Abstract
The safe and effective delivery of therapeutic genes into target cell interiors is of great importance in gene therapy. Chitosan has been extensively studied as a gene delivery carrier due to its good biocompatibility and biodegradability. Understanding the atomic interaction mechanism between chitosan and DNA is important in the design and application of chitosan-based drug and gene delivery systems. In this work, the interactions between single-stranded polynucleotides and different types of chitosan were systematically investigated by using molecular dynamics (MD) simulation. Our results demonstrate that the functional groups of chitosan, the types of base and length of polynucleotides regulate the interaction behavior between chitosan and polynucleotides. The encapsulation capacity of polynucleotide by chitosan is mainly balanced by two factors: the strength of polynucleotide binding to chitosan and the tendency of self-aggregation of polynucleotide in the solution. For –NH3+ chitosan, due to the strong electrostatic interaction, especially the H-bond between –NH3+ groups in chitosan and phosphate groups in polynucleotide, the aggregation effect could be partially eliminated. The good dispersal capacity of polynucleotides may improve the encapsulation of polynucleotides by chitosan, and hence increase the delivery and transfection efficiency of chitosan-based gene carrier.
Highlights
The safe and effective delivery of therapeutic genes into target cell interiors is of great importance in gene therapy[1,2,3,4,5]
The radial distribution functions (RDFs) was calculated between the center of mass of chitosan’s functional groups (e.g., –NH2, –NH3+ and –NHCOCH3, as shown in Fig. 1) and any atoms of single-stranded polynucleotides
The trajectory and snapshot showed that C3 dispersed into –NH2 chitosan, leading to a sandwich-like conformation, while –NHCOCH3 chitosan prefer to aggregate together and free C3 can be found distribute around the big condensates of –NHCOCH3 chitosan
Summary
The safe and effective delivery of therapeutic genes into target cell interiors is of great importance in gene therapy[1,2,3,4,5]. Chitosan forms polyelectrolyte complexes with negatively charged DNA, in which the DNA becomes better protected against nuclease degradation[16] These beneficial characters give chitosan the abilities to be a competent gene carrier. Guţoaia et al.[23] recommended that fine-tuned PEGylation of chitosan can be used to generate PEG-chitosan/siRNA delivery systems with maximum bioactivity These experiments greatly enhanced our understanding of the property of chitosan as a gene carrier. All of these experiments, including chitosan-based formulation parameters and chitosan modification show that the purposeful changing of functional group in the backbone of chitosan may provide an effective strategy in improving the transfection efficiency. With the goal of improving the transfection efficiency and realizing real application of chitosan-based gene systems, it is of great importance to investigate the effect of functional group on DNA delivery and underlying mechanism in details. Ding et al.[32] found that the property of polyelectrolyte chains grafted to nanovector and DNA molecules can have important impacts on the endocytosis
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