title: Tumor delivery of ultrasound contrast agents using Shiga toxin B subunit.
abstract: The present study demonstrates the targeting of ultrasound contrast agents to human xenograft tumors by exploiting the overexpression of the glycolipid Gb3 in neovasculature. To this end, microbubbles were functionalized with a natural Gb3 ligand, the B subunit of the Shiga toxin (STxB). The targeting of Gb3-expressing tumor cells by STxB microbubbles was first shown by flow cytometry and fluorescence microscopy. A significantly higher proportion of STxB microbubbles were associated with Gb3-expressing tumor cells compared to cells in which Gb3 expression was inhibited. Moreover, ultrasonic imaging of culture plates showed a 12 dB contrast enhancement in average backscattered acoustic intensity on the surface of Gb3-expressing cells compared to Gb3-negative cells. Also, a 18 dB contrast enhancement was found in favor of STxB microbubbles compared to unspecific microbubbles. Microbubble signal intensity in subcutaneous tumors in mice was more than twice as high after the injection of STxB-functionalized microbubbles compared to the injection of unspecific microbubbles. These in vitro and in vivo experiments demonstrated that STxB-functionalized microbubbles bind specifically to cells expressing the Gb3 glycolipid. The cell-binding moieties of toxins thus appear as a new group of ligands for angiogenesis imaging with ultrasound.
authors: Institut Langevin Ondes et Images, (CNRS UMR 7587), INSERM U979 Paris, France. olicou@gmail.com
authors: Olivier
authors: O
authors: Couture
authors: Estelle
authors: E
authors: Dransart
authors: Sabrina
authors: S
authors: Dehay
authors: Fariba
authors: F
authors: Nemati
authors: Didier
authors: D
authors: Decaudin
authors: Ludger
authors: L
authors: Johannes
authors: Mickael
authors: M
authors: Tanter
mesh_terms: D000818:Animals; D003287:Contrast Media / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods*; D005434:Flow Cytometry; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D045423:Microbubbles; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000000981:diagnostic imaging*; D017711:Nonlinear Dynamics; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism*; D022621:Shiga Toxin / Q000378:metabolism*; D014281:Trihexosylceramides / Q000378:metabolism; D014463:Ultrasonography; D023041:Xenograft Model Antitumor Assays
chemical_list: D003287:Contrast Media; D021122:Protein Subunits; D014281:Trihexosylceramides; C018549:globotriaosylceramide; D022621:Shiga Toxin