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Baking tumors with waves: nanoparticles and biomedical innovation

While mankind has very recently accomplished a feat of astronomical proportions, with Voyager 1 finally leaving the confines of our solar system, at the other end of the spectrum the world of nanoparticles is allowing for a giant leap towards our innermost exploration. The spectacular optical properties of nanoparticles are revolutionizing medical imaging. They also help to renew therapeutic techniques. On the occasion of the inauguration of the AXA-ESPCI Chair, Emmanuel Fort, professor at the Langevin Institute of ESPCI ParisTech, presented the latest advances in a promising field where two roads meet.

December 2013
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Executive Summary

Nanotechnology does not solely relate to mechanisms taking place at the nanometric scale – it is also about new materials whose properties are, to say the least, astounding. A dozen of these materials is currently being researched throughout the world: fullerenes and carbon nanotubes were the very first, and now the most insulating material ever to exist, boron nitride, is opening up new horizons. Without the shadow of a doubt, the laureate for most spectacular has to be graphene, whose host of applications will literally bring about a revolution in our daily lives, most notably with the transistor and the batteries of the future, tomorrow’s cold computers, and, last but not least, with computers or smartphones that will be literally printable thanks to this astonishing material... which is but one atom thick.

Less publicized, silver nanoparticles are the active substance behind antibacterial socks and the pregnancy test, which, incidentally, was their first commercial application. But there are also all the nanoparticles that have resulted from combustion, and they have been around since the days fire was domesticated.

In truth, nanoparticles have not waited for the latest advances in man-made technology to be among us. They are found in certain volcanic dusts. Or, when you admire the rose of Notre Dame cathedral in Paris, which dates back more than eight centuries, the rich iridescent color actually comes from gold, silver and copper nanoparticles that are present in the stained glass: all in all, a mere four grams that make the difference, evenly distributed, infinitely diluted at the heart of the matter, among several tons of glass. By the same token, the much more ancient Roman Lycurgus cup, held at the British Museum, and famous for its “mysteries,” is green when lighted from the outside, and red when lighted from the inside.

Nano-antennas and nano-emitters at once

But what exactly is a nanoparticle? It is an aggregate of matter of ultrafine size, of nanometric proportions – a scale at which the properties of physical bodies are vastly different from what they usually are.

For example, let us take gold nanoparticles. Their uncanny light properties, which occur only at the nanoscale, first and foremost come from the fact that an electromagnetic wave will completely pass through a particle of such a size, whereas in the bulk material, penetration depth is limited to a few tens of nanometers.

But there’s more. Below a certain mass of atoms - a few thousand of them - discrete energy phenomena appear and the laws of thermodynamics are not really applicable anymore. Let us just imagine: a nanometer is one thousand times smaller than a micron, that is to say... it’s one billionth of a meter. One millionth of a millimeter. To get an idea, inversely, a billion meters is about three times the distance between Earth and Moon.

The metal nanoparticles present in the stained glass windows of Notre Dame are 70 nanometers thick, and their presence is due to the extreme dilution, in the glass, of an alloy of gold and silver. However, this dimension happens to be close to the very wavelength of light: when hit by a light wave, a nanoparticle reacts in a strange way. The conduction electrons collectively shift around the nanoparticle, on both sides, excited by the oscillating electric field associated with the incident light. The charges thus created at the surface produce a restoring force which tends to cause the electrons to return to their equilibrium position. And with a particular excitation frequency, the amplitude of this displacing movement is large, yielding a resonance phenomenon. To the eye, it gives an amazing iridescence.

Whatever the bright colors thusly obtained, they are not pigments, but result from a phenomenon of interaction between light and the structure of the illuminated material: these are called structural colors. This phenomenon can be found in our famous Lycurgus cup of mysteries, or, in nature, for example in the metallic blue iridescent wings of the Morpho, a giant tropical butterfly...

