Effect of surface architecture on in vivo ultrasound contrast persistence of targeted size-selected microbubbles

Ultrasound Med Biol. 2012 Mar;38(3):492-503. doi: 10.1016/j.ultrasmedbio.2011.12.007.


Ultrasound molecular imaging is a powerful diagnostic modality using microbubbles coated with targeting ligands specific for endothelial biomarkers. The circulation persistence of ligand-bearing contrast agents is a key determinant in their contrast enhancement and targeting capability. Prior studies have shown that targeted microbubbles with ligands attached to the shell using the conventional exposed-ligand architecture (ELA) could trigger undesired ligand-induced complement activation and decreased circulation time. Microbubbles with the buried-ligand architecture (BLA), however, were found to inhibit complement activation and prolong circulation time. In the present study, we extended the stealth BLA microbubble design to size-selected (4 to 5-μm diameter) microbubbles targeted with cyclic RGD peptide using the postlabeling technique. Microbubble circulation persistence was measured in the healthy mouse kidney using a Visualsonics Vevo 770 scanner operating at 40 MHz in fundamental mode. The circulation persistence for targeted BLA microbubbles was significantly longer compared with their ELA counterparts and similar to no-ligand controls. Use of the BLA instead of the ELA increased the circulation half-life approximately two-fold. Analysis of the time-intensity and time-fluctuation curves with a two-compartment pharmacokinetic model showed a minimal degree of nonspecific vascular adhesion for any group. These results demonstrate the importance of surface architecture in the design of targeted microbubbles for ultrasound molecular imaging.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Computer Simulation
  • Contrast Media / pharmacokinetics*
  • Female
  • Image Interpretation, Computer-Assisted / methods*
  • Kidney / diagnostic imaging*
  • Kidney / metabolism*
  • Metabolic Clearance Rate
  • Mice
  • Microbubbles*
  • Models, Biological*
  • Organ Specificity
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Tissue Distribution
  • Ultrasonography


  • Contrast Media