Controlled Synthesis Of Stimuli-Responsive Chitosan Derivatives In Drug Delivery

Chitosan is a biocompatible, biodegradable and non-toxic natural polysaccharide, and has been widely used in many fields such as the biomedical industry. However, due to the hydrogen bonds between molecules and high crystallinity, it is not soluble in common organic solvents, which greatly limits the application of chitosan. Therefore, many chemists are dedicated to the modification of chitosan. Over the past decade, with the development of living/controlled radical polymerization, great progress has been achieved on controlled modification of chitosan. Polymer grafted chitosan not only has the characteristics of chitosan, but also has the advantages of synthetic polymers, which endow chitosan with more applications. Specific studies of this paper are as follows:(1) Poly(hydroxyethyl acrylate ) grafted chitosan (CS-g-PHEA) was synthesized via RAFT polymerization of N-phthaloylchitosan. First, chitosan macromolecular RAFT agent was obtained from the esterification of N-phthaloylchitosan with S-1-dodecyl-S'(α,α'-dimethyl-α"-acetic acid) trithiocarbonate (DDACT). The polymerization of hydroxyethyl acrylate (HEA) grafting onto N-phthaloylchitosan was performed in the presence of chitosan RAFT agent at 60℃. Then the polymer grafted chitosan was deprotected by hydrazine hydrate at 100℃. Due to the amphiphilic structure of the graft copolymer, it can self-assemble into nano-particles in the aqueous solution. Because the amino group of chitosan can be complexed with carboxyl group, the graft copolymer can be used as a pH-sensitive nanocarrier to package hydrophobic drugs with carboxyl group, such as Naproxen.(2) Poly(N-isopropylacylamide ) grafted chitosan (CS-g-PNIPAM) was synthesized via RAFT polymerization with p-toluenesulfonate salt of chitosan. It is known that N-phthaloylation protection and the subsequent deprotection processes are very tedious, and the chitosan backbone maybe subject to significant break down during the process. Therefore, p-toluenesulfonate was used to protect the amino group of chitosan. Then the chitosan reacted with DDACT to give macromolecular RAFT agent, wich could control the polymerization of NIPAM at 60oC. After the polymerization, the deprotection was performed in 15% trimethylol aqueous ammonium to give CS-g-PNIPAM. The graft copolymer can self-assemble into the nanoparticles with pH and temperature dual response properties. It is important that the amino group of chitosan can react with Vanillin to form schiff base. So Vanillin can be packaged when the graft copolymer self-assemble with Vanillin. The release rate of Vanillin can be adjusted by changing the temperature and pH.(3) The "one-pot" synthesis of pH- and temperature-sensitive chitosan nanoparticles and its application in amino acid delivery were investigated. The pH- and thermo-sensitive chitosan-based nanoparticles were synthesized by the polymerization of acrylic acid/chitosan with PNIPAM macro-RAFT agent in the presence of ammonium persulfate-sodium thiosulfate redox initiator at room temperature. PNIAPM could be"in situ"grafted onto chitosan due to RAFT process. It was found that the chitosan nanoparticles can be used as drug-nanocarrier of amino acid, such as L-Histidine. During the"one-pot"synthesis process, the preliminary protection of chitosan was omitted in comparison with the previous work, which greatly simplifies the preparation of chitosan derivative.