A Targeting Microbubble for Ultrasound Molecular Imaging

作者：Yeh James Shue Min; Sennoga Charles A; McConnell Ellen; Eckersley Robert; Tang Meng Xing; Nourshargh Sussan; Seddon John M; Haskard Dorian O; Nihoyannopoulos Petros^*

来源：PLos One, 2015, 10(7): e0129681.

DOI：10.1371/journal.pone.0129681

Rationale
Microbubbles conjugated with targeting ligands are used as contrast agents for ultrasound molecular imaging. However, they often contain immunogenic (strept) avidin, which impedes application in humans. Although targeting bubbles not employing the biotin( strept) avidin conjugation chemistry have been explored, only a few reached the stage of ultrasound imaging in vivo, none were reported/evaluated to show all three of the following properties desired for clinical applications: (i) low degree of non-specific bubble retention in more than one non-reticuloendothelial tissue; (ii) effective for real-time imaging; and (iii) effective for acoustic quantification of molecular targets to a high degree of quantification. Furthermore, disclosures of the compositions and methodologies enabling reproduction of the bubbles are often withheld.
Objective
To develop and evaluate a targeting microbubble based on maleimide-thiol conjugation chemistry for ultrasound molecular imaging.
Methods and Results
Microbubbles with a previously unreported generic (non-targeting components) composition were grafted with anti-E-selectin F(ab')(2) using maleimide-thiol conjugation, to produce E-selectin targeting microbubbles. The resulting targeting bubbles showed high specificity to E-selectin in vitro and in vivo. Non-specific bubble retention was minimal in at least three non-reticuloendothelial tissues with inflammation (mouse heart, kidneys, cremaster). The bubbles were effective for real-time ultrasound imaging of E-selectin expression in the inflamed mouse heart and kidneys, using a clinical ultrasound scanner. The acoustic signal intensity of the targeted bubbles retained in the heart correlated strongly with the level of E-selectin expression (vertical bar r vertical bar >= 0.8), demonstrating a high degree of non-invasive molecular quantification.
Conclusions
Targeting microbubbles for ultrasound molecular imaging, based on maleimide-thiol conjugation chemistry and the generic composition described, may possess properties (i)-(iii) desired for clinical applications.

• 出版日期2015-7-10