Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy

Abstract

Ultrasound contrast agents (UCAs) are used routinely in the clinic to enhance contrast in ultrasonography. More recently, UCAs have been functionalised by conjugating ligands to their surface to target specific biomarkers of a disease or a disease process. These targeted UCAs (tUCAs) are used for a wide range of pre-clinical applications including diagnosis, monitoring of drug treatment, and therapy. In this review, recent achievements with tUCAs in the field of molecular imaging, evaluation of therapy, drug delivery, and therapeutic applications are discussed. We present the different coating materials and aspects that have to be considered when manufacturing tUCAs. Next to tUCA design and the choice of ligands for specific biomarkers, additional techniques are discussed that are applied to improve binding of the tUCAs to their target and to quantify the strength of this bond. As imaging techniques rely on the specific behaviour of tUCAs in an ultrasound field, it is crucial to understand the characteristics of both free and adhered tUCAs. To image and quantify the adhered tUCAs, the state-of-the-art techniques used for ultrasound molecular imaging and quantification are presented. This review concludes with the potential of tUCAs for drug delivery and therapeutic applications.

Vibrational Responses of Bound and Nonbound Targeted Lipid-Coated Single Microbubbles

“…Others have reported lower radial excursions after binding for DSPCbased microbubbles [12], [14], but those studies had not covalently linked their model biomarker to their membrane. As a result, the biomarker that attached to the microbubble shell increased the stiffness [20] and therefore limits the radial oscillations.…”

“…reported in [17] for the model biomarker streptavidin that was physisorbed to an OptiCell membrane. Functionalization of lipid-coated microbubbles with streptavidin changes the properties, such as elasticity [18]- [20] and acoustic stability [20]. Consequently, the comparisons made in previous studies between bound microbubbles and nonbound microbubbles are in fact a comparison between bound lipid-coated microbubbles covered by streptavidin and nonbound lipid-coated microbubbles, which did not have streptavidin on their shell.…”

Ultrasound: The versatile energy source

“…This can lead to subtle changes, or to tissue tearing and obvious mechanical damage. Many of the therapeutic techniques currently under pre-clinical investigation involve the introduction of microbubbles with the aim of using their interaction with ultrasound at the intravascular lumen to cause a temporary opening of the blood-brain barrier, or other vessels, in order to enhance drug delivery [6][7][8][9]. It has also been suggested, for example, that inertial cavitation is needed before the adenovirus uptake can be enhanced in vivo [10].…”

Molecular Magnetic Resonance and Ultra Sound Imaging of Tumor Angiogenesis

“…US experiments gave access to measurement of the quantity of targeted microbubbles at only one time point, i.e. 10 minutes postinjection, as recommended by Van Rookie, et al [14]. The optimal window to perform MR imaging was assessed (Figure 4), and the targeted MR signal became significantly different from the non-targeted one after 37 minutes.…”