Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Sep 15:6:197.
doi: 10.3389/fphar.2015.00197. eCollection 2015.

Evolution of contrast agents for ultrasound imaging and ultrasound-mediated drug delivery

Vera Paefgen  1 , Dennis Doleschel  1 , Fabian Kiessling  1
Affiliations
Review

Evolution of contrast agents for ultrasound imaging and ultrasound-mediated drug delivery

Vera Paefgen et al. Front Pharmacol. .

Abstract

Ultrasound (US) is one of the most frequently used diagnostic methods. It is a non-invasive, comparably inexpensive imaging method with a broad spectrum of applications, which can be increased even more by using bubbles as contrast agents (CAs). There are various different types of bubbles: filled with different gases, composed of soft- or hard-shell materials, and ranging in size from nano- to micrometers. These intravascular CAs enable functional analyses, e.g., to acquire organ perfusion in real-time. Molecular analyses are achieved by coupling specific ligands to the bubbles' shell, which bind to marker molecules in the area of interest. Bubbles can also be loaded with or attached to drugs, peptides or genes and can be destroyed by US pulses to locally release the entrapped agent. Recent studies show that US CAs are also valuable tools in hyperthermia-induced ablation therapy of tumors, or can increase cellular uptake of locally released drugs by enhancing membrane permeability. This review summarizes important steps in the development of US CAs and introduces the current clinical applications of contrast-enhanced US. Additionally, an overview of the recent developments in US probe design for functional and molecular diagnosis as well as for drug delivery is given.

Keywords: contrast agent; drug delivery; microbubbles; molecular imaging; nanobubbles; theranostics; ultrasound.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
Behavior of SS-MB (lipid) and HS-MB (polymer) at different US intensities (modified from Hernot and Klibanov, 2008).
FIGURE 2
FIGURE 2
Active targeting by coupling of ligands to MB that bind to structures overexpressed or exclusively expressed on tumor endothelium (schematic illustration, not drawn to scale).
FIGURE 3
FIGURE 3
Passive targeting is enabled by ‘leaky’ vessels with fenestrae up to several 100 nm in tumor-associated endothelium and a poor lymphatic drainage, increasing both likelihood and retention time of nano-sized particles in the interstitium (EPR effect). After extravasation, NB/particles could also actively target specific surface molecules on cancer cells (schematic illustration, not drawn to scale).
FIGURE 4
FIGURE 4
Targeted MBs with entrapped drug/nucleic acids rupture under the US-induced acoustic pressure and release their loading specifically at the side of a tumor (schematic illustration, not drawn to scale).
FIGURE 5
FIGURE 5
Effect of US only (US) and USPIO-labeled MB with US (USPIO-MB+US) on the BBB. T2∗-weighted MRI images were taken before and after US/USPIO-MB+US application, R2∗ values of each measurement were color-coded and overlayed. The most striking difference can be seen after US application for 30 min, comparing pre- and post-scan in both groups (from: Lammers et al., 2015, ©2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim).
See this image and copyright information in PMC

References

    1. Albrecht T., Blomley M., Bolondi L., Claudon M., Correas J.-M., Cosgrove D., et al. (2004). Guidelines for the use of contrast agents in ultrasound: january 2004. Ultraschall. Medizin. 25 249–256. 10.1055/s-2004-813245 - DOI - PubMed
    1. Albrecht T., Blomley M. J., Heckemann R. A., Cosgrove D. O., Jayaram V., Butler-Barnes J., et al. (2000). Stimulated acoustic emissions with the ultrasound contrast medium Levovist: a clinically useful contrast effect with liver-specific properties. Rofo 172 61–67. 10.1055/s-2000-11101 - DOI - PubMed
    1. An L., Hu H., Du J., Wei J., Wang L., Yang H., et al. (2014). Paramagnetic hollow silica nanospheres for in vivo targeted ultrasound and magnetic resonance imaging. Biomaterials 35 5381–5392. 10.1016/j.biomaterials.2014.03.030 - DOI - PubMed
    1. Appis A. W., Tracy M. J., Feinstein S. B. (2015). Update on the safety and efficacy of commercial ultrasound contrast agents in cardiac applications. Echo Res. Pract. 2 R55–R62. 10.1530/ERP-15-0018 - DOI - PMC - PubMed
    1. Barr R. G. (2013). Off-label use of ultrasound contrast agents for abdominal imaging in the United States. J. Ultrasound Med. 32 7–12. - PubMed