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Ultrasound contrast agent enhances tissue imaging

Polymer-coated silica nanoparticles swell in response to pH changes

by Lakshmi Supriya, special to C&EN
April 15, 2020 | A version of this story appeared in Volume 98, Issue 15


Confocal microscopy image shows that polymer coated nanoparticles appear larger at higher pH.
Credit: ACS Sens.
Confocal microscopy image of coated silica nanoparticles in pH 4 and pH 7

A new contrast agent could allow real-time monitoring of pH changes in the body using an ultrasound scanner (ACS Sens. 2020, DOI: 10.1021/acssensors.0c00245). This expansion of the use of ultrasound could allow researchers to detect tumors more easily and could be extended to imaging other conditions in the body in the future.

Ultrasound is a widely used method for looking at changes or abnormalities inside the body and helping doctors to diagnose disease. The technique uses high-frequency sound waves, applied with a noninvasive handheld device, that penetrate tissues and reflect off areas of varying density to form images of different body parts and blood flow.

Compared with other imaging techniques like MRI, which requires large, complex instruments that are expensive to run, ultrasound is safe, inexpensive, and portable. The right contrast agents could expand the applications of ultrasound and make it a more useful diagnostic technique.

As a proof-of-principle, Simon Corrie of Monash University and his team decided to make an ultrasound contrast agent that could highlight differences in pH. The area outside tumors is often more acidic than healthy tissue. The researchers coated silica nanoparticles with alternating layers of poly(N-vinylpyrrolidone) (PVPON) and a thiol-functionalized poly(methacrylic acid). Such organosilica particles are known to be biocompatible. PVPON swells with increasing pH, changing the density of the polymer coating. This change in density leads to increased ultrasound contrast.

The team first tested the nanoparticles by incubating them in buffers at different pH and then embedding them in gels that mimic animal tissue. The ultrasound contrast increased two-fold in nanoparticle-laden gels for every unit drop in the pH.

They then tested the nanoparticles in live and dead mice injected under the skin with buffers in a range of pHs. Ultrasound images of these areas also showed enhanced contrast at lower pHs.

Microbubbles have previously been used to enhance contrast in ultrasound, but, they are unstable and have to be injected into the bloodstream. The solid nanoparticles can be injected directly into tissues, which is “an exciting advance for ultrasound-based biosensors,” says Andrew Goodwin of the University of Colorado Boulder, who was not involved in the study.

The pH of tissue is a relatively nonspecific marker, and many diseases and conditions have no pH signal, Corrie acknowledges. To expand the range of conditions that the method could detect, the team plans to explore different nanoparticle coatings that would change in response to more specific targets in tissues, such as cardiac proteins.



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