Molecular imaging with targeted contrast ultrasound

Abstract

Molecular imaging with contrast-enhanced ultrasound uses targeted microbubbles that are retained in diseased tissue. The resonant properties of these microbubbles produce acoustic signals in an ultrasound field. The microbubbles are targeted to diseased tissue by using certain chemical constituents in the microbubble shell or by attaching disease-specific ligands such as antibodies to the microbubble. In this review, we discuss the applications of this technique to pathological states in the cerebrovascular system including atherosclerosis, tumor angiogenesis, ischemia, intravascular thrombus, and inflammation.

Fig. 1

Schematic depiction of strategies employed for targeting microbubble contrast agents to disease-related antigens.

Fig. 2

Effect of microbubble ligation to endothelial cells on acoustic signal generation during phase inversion imaging [19]. a Example of VCAM-1-targeted microbubbles attaching to endothelial cells in vitro. b Relationship between percent of total microbubbles in an in vitro phantom attached to cells and the video intensity (VI), normalized to an equivalent concentration of microbubbles without cells. The relatively flat slopes of the relationships during high- and low-power (MI) imaging indicate minimal influence of ligation on signal enhancement.

Fig. 3

Targeted imaging of angiogenesis with α_v-integrin-targeted microbubbles [23]. a Hematoxylin and eosin staining of a coronal section of a human glioma cell tumor in an athymic rat. b Immunohistochemistry of α_v-integrin expression in the glioma illustrating dense expression on a neovessel. c Parametric contrast ultrasound perfusion imaging of microvascular blood volume and velocity in the area of a tumor illustrating discordance between volume and velocity with very high blood velocity at the tumor periphery but very slow velocity at its center. d Targeted imaging of α_v-integrin throughout the tumor (T), in the adjacent normal tissue, and at a site of micrometastasis (M).

Fig. 4

Targeted imaging of inflammation with leukocyte-targeted microbubbles in a rat model of acute stroke. Parametric contrast ultrasound imaging of microvascular blood volume (a) and blood velocity (b) demonstrate a peripheral left hemispheric perfusion defect during middle cerebral artery occlusion. c Targeted imaging of leukocyte recruitment with contrast ultrasound 1 h after reperfusion demonstrates an early inflammatory response in the postischemic region.

Fig. 5

Ultrasound images of the periventricular mesencephalic region from representative rats after injections of ICAM-1-specific microbubble [21]. a Rats suffering from encephalitis display a strong periventricular signal indicating ICAM-1 expression. b Only a background signal could be obtained in healthy control animals. c Steroid-treated rats display signal reduction. d The sonographic evidence for periventricular ICAM-1 expression is corroborated by anti-ICAM-1 immunohistochemistry. Reproduced with permission [21].

Fig. 6

Ultrasound images of human clot in vivo. a The clot (arrows) was preincubated in abciximab immunobubbles, washed in saline, and inserted into the right common carotid artery (asterisk) of the rat. b After ultrasonic destruction of the bubbles, thrombus echogenicity diminished. c Contrast re-enhancement was seen (arrow) during systemic application of a ReoPro microbubble suspension. Reproduced with permission [33].