Ultrasound-mediated Galactosylated Docetaxel-loaded Methoxypolyethyleneglycol-poly (Lactic- Co-glycolic Acid) Nanoparticles In The Targeting Therapy Of Human Hepatoma-bearing Nude

ObjectiveTo prepare galactosylated docetaxel-loaded methoxypolyethyleneglycol-poly(lactic-co-glycolicacid) nanoparticles (GDMN), and investigate the physiochemical properties, in vitro release and drug stability; and to investigate the effect and mechanism of ultrasound-mediated GDMN in the target therapy of human hepatoma-bearing nude mice.Methods1. GDMN were prepared by modified emulsification- solvent evaparation method. Laser scanning .Thedrug loading efficiency, drug encapsulation efficiency, and in vitro release were measured by high performance liquid chromatography HPLC . The acute toxicity of GDMN and docetaxel were also test in mice, death of mice was recorded to calculate half-lethal dose by modified Karber's method .2. Forty-eight nude mice were randomly enrolled into 8 group a mode group(M) docetaxel intravenous administration injection i.v. group(DTX) bare nanoparticles i.v. group BN GDMNi.v. group GDMN ultrasound irradiation group US DTX i.v. with ultrasound irradiating groupDU bare nanoparticles i.v. with ultrasound irradiating group BU GDMN i.v. with ultrasound irradiating group GU with 6 animals in each group.Four weeks after therapy,nude mice were examined by color doppler ultrasound and contrast-enhanced ultrasound following tumor parenchyma echo and blood supply were observed by color doppler flow imaging and contrast-enhance ultrasound.The tumor inhibition rate IR was calculated.Tumor tissues were examined on histopathology by microscopy, and on the expression of Survivin and Ki67 by immunohistochemical method.Results1. The GDMN were homogeneous, spherical and smooth particals with a mean diameter of 209.3 nm he optimal drug loading efficiency(3.51%) and encapsulation efficiency(72.28%). In the vitro drug release study,docetaxel was released from the GDMN in a slow but time-dependent manner,without occurrence of burst release.Stably the cumulative release was 84.3% within 4 days,kept stability of structure.Half-lethal dose calculated in GDMN group (219.5mg/kg) was far higher than docetaxel group (47.3mg/kg).2. Four weeks after therapy The tumor tumor of M group,BU group,US group and BU group were sustained growth obviously but the docetaxel groups were inhibitied in different degree especiallyin GU group,it displayed a potent antitumor effect on human hepatoma with a tumor inhibitory rate 65.97%, much higher than the other group,it showed significantly difference.Color doppler ultrasound and contrast-enhanced ultrasound founded that a large part of tumors parenchyma showed filling defect except slight enhancement.Extensive necrosis of tumor tissue was found in the histopathologic examination,and the expression of Survivin and Ki67 significantly decreased compared with the other groups.ConclusionGDMN were successfully prepared by modified emulsification-solvent evaparation method with optimal particle size,drug loading efficiency,encapsulation efficiency, stably drug release,and and low systemic toxicity,the effect of docetaxel in treatment of human hepatoma-bearing nude mice was promoted by Ultrasound-mediated galactosylated docetaxel-loaded methoxypolyethyleneglycol -poly(lactic-co-glycolic acid) nanoparticles in the targeting therapy. This new method of hepatoma treatment has potential clinical value.