Tocopherol Polyethylene Glycol1000Succinate (TPGS) Modified Chitosan Nanoparticles As Antitumor Drug Carrier

Cancer is one of the deadliest killers to human lives, chemotherapy as aneffective treatment is often limited by great toxicity and multidrug resistance (MDR).The development of nanotechnology enables nanocarrier, which can improve drugsolubility, enhance targeting to tumor, achieve sustained and controlled release, andeven overcome the MDR, to be promising in cancer treatment. Chitosan is a positivepolysaccharide with good biocompatibility and biodegradability, has been widelystudied for carriers of anti-tumor drugs, gene and peptide. We can obtain variouscarriers by modifying chitosan with various reactive groups. Tocopherol polyethyleneglycol1000succinate (TPGS) is a safe and excellent surfactant; what’s more, it cannot only promote endocytosis, but also inhibit P-gp efflux pump and therefore,overcome the multidrug resistance.In this paper, we synthesized TPGS-Chitosan polymer with different graft degree,and prepared Doxorubicin (DOX) encapsulated nanoparticles by O/W emulsion andionic cross linking method, which were investigated as anti-tumor carrier and reversalof MDR. Results were as follows:1. Amide bond was successfully formed between active TPGS and–NH2of chitosan,which can be proved by1H NMR, FTIR and TGA. The graft degree of3.58%,9.04%was calculated by1H NMR. CS and TPGS-Chitosan nanoparticles were preparedusing O/W emulsion combined with ionic cross linking method. The nanoparticleswere spherical shape with uniform particle size (100～300nm). Encapsulationefficiency exhibited increasing first but then decline trend with increasing graft degreeof TPGS. In vitro drug release under different pH (6.8and5.2) indicated thatTPGS-Chitosan was pH-sensitive and could achieve sustained drug release.2. In vitro cytotoxicity of CS nanoparticles, TPGS-g-CS nanoparticles and DOX tohuman HepG2cells, Bel-7402cells and7402/5-Fu cells were analyzed by MTT assay.With the increase of DOX concentration and extension of incubation time, theinhibitory rates of DOX and nanoparticles to all of the three cells increased, and the inhibition was more obvious with more TPGS on chitosan chain. But there was adifference between different cells.3. In vitro cellular uptake was incubated with HepG2cells, observed by Confocaland quantified by Flow cytometry. The quantity of cellular uptake wastime-dependent; it was also depended on the graft degree of TPGS.4. Reversal of multidrug resistance was carried out on MCF-7and MCF-7/DOXcells, and determined through MTT assay, Confocal observation, cell apoptosis andcell cycle distribution. We could conclude that TPGS-CS may be a promising carrierfor reversal of MDR.