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Nanomedicine: Small Particles, Big Concerns

Jonpaul Wright

Medicine, science, agriculture, communication, and technology all underwent many revolutionary changes during the 20th Century. Each grew faster during this period than at any time prior in recorded history, leading to an overall advance in the quality and duration of life for the industrialized world. Humanity owed a great deal to these improvements; innovation was to be lauded for helping solve important problems, such as allowing farmers to fight crop-killing insects with the introduction of DDT or insulating buildings with asbestos. Unfortunately the potential long-term hazards of DDT and asbestos were not fully understood, leading to their eventual banning in the United States once their unforeseen risks materialized. Had understanding of these new scientific developments been more robust it could have spared science the setback resulting from reneging on the promise these new technologies gave the public. Overwhelmingly, new scientific advancements do not result in such unexpected outcomes, but when they do it cripples science as a whole, causing a loss in the public’s trust and dampening enthusiasm and funding for future research. Society benefits most from scientific progress when it is incorporated into our lives wisely.

The newest, and perhaps most significant, technology to be thrust into our lives is nanotechnology, a scientific reality just now emerging from its infancy. Nanotechnology deals with objects very near the atomic scale; materials at this scale exhibit evocative properties that are not present in their bulk form. Nanotechnology, especially as it applies to medicine and biomedical science, is a burgeoning field and one that is hotly debated. Supporters of medical nanotechnology, termed nanomedicine, believe it holds the potential to revolutionize modern medicine, from allowing pinpoint diagnostic imaging specificity to providing new treatments against common cancers that are free of chemotherapy’s debilitating effects. Skeptics do not question the scientific efficacy of nanomedicine but do insist a responsible regulatory framework is in place before nanotechnology is integrated into medical practice. Their hesitation stems from a lack of conclusive scientific evidence detailing how nanoparticles travel through the body. Nanomedicine is so new that scientists simply have not had enough time nor experience with nanotechnology to know how to approach this issue adroitly. Introducing nanomedicine to the public now is an extremely short-sighted choice that would be detrimental to both citizens and the environment. Premature adoption of nanomedicine is irresponsible because without fully understanding how the human body reacts to nanoparticles, their implementation would be dangerous. Furthermore, because the longterm behavior of nanoparticles is not known, nanopollution could irreparably damage the environment by contaminating water sources and causing significant ecological damage.

What Exactly Is Nanotechnology?

Nanotechnology is perhaps the ultimate achievement in miniaturization. At its most basic level nanotechnology allows scientists and engineers to manipulate, or create, objects at the atomic scale—we can now move individual atoms with precision. The ramifications of this newfound level of control are monumental. From a scientific standpoint, the revolutionary aspects of nanotechnology stem primarily from the intrinsically different properties of materials when in the nanometer scale, “where unique phenomena enable novel applications,” and the freedom provided by being able to specify the exact shape, size, and atomic composition of a given product, be it a computer chip or a medical treatment (NNI).

The word “nano” means one-billionth a whole. In science, the unit nanometer (nm) to used to represent the length that is one-billionth of a meter. Consider the following items which illustrate just how small a nanometer is: human hairs are about 80,000 nm in diameter while red blood cells have a 7,000 nm diameter (O’Mathuna 2). Atoms themselves are about a tenth of a nanometer, meaning that almost any nonelementary molecule will have dimensions in nanometers. In conjunction with the new characteristics their small size grants, nanoparticles’ unique properties are a result of the structure of the component atoms and their increased surface area-to-volume ratio (Sellers 16). Many subclasses of nanoparticles have arisen with characteristic attributes, but all are set apart from their bulk material counterparts because of the inherently different properties named above. Still more qualities of nanoparticles are consistently being discovered as it is a developing field.

What Makes Nanoparticles Useful in Medicine?

The usefulness of nanomedicine is a direct result of being able to engineer new nanocompounds that have inherent advantages over existing treatments. Given that they are vastly smaller than human cells, many nanoparticles are readily accepted into cells. In fact, an average virus ranges from 75 nm2 -100 nm2 in surface area, and as demonstrated by the massive worldwide impact of HIV and the various strains of the flu, viruses are quite adept at infiltrating cells. Though their biological interaction differs from a virus’, nanoparticles can be encased in biological molecules, such as antibodies, which bind with and permeate cells through an otherwise normal process. This customized celltargeting capability gives nanoparticles unrivaled versatility.

