Gold nanorods increase contrast in optoacoustic imaging
Technique has potential to detect cancer
A team of researchers wants to use gold to mark a spot where a tumor in the earliest stage of breast or prostate cancer exists. To that end, a group from the University of Texas Medical Branch in Galveston, from Fairway Medical Technologies in Houston, from the Mayo Clinic College of Medicine in Jacksonville, Fla., and from the University of Michigan in Ann Arbor, used engineered gold nanorods as a contrast agent for a laser optoacoustic imaging system.
In the in vivo optoacoustic experiment, gold nanorods were injected subcutaneously into the lower abdomen and detected from the back using a single-channel acoustic transducer. Reprinted with permission of Nano Letters.
They demonstrated visualization of the nanoparticles in living mice at a concentration of 1.25 pM, a figure about 75 times more sensitive than that of magnetic resonance imaging of ferromagnetic nanoparticles. “The sensitivity that this technology is offering is extraordinary,” said researcher Massoud Motamedi, director of the Center for Biomedical Engineering at the University of Texas Medical Branch.
Motamedi noted that an ideal medical imaging diagnostic technique would probe deep within tissue, would offer great sensitivity so that the smallest tumors could be detected, and would be specific to cells or tissue with certain characteristics and biomarkers. Laser optoacoustic imaging meets the first of these three requirements but is somewhat lacking on the last two, which is where the use of gold nanoparticles as contrast agents comes into play.
In laser optoacoustic imaging, a short near-infrared laser pulse irradiates tissue, with the wavelength allowing deep penetration. When the tissue absorbs the light, it heats up and undergoes thermoelastic expansion, generating ultrasound waves that travel outward without scattering. The waves allow acoustic detectors and back-projection algorithms similar to those used in ultrasound imaging to locate the absorption point.
This optoacoustic image of a nude mouse shows it before (a) and after (b) subcutaneous injection of gold nanorods into the abdominal area. Injected nanoparticles were brightly visible in the optoacoustic image. The drawing depicts the approximate position of the mouse during the experiment.
Because the technique depends upon the optical absorption of the tissue, it offers greater contrast between diseased and normal tissue than is possible with ultrasound alone.
Fairway Medical Technologies has developed diagnostic systems based on this approach, with Seno Medical Instruments of San Antonio pursuing commercialization of this technology. Fairway is under the direction of Alexander Oraevsky, a member of the research team.
However, laser optoacoustic imaging requires the tumor to be optically different from the surrounding tissue, a condition that does not arise until the tumor has reached a certain growth phase. “If the tumor has developed its own blood supply network — or angiogenesis microvasculature — so that there is a good difference in the blood concentration relative to normal tissue, then you do get a good signal,” Motamedi said.
Enhancing the optoacoustic signal before that happens is of considerable interest. The research group turned to gold nanorods as a contrast agent and signal enhancer for several reasons. Gold is biologically safe, so nanoparticles of the element could be used in animals and possibly in humans. In addition, the shape of the nanorods produces a strong signal, with an absorption peak that can be tuned by adjusting their dimensions. They also can be made smaller than nanospheres, enabling them potentially to target specific cellular receptors more efficiently.
For its study, the research group used gold nanorods that were 50 nm long and 15 nm in diameter. These constructs had a peak absorption of 760 nm, which matched the wavelength of the commercially available alexandrite lasers used in the investigation. The work is detailed in the July issue of Nano Letters.
Gold nanoparticles show high sensitivity but need improvement in specificity.
After fabricating the gold nanorods, the researchers coated them with polyethylene glycol or polysodium styrenesulfonate to make them stable in solution without significantly altering their optical properties. They then used them with equipment from Fairway Medical to determine detection capability through a 4-cm-thick block of a phantom substance designed to mimic scattering in tissue. After placing drops of nanorods of either 1.25 or 12.5 pM concentration on one side of the sample and acoustic transducers on the other, they fired the pulsed laser and recorded the resulting signal. They found that they could detect the lowest concentration and that the signal was proportional to the nanorod concentration. A test with a water-only control showed no signal.
Besides proving the capabilities of the system and the contrast agent, the tests with the phantom were designed to help optimize the technology for a demonstration of nanoparticle detectability in living animals. After completing that fine-tuning, the researchers moved on to imaging the nanorods in a mouse. They sedated the animal, turned it over onto its back, injected the nanoparticles into the animal’s abdomen and placed it atop an acoustic transducer. They then irradiated it with a laser and measured the signal. The results were comparable to those observed using the phantom, except for an unexpected result. “I was surprised we could see as few particles and as much sensitivity as we had in vivo,” Motamedi said.
Although these contrast agents are promising because of their high sensitivity, he noted that they are not yet complete and ready for use. The next step for the research is an improvement in specificity. The nanoparticles accumulate at a tumor and make it detectable in two ways. The first is simply by circulation and consequent natural uptake, a process that takes time and requires that the tumors have some blood flow. The second approach is to functionalize the nanorods by conjugating them with some biochemical that specifically targets tumor cells of interest. If that is done, the ability to detect tumors at an early stage will be improved, so research in this area is ongoing.
However, because animal studies have to be completed first, it will be several years before clinical trials using the technology can get under way.
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