If medical research is taking a keen interest on wave-matter interactions and nanoparticles, it is because they have two essential properties. Firstly, they are antennas, which capture and focus the waves. They then scatter back the energy of these waves in the form of, on the one hand, light, and, on the other hand, heat. The challenge, for medicine, is therefore to achieve functionalizing nanoparticles by exploiting this feature of nano-antennas whose interaction with light is so strong.

An “ultrasound” scan at the scale of the cell: the road to virtual biopsy

In today’s medicine, representation, imaging, diagnosis and therapy are increasingly integrated. The boundaries of one are the boundaries of the other. For example, the resolution level achieved by a given technology determines the accuracy of what will or will not be liable to be detected, but also of what can be done about it. Moreover, be it at the stage of actual care and treatment or, prior to that, at the stage of medical observation, one major challenge is to achieve less invasive techniques. This is particularly the case in oncology. It’s almost as if in the battle against cancer tumors, our researchers had found inspiration in the famous “4 F” tactics of World War II troopers: Find, Fix, Flank & Finish. For indeed the goal will be to locate the cells, fix them in a given spot, and then shoot them with a focused wave, coming from several sides, that will destroy the tumor.

But first things first: let’s start with the starting point - imagery. The ability of nanoparticles to reflect light is something that will be exploited by tracing a given element inside the body: a biomedical marker (a single biomolecule if necessary). But how? With nanoscale emitters, that are going to be injected locally – at the level of a single cell if necessary. These nanoscale chemicals are excited whenever they receive a given wavelength of light. In turn, they emit light, either at the same wavelength (diffusion or “backscatter” phenomenon) or at other wavelengths (fluorescence). Today, it is possible to observe cellular mechanisms with ultimate sensitivity – at the scale of a single molecule – and with nanometric resolution.

Such is the process of cellular ultramicroscopy, which now makes it possible to illuminate the cell. “It’s just like illuminating the Eiffel Tower,” says Emmanuel Fort.

What for? Suppose that doctors want to detect the presence of a molecule, of a cell or a cluster of cells in a certain area of the body. They will first inject fluorescent emitters into this region and will then proceed to excite them with light waves, which will allow, in real time, to carry out a biopsy in high definition, much more accurate than a conventional MRI. For where the optical laws stop - at the scale of 0.2 micron, or 200 nm, about half the wavelength of visible light - ingenuity takes over, together with fine engineering revolving around a transmitter activation process. Instead of displaying the object in question as a whole, researchers have it sparkle with a myriad of nanoparticles which will outline its contours – just the same manner that a multitude of shimmering bright spots illuminate Paris’ most emblematic monument every evening. Quite naturally then, Professor Fort and his Paris-based team at Institut Langevin - ESPCI call this phenomenon the “Eiffel Tower effect.”

But, again, there’s more. After playing on photonics to obtain medical imagery in high definition, we will now get into the thick of it - literally - by playing on the excitation spectrum of nanoparticles so that instead of sending photons back... they send heat. And what is at stake here? Simply put... it’s about baking the tumor. And nothing but the tumor! The rest of the organ’s tissues are preserved. Enter the era of optical photothermy, or hyperthermia. It is also possible to create magnetic hyperthermia with magnetic particles, but, Emmanuel Fort notes, it is less effective. The use of optics allows for much higher accuracy. This feat is achieved through an infra-red laser: the infra-red wavelengths of the light spectrum are capable of crossing the body several cm deep. As a matter of fact, this one penetration effect is one we all know well since childhood because even before getting into infrared territory, the penetration effect is already visible in the (simply) red wavelength: this is the reason why, when we place a lamp behind our hand, our hand is translucent solely to red.

Stationary waves to ensnare tumors in a pincer movement

While this spectacular ability of nanoparticles is now the center of attention, it certainly doesn’t exhaust the potential of nanoparticles. Today other therapies and techniques are being developed, leveraging other phenomenology, most notably wave-matter interactions. Indeed, be it ultrasound or lasers, it was discovered that it is possible to synchronize several waves of the same frequency but coming from different directions so as to create what is called a stationary wave, also known as a standing wave. Rather than simply letting a single wave propagate, it is thus possible to create a vibration so perfectly synchronized that some of its elements, called pressure nodes, are fixed in time. Just like a continuous and perfectly even string of New York to Boston trains that would systematically intersect, at the same points, and at the same hours, with Boston to New-York trains coming the other way.

