The five-year survival rate for early stage melanoma is very high (98%), but the rate drops precipitously if the cancer is detected late or there is recurrence. So a great deal rides on the accuracy of the initial surgery, where the goal is to remove as little tissue as possible while obtaining "clean margins" all around the tumor. So far, no imaging technique has been able to define the melanoma's boundaries accurately enough to guide surgery. Instead, surgeons tend to cut well beyond the visible margins of the lesion in order to be certain they remove all the malignant tissue.
Two scientists at Washington University in St. Louis (MO, USA) have developed technologies that together promise to solve this difficult problem. Their solution, described in the July 2010 issue of the journal ACS [American Chemical Society] Nano, combines an imaging technique developed by Lihong Wang, Ph.D., a professor of biomedical engineering, and a contrast agent developed by Younan Xia, Ph.D., a professor of biomedical engineering.
The imaging technique is based on the photoacoustic effect discovered by Alexander Graham Bell 100 years ago. Bell exploited the effect in what he considered his greatest invention ever, the photophone, which converted sound to light, transmitted the light, and then converted it back to sound at the receiver. In Bell's effect, the absorption of light heats a material slightly, typically by a matter of millikelvins, and the temperature rise causes thermoelastic expansion. "Much the same thing happens," said Dr. Wang "when you heat a balloon and it expands."
If the light is pulsed at the right frequency, the material will expand and contract, generating a sound wave. "We detect the sound signal outside the tissue, and from there on, it's a mathematical problem," noted Dr. Wang. "We use a computer to reconstruct an image. We're essentially listening to a structure instead of looking at it. Using pure optical imaging, it is hard to look deep into tissues because light is absorbed and scattered. The useful photons run out of juice within 1 mm."
Photoacoustic tomography (PAT) can detect deep structures that strongly absorb light because sound scatters much less than light in tissue. "PAT improves tissue transparency by two to three orders of magnitude," remarked Dr. Wang. Moreover, it is a lot safer than other means of deep imaging. It utilizes photons whose energy is only a couple of electron-volts, whereas X-rays have energies in the thousands of electron-volts. Positron emission tomography (PET) also requires high-energy photons, according to Dr. Wang.
Photoacoustic images of biologic tissue can be made without the use of contrast agents, particularly if tissues are pigmented by molecules such as hemoglobin or melanin. However, photoacoustic images of melanomas are fuzzy and vague around the edges. To improve the contrast between the malignant and normal tissue, Dr. Xia loads the malignant tissue with gold. "Gold is much better at scattering and absorbing light than biological materials," Dr. Xia stated. "One gold nanocage absorbs as much light as a million melanin molecules."
Dr. Xia's contrast agent consists of hollow gold cages, so small they can only be seen through the color they collectively lend to the liquid in which they float. By altering the size and geometry of the particles, they can be tuned to absorb or scatter light over a wide range of wavelengths. In this way, the nanoparticles behave quite differently than bulk gold.
For photoacoustic imaging, Dr. Xia's team tunes the nanocages to absorb strongly at 780 nm, a wavelength that falls within a thin window of tissue transparency in the near-infrared. Light in this sweet spot can penetrate as deep as several inches in the body. Once injected, the gold particles naturally tend to accumulate in tumors because the cells that line a tumor's blood vessels are jumbled and leaky.
However, Dr. Xia has dramatically increased the uptake rate by embellishing the nanoparticles with a hormone that binds to hormone receptors on the melanoma's cells. The molecule is alpha-melanocyte-stimulating hormone, slightly modified to make it more stable in the body. This hormone normally stimulates the production and release of the brown pigment melanin in the skin and hair.
As is the case in many types of cancers, this hormone seems to trigger the growth of cancerous cells, which produce more hormone receptors than normal cells. In experiments with mice, melanomas took up four times as many "functionalized" nanocages than nanocages coated with an inert chemical. With the contrast agent, the photoacoustic signal from the melanoma was 36% stronger. Subcutaneous mouse melanomas barely visible to the unaided eye show up distinctly in the photoacoustic images, their areas of malignancy starkly revealed.
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