Researches On The Applications Of PEGylated Chitosan In Microparticlar Drug Delivery System

Chitosan, a (l-4)2-amino 2-deoxy ? -D glucan, is a kind of nature cationic, hydrophilic polysaccharide, with non-toxicity and biocompatibility. Its unique chemical and biological properties make it applicable in the pharmaceutical and biomedical fields, also in the drug delivery system.There are problems in using chitosan because of a lot of hydroxy groups and amino groups present in the glycosaminoglycan units of chitosan. These groups constitute the intra-, inter-molecular hydrogen bonds. These hydrogen bonds make chitosan insoluble in water and many organic solvents, unless it is protoned in acetic acid. So, various studies were conducted to make water-soluble derivatives of chitosan by chemical modification techniques.Poly (ethylene glycol) is a kind of polyether biopolymer, widely used as a pharmacological product of preferable hydrophilicity and biocompatibility with low biodegradability. It can dissolve in water and many other solvents, especially in tissue fluid. It can be eliminated ex vivo without any toxicity. Its good properties can be transferred when poly (ethylene glycol) is conjugated to other substances. When poly (ethylene glycol) is grafted to the surface of proteins and microparticlar drug delivery system, the soft poly (ethylene glycol) chains overlap the microparticlular surface alternatively and develop the stealthy cloud. PEG-grafted carriers show dose-independent long-circulating blood lifetimes, reduce interaction with and uptake by the reticuloendothelial system (RES). Poly (ethylene glycol) (PEG) polymer ensures the microparticles' stabilisation and turns them into potential long-circulating drug carriers, the so-called sterically stabilised carriers.From all above, we conjugated PEG via an amide linkage to the glycosaminoglycan units of chitosan. Then PEGylated chitosan was applied in two kinds of microparticular drug delivery systems in this disseration.The main contributions of this disseration are as follows:1) A new routine of synthesis PEGylated chitosan was developed. Methoxypolyethyleneglycol (mPEG)-graft-Chitosan is obtained through three steps of reactions. The structures of the activated mPEG and mPEGylated Chitosan were confirmed with 'H-NMR; 13C-NMR and Fourier transform infrared (FTIR) spectrum. PEGylated chitosan was synthesized successfully.2) Synthesised various PEGylated chitosan in different PEGylated degree and different molecular weight chitosan in the same synthesis routine. The swelling behaviors of various PEGylated chitosan in water were investigated. The solubility of PEGylated chitosan in water was dependent on the degree of PEG substitution, the molecular weight of chitosan. The more degree of PEG grafted, the lower molecular weight of chitosan was chosen as backbone, the more solubility of PEGylated chitoan was, the more of the turbidity of PEGylated chitosan decreased.3) Prepared PEGylated chitosan/DNA complex using an auto-coacervation process. Plasmid pEGFP-Ni was chosen as model DNA. The transfection efficiency of PEGylated chitosan/DNA complex in Hela cells in vitro was 86.85% by flow cytometer,.Thus, The PEGylated chitosan could be a potential non-viral vector for gene delivery system.4) Prepared PEGylated chitosan modified cyclosporin A lecthin vesicle by the way of emulsification-solvent evaporated. The drug contents and encapsulation efficiency(E.E.) was 37. 04 % and 69. 22 %. The size of the nanoparticle was 89.4nm, the zeta potential was -8.5mv.The release of the nanoparticle in vitro was very fast, releasing 30% in 48 hours, without a burst release at first. The release of nanoparticle in vitro was coincident with bulk erosion system.5) Use Tamoxifen as inner-standard of Cyclosporin in HPLC. Investigated the pharmacokinetics of PEGylated chitosan modified Cyclosporine A lecthin vesicle in rabbit by intravenous injection. The results showed ti/2beta of nanoparticle was 21 times of cyclosporine injection; AUC of nanoparticle was 25.8 times of injection.