title: Ultrasound targeted microbubble destruction increases capillary permeability in hepatomas.
abstract: Ultrasound-targeted microbubble destruction (UTMD) has evolved as a promising tool for organ-specific gene and drug delivery. Taking advantage of high local concentrations of therapeutic substances and transiently increased capillary permeability, UTMD could be used for the treatment of ultrasound accessible tumors. The aim of this study was to evaluate if UTMD can locally increase capillary permeability in a hepatoma model of the rat. Furthermore, we evaluated whether UTMD can transfect DNA into such tumors. Subcutaneous Morris hepatomas were induced in both hind limbs of ACI rats by cell injection. A total of 18 rats were divided into three groups. Only one tumor per rat was treated by ultrasound. The first group received injection of Evans blue, followed by UTMD. The second group received a phosphate-buffered saline solution infusion and ultrasound to the target tumor after Evans blue injection. The third group received UTMD first, followed by Evans blue injection. Tumors and control organs were harvested, and Evans blue extravasation was quantified. Another 12 rats received DNA-loaded microbubbles by UTMD to one tumor, encoding for luciferase. Evans blue injection followed by UTMD showed about fivefold higher Evans blue amount in the target tumors compared with the control tumors. In contrast, no significant difference in Evans blue content was detected between target and control tumors when ultrasound was applied without microbubbles or when UTMD was performed before Evans blue injection. Plasmid transfection was not successful. In conclusion, ultrasound targeted microbubble destruction is able to transiently increase capillary permeability in hepatomas. Using naked DNA, this technique does not seem to be feasible for noninvasive transfection of hepatomas.
authors.affiliation: Internal Medicine III, University of Heidelberg, Heidelberg, Germany. raffi.bekeredjian@med.uni-heidelberg.de
authors.forename: Raffi
authors.initials: R
authors.lastname: Bekeredjian
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kroll
authors.forename: Evelyn
authors.initials: E
authors.lastname: Fein
authors.forename: Steliyan
authors.initials: S
authors.lastname: Tinkov
authors.forename: Conrad
authors.initials: C
authors.lastname: Coester
authors.forename: Gerhard
authors.initials: G
authors.lastname: Winter
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Hasan
authors.initials: H
authors.lastname: Kulaksiz
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000000981:diagnostic imaging* / Q000628:therapy; D003287:Contrast Media / Q000493:pharmacokinetics; D004247:DNA / Q000008:administration & dosage; D016503:Drug Delivery Systems; D005070:Evans Blue / Q000493:pharmacokinetics; D005119:Extravasation of Diagnostic and Therapeutic Materials; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D006614:Hindlimb; D008113:Liver Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging* / Q000628:therapy; D008156:Luciferases / Q000235:genetics; D008297:Male; D045423:Microbubbles; D009368:Neoplasm Transplantation; D051381:Rats; D011919:Rats, Inbred Strains; D014162:Transfection / Q000379:methods; D014463:Ultrasonography
chemical_list: D003287:Contrast Media; D005070:Evans Blue; D004247:DNA; D008156:Luciferases