ABSTRACT
The delivery of small interfering RNAs (siRNAs) is a promising approach to silencing gene expression aimed at treating infections, cancer, neurodegenerative diseases and various other disorders. Recent progress in this area has been achieved with nanodevices possessing multiple properties and assembled with new, biodegradable, synthetic polymers and polysaccharides. Different synthetic routes and multiple strategies, such as multilayer systems and stimuliresponsive polymers, have been developed to attain high efficiencies. This review covers the most important, promising and successful approaches to improve siRNA delivery. It is a concise report on multiple strategies employed, including cell-specific delivery coupling ligands or antibodies with nanodevices to improve siRNA efficiency and specificity.
Subject(s)
Drug Delivery Systems , Nanoparticles/chemistry , Polymers/chemistry , RNA, Small Interfering/genetics , Animals , Disease Models, Animal , Gene Silencing , Gene Targeting/methods , Genetic Therapy , Humans , RNA, Small Interfering/metabolismABSTRACT
At present, gene transfection insufficient efficiency is a major drawback of non-viral gene therapy. The 2 main types of delivery systems deployed in gene therapy are based on viral or non-viral gene carriers. Several non-viral modalities can transfer foreign genetic material into the human body. To do so, polycation-based gene delivery methods must achieve sufficient efficiency in the transportation of therapeutic genes across various extracellular and intracellular barriers. These barriers include interactions with blood components, vascular endothelial cells and uptake by the reticuloendothelial system. Furthermore, the degradation of therapeutic DNA by serum nucleases is a potential obstacle for functional delivery to target cells. Cationic polymers constitute one of the most promising approaches to the use of viral vectors for gene therapy. A better understanding of the mechanisms by which DNA can escape from endosomes and traffic to enter the nucleus has triggered new strategies of synthesis and has revitalized research into new polycation-based systems. The objective of this review is to address the state of the art in gene therapy with synthetic and natural polycations and the latest advances to improve gene transfer efficiency in cells.
Subject(s)
Genetic Therapy/methods , Genetic Therapy/trends , Polyamines/chemistry , Animals , Cell Nucleus/genetics , Cell Nucleus/metabolism , Chitosan/chemistry , DNA/genetics , DNA/metabolism , Dendrimers/chemistry , Dextrans/chemistry , Endosomes/genetics , Endosomes/metabolism , Gene Transfer Techniques , Genetic Vectors , Humans , Lysosomes/genetics , Lysosomes/metabolism , Methacrylates/chemistry , Nylons/chemistry , Polyelectrolytes , Polyethyleneimine/chemistry , Polylysine/chemistry , Polymers/chemistry , TransfectionABSTRACT
A polymer analogous synthesis involving the reductive amination of phosphorylcholine (PC)-glyceraldehyde with primary amines of deacetylated chitosan (M(w) approximately 57000 g mol(-1)) was used to prepare phosphorylcholine-substituted chitosans (PC-CH) with a degree of substitution (DS) ranging from approximately 11 to approximately 53 mol % PC-substituted glucosamine residues. The PC-CH derivatives were characterized by (1)H NMR spectroscopy, FTIR spectroscopy, and multiangle laser light scattering gel permeation chromatography (MALLS-GPC). The pK(a) of the PC-substituted amine groups (pK(a) approximately 7.20) was determined by (1)H NMR titration. The PC-CH samples (1.0 g L(-1)) were shown to be nontoxic using an MTT assay performed with human KB cells. Aqueous solutions of PC-CH samples (4.0 g L(-1)) of DS >or= 22 mol % PC-substituted glucosamine residues remained clear, independently of pH (4.0 < pH < 11.0). The remarkable water solubility and nontoxicity displayed by the new PC-CH samples open up new opportunities in the design of chitosan-based biomaterials and nanoparticles.
Subject(s)
Chitosan/chemical synthesis , Phosphorylcholine/chemistry , Acetylation , Carbohydrate Sequence , Chitosan/chemistry , Chromatography, Gel , Hydrogen-Ion Concentration , Magnetic Resonance Spectroscopy , Molecular Sequence Data , Solubility , Spectroscopy, Fourier Transform InfraredABSTRACT
Currently, the major drawback of gene therapy is the gene transfection rate. The two main types of vectors that are used in gene therapy are based on viral or non-viral gene delivery systems. There are several non-viral systems that can be used to transfer foreign genetic material into the human body. In order to do so, the DNA to be transferred must escape the processes that affect the disposition of macromolecules. These processes include the interaction with blood components, vascular endothelial cells and uptake by the reticuloendothelial system. Furthermore, the degradation of therapeutic DNA by serum nucleases is also a potential obstacle for functional delivery to the target cell. Cationic polymers have a great potential for DNA complexation and may be useful as non-viral vectors for gene therapy applications. The objective of this review was to address the state of the art in gene therapy using synthetic and natural polycations and the latest strategies to improve the efficiency of gene transfer into the cell.
