One-step Synthesis Of Chitosan-graft-polycaprolactone Copolymer And Its Properties As Drug Carrier

Polymeric nanomicelle has been paid extensive attention as a new type of drug delivery system in recent years. It is well known that polymeric micelles usually have the unique core-shell architecture composing of hydrophobic segments as internal core and hydrophilic segments as surrounding corona in aqueous medium. The hydrophobic core provides a loading space for poorly water-soluble drugs and defends the drugs from decomposition in order to remain their stability. The hydrophilic shell allows polymeric micelle gain the stability in aqueous environment. Furthermore, a polymeric micelle in a size of lower than 200 nm permits the efficient accumulation in tumor tissue via the enhanced permeability and retention (EPR) effect, which is termed as passive targeting. Currently, the synthesis of amphiphilic polymers and their aggregation behavior has been studied extensively, but there are a few reports on aggregation behavior based on natural polymer and its derivatives. Chitosan has been extensively investigated in drug delivery, gene delivery and other biomedical areas due to its biocompatible, biodegradable and non-toxic properties. However, the poor solubility in organic solvents and in aqueous media with physiological pH, due to the strong intra- and inter-molecular hydrogen bonds, limits its wide applications, and so the graft copolymerization of CS becomes an attractive way to regulate the physical properties of CS. It will greatly facilitate its application in drug delivery systems.In this study, cationic CS-g-PCL copolymers with different graft ratios were synthesized with a facile one-pot manner via ring-opening polymerization ofε-CL onto CS by using methanesulfonic acid as solvent and catalyst. The physicochemical properties, such as critical aggregation concentration (CAC), size and zeta potential, of the assembled CS-g-PCL nanomicelles were investigated. And then, water-insoluble antitumor drug, SN-38, was incorporated into the micelles. The encapsulation efficiency (EE), drug loading (DL), accumulative release and the cytotoxicity against L929 cell line in vitro of drug-loaded micelles were investigated in detail. The details are as follows: Chapter 1:IntroductionFor decades, the delivery of small molecular drugs using polymeric materials has attracted considerable attention from polymer chemists, chemical engineers, and pharmaceutical scientists. The review of the chapter will discuss drug controlled release system and its mechanism, the properities of chitosan and its application in the drug controlled release area, anti-cancer mechanism and the relationship of camptothecin derivatives between structure and efficacy in cancer therapy.Chapter 2:One-step synthesis of anmino-resevered chitosan-graft-polycaprolactone copolymersIn this chapter, one-step approach was developed to synthesize amino-reserved chitosan-graft-polycaprolactone (CS-g-PCL) by graftingε-CL oligomers onto the hydroxyl groups of CS via ring-opening polymerization by using methanesulfonic acid as solvent and catalyst, and characterized by FTIR and NMR. The controllable grafting content of PCL within CS-g-PCL provided the possibility to manipulate the biodegradation rate, hydrophilicity, and hence the cytotoxicity of CS-g-PCLChapter 3:The self-assembly behavior of chitosan-graft-polycaprolactone copolymers in aqueous mediaThe CS-g-PCL copolymer micelles have been prepared by dialysis method. The formation of CS-g-PCL nanomicelles was confirmed by fluorescence spectrophotoscopy and particle size measurements. It was found that all the nanomicelles showed spherical shapes with narrow size distributions. Their sizes ranged from 47 to 113 nm, and the zeta potentials ranged from 26.7 to 50.8 mV, depending on the grafting content of PCL in CS-g-PCL, suggesting their passive targeting to tumor tissue and endocytosis potential.Chapter 4:Fabrication of cationic nanomicelle from chitosan-graft-polycaprolactone copolymers as the carrier of 7-ethyl-10-hydroxy-camptothecinWater-insoluble antitumor drug, SN-38, was easily encapsulated into CS-g-PCL nanomicelles by lyophilization method. In comparison with bare CS-g-PCL nanomicelles, the corresponding SN-38-loaded nanomicelles showed increased particle sizes and a little reduced zeta potentials. With an increase of grafting PCL content, the drug encapsulation efficiency (EE) and drug loading (DL) of the nanomicelles increased from 64.3 to 84.6% and 6.43 to 8.66%, respectively, whereas their accumulative drug release showed a tendency to decrease due to the enhanced hydrophobic interaction between hydrophobic drug and hydrophobic PCL segments in CS-g-PCL. Also, the CS-g-PCL nanomicelles effectively protected the active lactone ring of SN-38 from hydrolysis under physiological condition, due to the encapsulation of SN-38 into the hydrophobic cores in the nanomicelles. Compared with free SN-38, the SN-38-loaded nanomicelles showed essential decreased cytotoxicity against L929 cell line, and bare CS-g-PCL nanomicelles almost showed nontoxicity. These results suggested the potential utilization of the CS-g-PCL nanomicelles as the carriers of hydrophobic drugs with improving the delivery and release properties.