carbpol.2014.12.054 · 3.92 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Natural polysaccharides from different sources have long been studied and widely used in different areas, such as food and feed, medicine and pharmaceutics, and in papermaking. In recent decades, there has been an increased interest in the utilization of polysaccharides, particularly bioactive ones, for various novel applications owing to their biocompatibility, biodegradability, non-toxicity, and some specific therapeutic activities. The main goal of this paper was to review the sources, natively biological activities, isolation, characterization, and the structural features of natively bioactive polysaccharides. Moreover, the article has also been forcused on the chemical/chemo-enzymatic functionalizations that may create novel opportunities to maximally exploit the various valuable properties of polysaccharides, particularly from wood species, in previously unperceived applications especially for biomedical applications, such as tissue engineering, wound healing, and drug delivery. This article was to review novel strategies to tailor functional materials with above mentioned application potentials for the polysaccharides from wood species.
    01/2015; 5(1):31-61. DOI:10.1016/j.bcdf.2014.12.001
  • [Show abstract] [Hide abstract]
    ABSTRACT: Combined treatment of chemotherapeutics and small interfering RNAs (siRNAs) is a promising therapy strategy for breast carcinoma via their synergetic effects. In this study, to improve the therapeutic effect of doxorubicin (DOX), novel triblock copolymers, folate/methoxy-poly(ethylene glycol)-block-poly(L-glutamate-hydrazide)-block-poly(N,N-dimethylaminopropyl methacrylamide) (FA/m-PEG-b-P(LG-Hyd)-b-PDMAPMA), were synthesized and used as a vehicle for the co-delivery of DOX and P-glycoprotein (P-gp) siRNA into breast cancer cells. The triblock copolymers were synthesized by a combination of ring-opening polymerization of γ-benzyl-L-glutamate-N-carboxyanhydride using cystamine-terminated heterotelechelic PEG derivatives possessing folate or methoxy end groups (FA/m-PEG-Cys) as initiators and reversible addition-fragmentation chain transfer polymerization of N,N-dimethylaminopropyl methacrylamide. The successful synthesis of the copolymers was confirmed by 1H NMR and gel permeation chromatography. DOX was covalently conjugated onto the poly(L-glutamate-hydrazide) blocks via a pH-labile hydrazone linkage, and the DOX-conjugated triblock copolymers could self-assemble into nanoparticles in aqueous solutions. P-gp siRNA was then bound to the cationic poly(N,N-dimethylaminopropyl methacrylamide) (PDMAPMA) blocks through an electrostatic interaction, resulting in the formation of spherical nanocomplexes with an average diameter of 196.8 nm and a zeta potential of +28.3 mV. The in vitro release behaviors of DOX and siRNA from the nanocomplexes were pH- and reduction-dependent, and the release rates were much faster under a reductive acidic condition (pH 5.0, glutathione: 10 mM) simulating the intracellular endo-lysosomal environment of cancer cells compared to physiological conditions. The fast payload release rates were closely related to both the glutathione-triggered detachment of PEG blocks from the nanocomplex surface and the pH-sensitive cleavage of hydrazone linkages. FA-decorated nanocomplexes showed higher cellular uptake efficiency and cytotoxicity against MCF-7 cells than FA-free nanocomplexes, as confirmed by confocal laser scanning microscopy, transmission electron microscopy, MTT and flow cytometry analyses. Our results demonstrated that the multifunctional triblock copolymer-mediated co-delivery of DOX and P-gp siRNA might be a new promising therapeutic strategy for breast cancer treatment.
    01/2015; DOI:10.1039/C5TB00031A