title: Ultrasound exposure improves the targeted therapy effects of galactosylated docetaxel nanoparticles on hepatocellular carcinoma xenografts.
abstract: OBJECTIVE
  The distribution of targeted nanoparticles in tumor tissue is affected by a combination of various factors such as the physicochemical properties of the nanoparticles, tumor hemoperfusion and tumor vascular permeability. In this study, the impact of the biological effects of ultrasound on nanoparticle targeting to liver carcinoma was explored.
  
  
  METHODS
  The copolymer MePEG-PLGA was used to prepare the galactosylated docetaxel nanoparticles (GDN), and the physical and chemical properties as well as the acute toxicity were then assayed. The impact of ultrasound exposure (UE) on tumor hemoperfusion was observed by contrast-enhanced ultrasonography (CEUS), and the distribution of docetaxel in tumors and liver were detected by high performance liquid chromatography (HPLC). In the GDN combined with UE treatment group, the mice were injected intravenously with GDN, followed by ultrasound exposure on the human hepatocellular carcinoma xenografts. Twenty-eight days post-administration, the tumor growth inhibition rate was calculated, and the expression of Survivin and Ki67 in tumor tissues were determined by immunohistochemistry assay and quantitative real-time PCR.
  
  
  RESULTS
  The mean size of prepared liver-targeting nanoparticles GDN was 209.3 nm, and the encapsulation efficiency was 72.28%. The median lethal dose of GDN was detected as 219.5 mg/kg which was about four times higher than that of docetaxel. After ultrasound exposure, the tumor peak - base intensity difference value, examined by CEUS, increased significantly. The drug content in the tumor was 1.96 times higher than in the GDN treated control. In vivo, GDN intravenous injection combined with ultrasound exposure therapy achieved the best anti-tumor effect with a tumor growth inhibition rate of 74.2%, and the expression of Survivin and Ki67 were significantly decreased as well.
  
  
  CONCLUSIONS
  Ultrasound exposure can improve targeting nanoparticles accumulation in the tumor, and achieve a synergism antitumor effect on the hepatocellular carcinoma xenografts.
authors.affiliation: Department of Ultrasonography, Affiliated Union Hospital of Fujian Medical University, Fuzhou, China.
authors.forename: Hongfen
authors.initials: H
authors.lastname: Wei
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Liwu
authors.initials: L
authors.lastname: Lin
authors.forename: Ensheng
authors.initials: E
authors.lastname: Xue
authors.forename: Zhikui
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015415:Biomarkers / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000077143:Docetaxel; D004337:Drug Carriers / Q000138:chemical synthesis*; D005260:Female; D005690:Galactose / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000032:analysis; D019394:Ki-67 Antigen / Q000032:analysis; D019344:Lactic Acid / Q000737:chemistry; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000032:analysis; D013016:Sound; D000077022:Survivin; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; C117749:Birc5 protein, mouse; D004337:Drug Carriers; D051034:Inhibitor of Apoptosis Proteins; D019394:Ki-67 Antigen; D012097:Repressor Proteins; D000077022:Survivin; D043823:Taxoids; D000077143:Docetaxel; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D005690:Galactose