Contained Paclitaxel And Hyaluronic Acid - Poly Cyanoacrylate N-butyl Nanoparticles

Paclitaxel, a kind of widely used anticancer drug, has been proved to have prominent anticancer activities. It has been applied in the treatement of many malignant tumors such as ovarian cancer, cervical cancer, breast cancer, small cell lung cancer and so on. The commonly used clinical dosage form is Taxol^?, produced by Bristol-Myers Squibb, USA. Taxol^? contains Cremophoro EL, which could cause hypersensitive response. The aim of current investigation is to develop a kind of biodegradable nanoparticles as a safe and effective delivery carrier for paclitaxel.The amphiphilic copolymer hyaluronic acid-poly(butyl cyanoacrylate) (HA-PBCA) were synthesized through radical polymerization of butyl cyanoarylate (BCA) initiated by cerium ions in the presence of HA. It could self-assemble into nanoparticles in water with HA as the shell and PBCA as the core in water.The FTIR and ¹H NMR spectra verified covalent binding between HA and PBCA. The molar ratios of disaccharide units of HA to BCA monomers were calculated to be about 1:12, 1:24, and 1:60, corresponding to the HA/BCA feed ratio (w/w) of 1:2, 1:4, and 1:6, respectively. The X-ray diffraction (XRD) spectra suggested that the polymerization of BCA onto HA chains led to the decrease of hydrogen bonding interaction of HA, and the crystalline structure of HA-PBCA appeared amorphous.From the transmission electron micrographs, it could be seen that the nanoparticles appeared monodispersed spheres with a solid and consistent structure.The particle diameters could be influenced by HA/BCA ratio, cerium concentration, and HA molecular weight, and were mainly dependent on the molecular weight of HA. The proper nanoparticles were obtained with HA molecular weight of 18 kDa and cerium concentration of 0.8 mmol/L. The HA/BCA ratio had inappreciable influence on the Zeta potential. The Zeta potential of the nanoparticles depended on the nature of the polysaccharide. The Zeta potential was pH dependent within the range of 3.0-10.0.The hemolysis and the cytotoxicity measurement showed that the hemolytic potential of all HA-PBCA nanoparticles were below 2%, and an increase in the HA content caused a slight decrease in the hemolysis ratio. HA modification on the surface of PBCA nanoparticles could successfully decrease the cytotoxicity.Paclitaxel-loaded HA-PBCA nanoparticles were prepared using the sonication method. The effects of different HA/BCA ratios on the encapsulation efficiencies of nanoparticles and in vitro drug release were evaluated. The results indicated that HA-PBCA nanoparticles could be an effective vehicle for paclitaxel, and the encapsulation efficiencies were augmented with the increase of HA amount. The nanoparticles with higher HA component corresponded to slower drug release and initial burst of paclitaxel was restricted.The result of cellular uptake in Sarcoma-180 (S-180) demonstrated that HA-PBCA nanoparticles possessed stronger affinity towards S-180 cells than PBCA nanoparticles.Paclitaxel-loaded PBCA nanoparticles, paclitaxel-loaded HA-PBCA and paclitaxel injection were administered to S-180 and H-22 tumor bearing mice through intravenous injection, respectively, and the tumor inhibition ratio were evaluated. The results indicated that paclitaxel-loaded HA-PBCA nanoparticles were more potent in tumor growth suppression than paclitaxel-loaded PBCA nanoparticles or paclitaxel injection. After the administration of paclitaxel-loaded HA-PBCA nanoparticles to S-180 tumor bearing mice through intravenous injection, it was found that the paclitaxel distribution in heart and kidney were lower than that of paclitaxel injection, while the distribution in tumor were higher than that of paclitaxel injection with prolonged retention. It would be suggested that HA-PBCA nanoparticles possessed tumor-targeting effect and long-circulation ability.