Radiation-Force Assisted Targeting Facilitates Ultrasonic Molecular Imaging

Abstract

Ultrasonic molecular imaging employs contrast agents, such as microbubbles, nanoparticles, or liposomes, coated with ligands specific for receptors expressed on cells at sites of angiogenesis, inflammation, or thrombus. Concentration of these highly echogenic contrast agents at a target site enhances the ultrasound signal received from that site, promoting ultrasonic detection and analysis of disease states. In this article, we show that acoustic radiation force can be used to displace targeted contrast agents to a vessel wall, greatly increasing the number of agents binding to available surface receptors. We provide a theoretical evaluation of the magnitude of acoustic radiation force and show that it is possible to displace micron-sized agents physiologically relevant distances. Following this, we show in a series of experiments that acoustic radiation force can enhance the binding of targeted agents: The number of biotinylated microbubbles adherent to a synthetic vessel coated with avidin increases as much as 20-fold when acoustic radiation force is applied; the adhesion of contrast agents targeted to A v B 3 expressed on human umbilical vein endothelial cells increases 27-fold within a mimetic vessel when radiation force is applied; and finally, the image signal-to-noise ratio in a phantom vessel increases up to 25 dB using a combination of radiation force and a targeted contrast agent, over use of a targeted contrast agent alone. Mol Imaging (2004) 3, 135 -148.

Acoustically-active microbubbles conjugated to liposomes: Characterization of a proposed drug delivery vehicle

“…Current FDA-approved microbubble contrast agents are based on a lipid monolayer or albumin shell encapsulating a high-molecular weight gas [6][7][8]. The gas core provides the acoustic impedance mismatch which makes microbubbles highly echogenic and allows the microbubbles to be manipulated with acoustic radiation force [9][10][11][12].…”

“…Since spatial localization with ultrasound radiation force permits higher vehicle delivery rates than can be achieved by flow/adhesion dynamics alone, it is desirable to produce a drug-carrier vehicle which retains the capability to be acoustically concentrated [4,10,11,28]. Taking advantage of the acoustic properties of lipid-coated microbubbles and the fusogenicity of liposomes motivated us to create a new drug delivery vehicle by mounting the liposomes on microbubble shells.…”

Vascular Endoluminal Delivery of Mesenchymal Stem Cells Using Acoustic Radiation Force

“…The capacity to impart kinetic energy to gas-filled microbubbles by ultrasound has been previously characterized by Dayton et al, 8,9 and has been employed to modulate microbubble adhesion to endothelial epitopes for molecular imaging, 11,12 or to deliver a cytotoxic drug to tumor cells. 13 The radiation force on a given microbubble is maximal when the incident ultrasound is at the natural resonance frequency of the microbubble.…”

“…For the lipid-shelled microbubbles used in this study, the average resonance frequency is close to 2.2 MHz. 9,11 The intravascular ultrasound catheter used in our in vivo studies is FDAapproved to facilitate thrombolysis for treatment of stroke. Importantly, no major direct detrimental biological effects to the vessel wall were observed with this type catheter delivering the same amount of energy as in our study.…”

Quantitative Ultrasound Molecular Imaging in Large Blood Vessel Environments

“…In vitro studies have demonstrated an over 100-fold increase of microbubble adhesion due to ARF usage [58], [59]. Additionally, the image signal-to-noise ratio increased significantly due to the application of ARF [60]. In vivo validations have verified that the application of ARF enhanced the detection sensitivity and diagnostic utility of ultrasound molecular imaging [62], [63].…”