Hydrosoluble Chitosan Study Based On The Targeting And Repairing Of Renal Fibrosis

Due to the excellent biocompatibility and biodegradability, chitosan has been widely used in biomedical field. Over the past decades, chitosan has played a significant role in the development of drug delivery system, such as specific site delivery, controlled drug release and delivery of gene or protein drug.Renal fibrosis is a common consequence of virtually all progressive kidney diseases, and the number of patients suffering from renal fibrosis has remarkably increased for the past decades. Failure to treat renal fibrosis can lead to end-stage kidney disease, which requires dialysis or kidney transplantation. There is no effective treatment method to directly halt or reverse renal fibrosis. Nevertheless, renal fibrosis drugs have also shown low aqueous solubility, short retention time, and non-specific biodistribution that may compromise availability. Therefore, the objective of this thesis is to seek a water-dispersible drug delivery system with specific renal targeting capability.Based on the specific renal targeting capability of chitosan, this thesis prepared good hydrosoluble N-acetylated chitosan(NC), N-acetylation thiolated chitosan(NTC) and N-acetylated chitosan-N-acetylation thiolated chitosan(N-NTC) from cheap commercial chitosan; then complexing with drug molecule and being loaded on carrier, chitosan derivative were acquired; finally, chitosan derivative effect on renal fibrosis repairing and targeting were studied. Major results of this thesis were as follows:1. Low molecule weight chitosan was synthesized using hydrogen peroxide degradation of commercial high molecule weight chitosan, then different N-acetylated chitosan products were acquired for adding different acetylation reagent. Our studies indicated that the degradation reaction temperature, acetylation reagent types and amount played an important role in the sizes and water-solublities of chitosan products. Hydrosoluble low molecule weight chitosan could be synthesized through adjusting above-mentioned parameters.2. Using thiol modified on chitosan to complex with bivalent cobalt ions, the drug cobalt was loaded on chitosan carrier successfully and the N-acetylation thiolated chitosan cobalt complex was acquired(NTCC). Biological experiments demonstrated that NTCC showed great specific kidney targeting and biocompatibility; then unilateral ureteral obstruction(UUO) mice model was established, which are available to mimic renal fibrosis. NTCC specifically recognized onto the surface of tubular epithelial cells through intraperitoneal injection, blood circulation and chitosan megalin-receptor interaction; then NTCC was endocytosed; the acid lysosomal environment and adjacent lesion region served as pH-trigger for drug cobalt ions releasing. Renal fibrosis has been improved through NTCC treatment.3. N-NTC was modified on the surface of core-satellite(CS) DNA gold nanoparticles(AuNPs) assembly(N-NTC-CS) using the thiol modified on N-NTC and AuNPs interaction. Biological experiments showed that the carrier material owns good biocompatibility and significant specific kidney targeting.