Molecular Dynamics Of The Aggregation And Drug Encapsulation Process Of Hydrophobic Group Grafted Chitosan Oligosscharide

Cancer has been one of the major threats to human life. Chemotherapy has an important role in several major tumor therapies. The direction of practice and exploration of the medical experts is to develop new anticancer drug delivery systems constantly, to improve targeting and bioavailability of the drugs, to reduce toxicity of the drugs and improve the therapeutic effect. Amphiphilic copolymers undergo intramolecular or intermolecular associations and form nanoscopic core-shell structures that may be applied as promising drug carriers in the fields of pharmaceutical, biomaterials, and biotherapy. The polymeric micelles can entrap the drugs into their interior structures. The polymer micelle could be applied as promising drug carriers because of its stability, molecular design feasibility and high drug loading capacity. It can be improved the drug loading and the stability of the micelles by the design of the hydrophobic segment; It also can be improved the targeting, the stimuli-responsive release of the drugs and the endocytosis of the micelles by the design of the hydrophilic segment. As a natural polymer material, chitosan has been widely used as a drug delivery carrier because of its good biocompatibility, biodegradability and low toxicity.The research on the interaction between the drug and the carrier materials from the molecular level is very important and useful, which can guide people to design and develop suitable carrier materials. In order to understand the mechanism of the actions of the paclitaxel (PTX) encapsulated by the nanoparticles based on salicylic acid-grafted chitosan oligosaccharide (COS/SA), all-atom molecular dynamics simulations are performed to analyze the aggregation of COS/SA molecules. The results reveal that the COS/SA chains spontaneously aggregate and encapsulate PTX molecules to form a nanoparticle. Analyses of the radial distribution functions and solvent accessible surface area indicate that the resulting nanoparticles are hydrosoluble and can therefore significantly enhance the aqueous solubility of a hydrophobic drug. The SA block, consisting of a hydrophobic core to entrap the drug, and the COS block, as a hydrophilic shell, improve the aqueous solubility of hydrophobic drugs. The encapsulation process is mainly driven by hydrophobic and van der Waals interactions; electrostatic and hydrogen-bonding interactions also play helpful roles during aggregation. Three different drug loadings are studied to obtain the optimal theoretical drug/polymer ratio. The optimal theoretical drug loading is around10%(w/w).Then, based on above research, the influence of the different hydrophobic groups grafted to the chitosan oligosaccharide chains (salicylic acid, stearic acid, deoxycholic acid) on the encapsulation process is preliminary studied by all-atom molecular dynamics simulations. The major driving force in the encapsulation process of drug is van der Waals interactions in the three systems. The relative hydrophobicity of the three hydrophobic groups is compared by the analyses of solvent accessible surface area. It finds that the relative hydrophobic sequence is:stearic acid> salicylic acid> deoxycholic acid. The encapsulation process of the three hydrophobic groups grafted chitosan oligosaccharide is performed. The results indicate that the nanoparticle formed by stearic acid grafted chitosan oligosaccharide has the best encapsulated degree, the deoxycholic acid grafted chitosan oligosaccharide chains are more loosely packed than others, which implies that the stronger hydrophobic group, the high drug loading capacity. It provides the theoretical basis for the design of drug delivery carriers.