Deformable gas-filled microbubbles targeted to P-selectin

Joshua J. Rychak, Jonathan R. Lindner, Klaus Ley, Alexander L. Klibanov

    Research output: Contribution to journalArticle

    100 Scopus citations

    Abstract

    Ultrasound contrast microbubbles have been successfully targeted to a number of intravascular disease markers. We hypothesized that targeted delivery could be improved further, by making the microbubbles deformable, leading to increased microbubble-endothelium adhesion contact area and stabilized adhesion. Activated leukocytes utilize such strategy; they deform after binding to inflamed endothelium in the vasculature. Lipid-shell microbubbles were targeted to the endothelial inflammatory protein P-selectin with a monoclonal anti-P-selectin antibody attached to the microbubble shell. Deformable microbubbles were created by controlled pressurization with partial gas loss, which generated an average excess shell surface area of ∼ 30% and the formation of outward-projected wrinkles and folds. Targeted microbubble adhesion and deformability were assessed in the parallel plate flow chamber under shear flow. Sustained adhesion of deformable microbubbles at wall shear stresses between 0.4 and 1.35 dyn/cm2 was consistently better than adhesion of wrinkle-free microbubbles. Over this shear range, targeted wrinkled microbubbles were deformed by shear flow, unlike wrinkle-free microbubbles. In a murine cremaster inflammation model, a significant improvement of deformable microbubble targeting was observed by intravital microscopy. Overall, the mechanical aspects of adhesion, such as particle shape, deformability and surface microstructure, are important in engineering efficient site-targeted particle-based agents for medical imaging and therapy.

    Original languageEnglish (US)
    Pages (from-to)288-299
    Number of pages12
    JournalJournal of Controlled Release
    Volume114
    Issue number3
    DOIs
    StatePublished - Sep 12 2006

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    Keywords

    • Adhesion
    • Microbubbles
    • Targeted imaging
    • Targeting
    • Ultrasound contrast

    ASJC Scopus subject areas

    • Pharmaceutical Science

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