The point, therefore, is to focus energy on these very spots - and solely on those spots. And regarding amplitude, it is not unlike the fact that on a jump rope, the spot where the string varies the least in its ups and downs is where the hands are; a standing wave somehow being a series of jump ropes alternating between peaks and troughs (areas of maximum amplitude being called anti-nodes). And so, these immobile spots and them only are the points where the energy of the treatment is going to be concentrated – leaving the rest of the body unscathed. “We bombard one spot, as opposed to an entire organ. The whole point is not to harm people,” states Emmanuel Fort.

Pr. Fort hopes to create new types of imagery tomorrow with his team. Imagery whose mission, once again, would be the path of theragnostics, where diagnosis and therapy techniques form but one close-knit superstructure.

Therapeutic advances... but what of health hazards?

The pace of innovation is thus dramatic, and diagnostic and therapeutic advances are more than significant. But what of the harmful effects of nanoparticles on our health - and even on the very fauna and flora we depend upon? Researchers are questioning the potential ecotoxicity of these materials, such as the ones that are ever more widely integrated in cosmetics and bath products.

Today, researchers at the Langevin Institute are encouraging us to exercise caution in dealing with the proliferation of cosmetic products containing nanoparticles - especially where silver nanoparticles are concerned. As for the gold nanoparticle, it is supposedly harmless, especially if it is coated with a silica layer, but then again conflicting findings have been published. Radium, which was discovered by Marie Curie and that was to slowly prove fatal to her, has also had its heyday and was used until the late 1930s in all kinds of consumer products – from toothpaste to fluorescent needles on clocks, or even in sodas. Female blue-collar workers were even enticed to adorn their hair with radium dust every day for its fashionable glitter effect; even children have been victims of this as radium prescriptions for ear, nose and throat problems persisted in the United States, in some cases, until as late as the 1970s.

Let us remember the mere few grams of gold and silver nanoparticles within the windows of Notre-Dame: today, global production totals several million tons of nanoparticles – and their ecotoxicity is still remarkably unknown. They have already been detected in wastewater. Nanoremediation, which is gaining momentum in North America, is resorting to high doses of nanoparticles for soil remediation. While 54 consumer products already contained nanoparticles in 2005, according to the NanoTech Project, the figure had already exploded by 2009, skyrocketing to 1015 products. Increased by a factor of twenty... in just four years! And four more years later, today, in 2013, the evolution of these figures, after such a tremendous first assessment, is nowhere to be found. Suffice to say we are leaping into the unknown.

Researchers are particularly worried about the risk of human cell penetration. One must keep in mind that the cell is absolutely huge compared to nanoparticles. Comparing a 70 nm nanoparticle to our living cells - whose sizes vary between 20 and 100 microns (one fiftieth and one-tenth of a millimeter, respectively, 100 microns being in passing the resolution limit of the human eye) - is like putting the moon next to the sun: 70 microns is a full 70,000 nanometers. The nanoparticle being, of course, the moon, and our every cell, the sun, in this size ratio comparison. And obviously, all manners of organisms, from fungi to animals, plants or even microbes are also just as easily penetrated. And it so happens that nanoparticles are often more toxic than their larger counterparts. For example lots of people have seen the film about Erin Brockovich but who remembers that the toxic material she fought to see removed from drinking water was hexavalent chromium? We need to consider this: if the chromium VI that is ever more present in the leather we use for clothing and seats is already dangerous, in nanomolecular form, it takes a catastrophic... dimension. A Trojan horse of infinitesimal size. Some nanoparticles (Au, or TiO2 for example) are even suspected to damage our very DNA. Without anyone even knowing yet whether this effect is due to oxidative stress or to other causes. If we are to continue to harness the promise of nanoparticles, it is therefore an imperative that we strive to assess the risks that come in the bundle.