Self-assembled nanoparticles of chitosan oligosaccaride derivatives for targeted delivery of anticancer drugs

Abstract

Chitosan oligosaccharide (CSO) derivatives were successfully synthesized and used for the development of self-assembled nanoparticles for targeted delivery of doxorubicin (DOX) as a model of anticancer drug. The novel amphiphilic polymer, arachidyl chistosan oligosaccharide (CSOAA), was firstly synthesized in this study. In addition, CSOAA was further developed by grafting polyethylene glycol (PEG) (CSOAA-PEG) and diethylenetriaminepentaacetic dianhydride (DTPA)-Gadolinium (III) (CSOAA-DTPA-Gd) on the CSOAA backbone for a prolonged drug circulation time in blood stream and improving intensity of contrast agent for magnetic resonance imaging (MRI) of neoplastic lesions, respectively. The CSOAA formed self-assembled nanoparticles with nano-sized less than 200 nm in diameter, narrow particle size distribution, and low critical aggregation concentration (CAC) that could imply to stability of the nanoparticles. DOX-loaded CSOAA nanoparticles exhibited sustained drug released profile and improved drug releasing in acidic condition. In vitro cellular uptake of DOX in FaDu cells of the NPs-treated group were higher than free DOX group. In vivo antitumor efficacy of DOX-loaded CSOAA NPs was also verified in FaDu tumor xenografted mouse model. In the CSOAA-DTPA-Gd studies, the amount of Cy5.5-labled nanoprobes taken-up by FaDu and Hep-2 cells, as observed by confocal laser scanning microscopy (CLSM), increasing according to incubation time (up to 12 h). A phantom study of CSOAA-DTPA-Gd nanoprobes showed a T1-positive contrast-enchancing effect, compared to that of the commercial formulation (Gd-DTPA

Magnevist®). In the CSOAA-PEG studies, the stability of nanoparticles were investigated that the mean diameter both of CSOAA and CSOAA-PEG nanoparticles remain in DDW over 72 h, but the mean diameter of CSOAA-PEG nanoparticles remained relatively constant in serum over 72 h, compared with CSOAA nanoparticles (changed of 20.92% and 223.16%, respectively). The uptake of DOX in the nanoparticles by K562 human leukemia cells was higher than DOX solution. From the pharmacokinetic studies in rats, in vivo clearance rate of DOX in the CSOAA-PEG nanoparticles group was slower than other groups (CSOAA nanoparticles and DOX solution groups), subsequently extending the circulation period. All of the results suggested that the synthesized CSO derivatives could be used for preparation in self-assembeld nanoparticles as an effective candidate for targeted anticancer drug delivery and neoplastic diagnosis system. They could be applied for the other anticancer drugs to improve the specificity uptake of drugs at tumor site, thereny optimizing pharmacokinetics, antitumor efficacy, and side effect.