Ultrasound imaging beyond the vasculature with new generation contrast agents

Abstract

Current commercially available ultrasound contrast agents are gas-filled, lipid- or protein-stabilized microbubbles larger than 1 μm in diameter. Because the signal generated by these agents is highly dependent on their size, small yet highly echogenic particles have been historically difficult to produce. This has limited the molecular imaging applications of ultrasound to the blood pool. In the area of cancer imaging, microbubble applications have been constrained to imaging molecular signatures of tumor vasculature and drug delivery enabled by ultrasound-modulated bubble destruction. Recently, with the rise of sophisticated advancements in nanomedicine, ultrasound contrast agents, which are an order of magnitude smaller (100-500 nm) than their currently utilized counterparts, have been undergoing rapid development. These agents are poised to greatly expand the capabilities of ultrasound in the field of targeted cancer detection and therapy by taking advantage of the enhanced permeability and retention phenomenon of many tumors and can extravasate beyond the leaky tumor vasculature. Agent extravasation facilitates highly sensitive detection of cell surface or microenvironment biomarkers, which could advance early cancer detection. Likewise, when combined with appropriate therapeutic agents and ultrasound-mediated deployment on demand, directly at the tumor site, these nanoparticles have been shown to contribute to improved therapeutic outcomes. Ultrasound's safety profile, broad accessibility and relatively low cost make it an ideal modality for the changing face of healthcare today. Aided by the multifaceted nano-sized contrast agents and targeted theranostic moieties described herein, ultrasound can considerably broaden its reach in future applications focused on the diagnosis and staging of cancer.

Contrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis and β-cell mass decline in mouse models of type 1 diabetes

“…We also demonstrated that bubbles of >1μm diameter did not extravasate and accumulate, which is also consistent with our prior measurements of microbubbles within the pancreas in models of T1D 11 , as well as being consistent with use of high MW fluorophore dextrans for labelling the vasculature 36,37 . These results are also consistent with prior imaging of NB accumulation within tumors by ultrasound and histology 33,38,39 .…”

Improving performance of nanoscale ultrasound contrast agents using N,N-diethylacrylamide stabilization

“…Recently, UCAs have gained more attention as theranostic agents and are currently being explored as an image-guided, ultrasound-triggered drug delivery system in various applications 1–4 . Clinically available UCAs are FDA approved in the United States for use in echocardiography studies, and are in clinical trials for other applications such as liver tumor diagnosis 5–7 . However, existing UCAs have a relatively large hydrodynamic diameter (1–8 μm) confining them to the vasculature and a short circulation half-life stemming from relatively limited structural stability 8 .…”

Folate receptor-targeted ultrasonic PFOB nanoparticles: Synthesis, characterization and application in tumor-targeted imaging

“…Although many types of ultrasound contrast agents have been developed for clinical application, some clinical studies have indicated that the contrast agents currently used are limited by insufficient sensitivity and specificity (1,4,35). …”