Binding and detachment dynamics of microbubbles targeted to P-selectin under controlled shear flow

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

    Research output: Contribution to journalArticle

    179 Scopus citations

    Abstract

    This study was performed to assess the binding kinetics of a targeted microbubble contrast agent exposed to shear stress. An ultrasound contrast targeted to P-selectin was designed by conjugating monoclonal antibodies against murine P-selectin (RB40.34) to the lipid monolayer shell of the microbubble using poly(ethylene glycol)-biotin-streptavidin. The attachment and detachment of targeted microbubbles to P-selectin immobilized on a culture dish were assessed in a parallel-plate flow chamber. Targeted microbubbles (5×106 particles/ml) drawn through the flow chamber coated with P-selectin (109 sites/μm2) at a shear stress of 0.3 dyn/cm 2 accumulated at a rate of 565 mm-2 min-1. Attachment rates increased at higher plate surface densities of P-selectin, and microbubble detachment was reduced. Accumulation rate first increased with shear stress, reached a maximum at ∼0.6 dyn/cm2 and then decreased. Control experiments on a plate that lacked P-selectin, or was blocked with mAb RB40.34, resulted in minimal bubble attachment. Microbubble detachment was tested by ramping up shear stress at 30-s intervals. Half-maximal detachment was reached at 34 dyn/cm2. Overall, accumulation and retention of targeted ultrasound contrast agents is possible under physiologic flow conditions and is strongly influenced by shear stress and surface density of the target receptor.

    Original languageEnglish (US)
    Pages (from-to)473-482
    Number of pages10
    JournalJournal of Controlled Release
    Volume96
    Issue number3
    DOIs
    StatePublished - May 18 2004

    Keywords

    • Adhesion
    • Microbubbles
    • P-selectin
    • Targeting
    • Ultrasound contrast

    ASJC Scopus subject areas

    • Pharmaceutical Science

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