In vitro characterization of a novel, tissue-targeted ultrasonic contrast system with acoustic microscopy

Abstract

Targeted ultrasonic contrast systems are designed to enhance the reflectivity of selected tissues in vivo [Lanza et al., Circulation 94, 3334 (1996)]. In particular, these agents hold promise for the minimally invasive diagnosis and treatment of a wide array of pathologies, most notably tumors, thromboses, and inflamed tissues. In the present study, acoustic microscopy was used to assess the efficacy of a novel, perfluorocarbon based contrast agent to enhance the inherent acoustic reflectivity of biological and synthetic substrates. Data from these experiments were used to postulate a simple model describing the observed enhancements. Frequency averaged reflectivity (30-55 MHz) was shown to increase 7.0 +/- 1.1 dB for nitrocellulose membranes with targeted contrast. Enhancements of 36.0 +/- 2.3 dB and 8.5 +/- 0.9 dB for plasma and whole blood clots, respectively, were measured between 20 and 35 MHz. A proposed acoustic transmission line model predicted the targeted contrast system would increase the acoustic reflectivity of the nitrocellulose membrane, whole blood clot, and fibrin plasma clot by 2.6, 8.0, and 31.8 dB, respectively. These predictions were in reasonable agreement with the experimental results of this paper. In conclusion, acoustic microscopy provides a rapid and sensitive approach for in vitro chracterization, development, and testing of mathematical models of targeted contrast systems. Given the current demand for targeted contrast systems for medical diagnostic and therapeutic use, the use of acoustic microscopy may provide a useful tool in the development of these agents.

Acoustic response from adherent targeted contrast agents

“…The formation of layers of perfluorocarbon nanoparticle contrast agents has also been reported to substantially increase their echogenicity over that observed when in solution. 13 Second, optical observations indicated that adherent microbubbles formed aggregates ͑Fig. 2͒, which increases the coupling between adjacent agents and the effective scattering cross section.…”

Targeted ultrasound contrast agent for molecular imaging of inflammation in high-shear flow

“…The design of targeted contrast particles can be a multilayer liposome (8), a liquid fluorocarbon particle (9), or a gas-filled microbubble (10). Gas-filled particles possess an excellent acoustic backscatter response; ultrasound imaging is capable of detection of individual micron-size particles (picogram level detection sensitivity) (10).…”

Applications of Nanotechnology to Atherosclerosis, Thrombosis, and Vascular Biology

“…MR imaging of vascular cell adhesion molecule also has been reported recently with the use of peptide-targeted superparamagnetic nanoparticles in aortas of apolipoprotein E null mice by Kelly et al 35 For MRI, perfluorocarbon particles loaded with 50 to 90 000 gadolinium atoms per particle yielded a substantial amplification of signal from fibrin clots at 1.5T both in vitro and in vivo (Figure 2). 6,36 Furthermore, the detection of disrupted plaque was illustrated in actual human carotid endarterectomy specimens obtained from patients symptomatic with transient ischemic attacks, stroke, or bruits ( Figure 2). 12 Epix Pharmaceuticals more recently has used phage display methods to produce a peptide ligand specific for fibrin (EP-2104R), which may be useful for imaging thrombi in various body locations such as the left atrium, pulmonary arteries, or coronary arteries in experimental preparations.…”