One of the ways to kill a cancer is to cook it, since heat can kill cells. The trick, of course, is to only cook the cancer and not the surrounding tissue. To do this, you need to have an accurate idea of the extent of a tumor, a precise mechanism for delivering heat, and a damn good thermometer. It may surprise you to learn that gold nanoparticles do a pretty good job of achieving the first two. The third—a good thermometer—has eluded researchers for quite some time. But, now it seems that gold nanoparticles may provide the full trifecta.

Drowning a tumor in molten gold

Some cancers—the ones most people imagine when they think of cancer—form lumps of tissue. At some point, these lumps require a blood supply. Once supplied with blood vessels, the tumor can not only grow, but it has a readily available transport system to deliver the cells that can spread the cancer throughout the body. For the patient, this is not good news.

The development of a blood supply opens up new imaging and treatment options, though. Cancer tumors are not well-organized tissues compared to healthy tissue like muscle or kidney tissue. So there are lots of nooks and crannies in a tumor that can trap small particles. And this disorganization is exactly what researchers hope to take advantage of. Gold nanoparticles are injected into the blood stream; these exit the blood supply, but, in most of the body, they get rapidly cleaned out. Except that, inside tumors, the nanoparticles lodge all over the place.

This tendency of tumors to collect the gold nanoparticles results in a nice marker that can be used to image the cancer. For instance, gold nanoparticles will glow very brightly when you shine light on them (typically red light). This glow can be imaged, even if the tumor is quite deep in the body. Alternatively, gold nanoparticle can be attached to a contrast agent designed to show up in an MRI scanner. Even X-ray imaging can be used.

And the nanoparticles can help kill cancers, too. When you shine light on the gold nanoparticle, it doesn't just glow brightly, it also heats up. So, in principle, you can shine laser light through the skin and locally heat the cancer to the point where the tumor cells are killed.

The problem is judging the treatment correctly: if you apply too much heat, you will damage surrounding tissue; if you don't apply enough heat, the tumor will not be damaged. To hit the sweet spot between the two consistently, you would need to be able to measure the temperature of the nanoparticles. That would enable a kind of guided treatment.

Seeing the heat

The way a nanoparticle glows can also contain information about the temperature. Perfecting the treatment, then, is just a matter of extracting this information. So let's get messy and look at the details.

When laser light hits a metal, the electrons, which are free to move around, chase the light's electric field. So, as the light electric field changes amplitude and direction, the electrons feel the force of the field and are driven back and forth.

In a nanoparticle, the electrons don't have much space to move around. So as the light drives the electrons, the electrons can only slosh from one end of the nanoparticle to the other. This is very much like water in a pot. Shake the pot at the right frequency and the water waves will build up until you end up with wet feet. This is because the pot was shaken at the resonant frequency of the waves sloshing around within it. The same is true for gold nanoparticles: shine the right color light on the particle, and the electrons will be driven at a resonance called a surface plasmon resonance.

The strength of these oscillations is what makes gold nanoparticles glow so brightly: they hold a large number of electrons accelerating back and forth, radiating energy as photons. The nanoparticles don't glow exclusively at the same color as the laser light we shone on it. A large amount of the light has a redder color, and a small amount has a bluer color.

The key thing for this new work is that these colors' shifts are temperature dependent.

The electrons are a bit like a gas that is flowing through the lattice structure of the gold nuclei, which is like a 3D grid. The speed at which they move is given by the temperature. In other words, temperature is a measure of the average energy of the electrons.

Good vibrations

The electrons are not careful drivers, carefully navigating between the gold nuclei. Instead, they careen like the ball on a pinball table, crashing into nuclei every femtosecond or so. When they do, they can lose energy by setting the gold nuclei vibrating (which causes its neighbors to vibrate, as the resulting sound wave travels away from the location of the collision). The electron can also gain energy if it hits a nuclei that's already vibrating. The vibrations of the gold nuclei represent energy stored in the lattice of nuclei, and there are always some vibrations present.

This means that there are two relevant temperatures: the temperature of the electrons and the temperature of the lattice of gold nuclei. Under normal circumstances, energy is transferred back and forth very rapidly between the two, so the two temperatures are nearly always the same.

When we switch the laser on, this careful balance is violently upset as the electrons are accelerated by the light. If we could measure their temperature, we would get a very high number. At the same time, the electrons are still colliding with nuclei. As a result, the lattice begins to heat up as well. Most of the energy put into shaking the gold nuclei about ends up transferred to the outside world—the tumor in this case. That's what can be used to kill it.

Meanwhile, the electrons are emitting light. Because most of the electrons are losing energy to the lattice, the glow of the nanoparticle is dominated by colors that are redder than the illuminating light. But the process goes both ways. Electrons that absorb energy from a lattice vibration will emit light that is bluer than the original laser light. This process is much rarer, because the lattice is quite cold. However, as the lattice heats up, the intensity of the blue light grows. So, by measuring the ratio of blue to red light, you can get an accurate measure of the temperature.

Measuring heat

This is actually a common technique in combustion physics, as it allows researchers to remotely measure the temperature of gases in combustion chambers (they usually measure nitrogen). But applying it to nanoparticles is a vastly different proposition. The problem is that the resonance that makes the emitted light so much brighter only works for some colors. If those are the colors you're measuring to track temperatures, then this will throw everything off. For instance, the redder colors might be more strongly enhanced than the blue colors, in which case, you would calculate a much lower temperature than is actually the case.

This is where good chemistry and calculations come in. When gold nanoparticles are synthesized, it is possible to tune their shape and size so that the vast majority of particles have similar dimensions. In this case, it is possible to calculate how each color is enhanced by the resonance. Once you take the resonant enhancement into account, you have a model with exactly one free parameter (the lattice temperature). Fit the data with your model, and you have the temperature.

Once you know the way the nanoparticle responds, you can also use that to increase the precision of the temperature measurement. You see, the blue light is often somewhere between 100 to 10,000 times weaker than the red light (because lattice vibrations are rare when the lattice is cold). But, if the laser illumination wavelength and nanoparticle shape is chosen so that the blue light is strongly enhanced compared to the red, then the ratio of blue to red light approaches one. This means that the time spent gathering light to make a measurement is much shorter, and more accurate temperatures can be obtained.

The whole idea is pretty cool.

The light of day is not to be seen

That said, I think this will be very tricky to use in therapeutic applications. First of all, even if the nanoparticles enhance the bluer part of the light spectrum, the intervening tissue will scatter it quite strongly. So, at the end, there may not be enough blue light left to obtain an accurate measure at any distance from the tumor. And it will take a more involved calculation to figure out how that scattering will change the measured ratio.

The bigger problem is the link between temperature and the surface plasmon resonance. As we said, that resonance depends on the shape of the particle. During the experiments, the researchers continually checked that the shape had not changed. Why would they do that? Because the heat that they generate while exciting the nanoparticle will melt it, and when you do that, the nanoparticle shape will change. In the body, there is no way to verify that the shape has not changed.

In therapeutic treatments, spherical particles are usually used. In that case, there will be no change in shape with heating. The research, however, was performed on rod-shaped particles, because they allow you to tune the frequency of the resonance and enhance the blue light. There is no possibility for tuning spherical nanoparticles, which brings you back to the lack of blue light. This seems like a catch-22.

So, this is a cool idea that I hope makes it further than the lab. But it's going to take a few years to work out the kinks.

Nano Letters, 2017, DOI: 10.1021/acs.nanolett.7b04145