Another advantage of their size is the affinity nanoparticles have for cancerous tumors, aggregating at the site of the cancer, a phenomenon called enhanced permeability and retention (EPR) (Rhyner 414). This proclivity for certain nanoparticles to accumulate at the tumor location has been used to develop a new treatment for cancer that involves injecting gold nanoparticles into patients, and, once they have latched onto the cancer cells, harmlessly burning the tumors away by shining a specific light onto the area of the body housing the tumor (Bland 1). The gold nanoparticles react to the carefully chosen wavelength of light by rapidly heating up and burning away the cancer cells.

Unlike some recently popular scientific discoveries, such as embryonic stem cells, the efficacy of nanomedicine is more reliable. Nanoparticles can be engineered from the ground up, meaning their applications can be specifically tailored to a degree far beyond existing treatments. Nanomedicine is also far less politically polarizing than the medical use of embryonic stem cells as it does not infringe on religious or ethical beliefs by relying on human embryos for source material. These qualities add up to make nanotechnology an appealing choice for the advancement of medicine.

The Danger of Nanoparticles In Our Bodies

While nanomedicine is more sensitive to the public’s spiritual and political palate than are embryonic stem cells, it has a few salient weaknesses, all of which arise from its unknown long-term effects. Of primary concern are the unintended repercussions nanomedicine could have on human health. Nanomedicine is like any other advance in medicine in that it requires careful study and planning to ensure successful implementation. While there is no exact birth date for nanomedicine, considering its rise as a function of research funding, it is reasonable to say nanomedicine began with the turn of the millennium (Maynard 119). Being a new technology means that there is a limited amount of relevant research data to draw from. In theory, it is possible to predict how the particles travel through a human body, such as where they might be metabolized or which organs they might avoid. But relying on a theoretical forecast is fraught with danger especially since the technology is new. In this section we will examine the two most prominent means of human exposure to nanoparticles: injection, in the case of nanomedicine, and inhalation. Early studies have produced some alarming results for the potential hazard both inhalation and injection of nanoparticles present.

Nanoparticle Injection

The majority of research involving nanomedicine has relied on injecting the particles into an animal subject largely because this is the anticipated means of administration into humans. As such, nanomedicine was first injected into rats, as is customary in the development of new medical treatments. And after enough data were gathered from rodent trials that scientists felt secure in their basic understanding of nanomedicine, the next logical step was to conduct a clinical trial. So, how do nanoparticles interact with human bodies? Not always as predicted, as six British volunteers discovered in 2006.

The now well-known clinical trial took place in London. The experimental nanomedicine being tested was called TGN1412, and was to be administered to six “healthy male volunteers” intravenously (O’Mathuna 111). This was the first clinical trial of nanomedicine and no one involved knew exactly what to expect. Within one hour of administration, all six volunteers that received the experimental nanomedicine “developed back pain and severe headaches” (O’Mathuna 111). This unnerving response was soon followed by a litany of serious reactions such as vomiting, diarrhea, and involuntary convulsions. First their necks, then their heads started swelling and their blood pressure plummeted (O’Mathuna 111).

These symptoms abated hours later, seemingly signaling the end of what was surely a harrowing experience. Just then, the men began to struggle breathing and their organs began failing them. They were dying. All were rushed to the nearest hospital where they remained in intensive care for days. Four of the six were released a few days after the incident, but the other two “required months of follow-up care” (O’Mathuna 111).

How did this near-disaster happen? It was largely a result of having insubstantial research to draw from, which itself is a result of nanomedicine’s recency. The inability to review a long history of similar experiments in hopes of designing a better clinical trial is a problem faced by all revolutionary treatments, and TGN1412 is no exception. As mentioned above, substantial animal trials had been performed prior to the clinical trial. The clinical trial’s plans were drawn up correctly, having received the necessary approval from the UK regulatory agencies, yet the results were nearly catastrophic (O’Mathuna 111). Not all new drugs encounter this scenario. If a new cholesterol medicine is developed, doctors and scientists can review a wealth of existing literature to hopefully prevent any major clinical pitfalls. But this is not the case with nanomedicine.

At some point human trials of nanomedicine will need to be conducted in order to begin building a valuable database of knowledge. But nanomedicine is still new to be safely introduced into human subject, as shown by the debacle in London. Had the failed human trial in London, which brought the acute dangers of nanomedicine into stark contrast with the potential benefits, been more widely publicized the general public would have likely had a negative, knee-jerk reaction to nanomedicine. Such reaction would have been warranted given the severity of the volunteers’ symptoms. However, the public should be concerned more about the long-term health consequences of nanomedicine than the acute problems, which are likely to be resolved with continued research.

The two important issues with long-term nanoparticle behavior, as it concerns human health, are the lack of standardized testing procedures and the difficulty of predicting the fate of nanoparticles in the body. As is expected in a nascent technology, there exists few widely accepted protocols for experimentally testing nanoparticle behavior in a living animal, a method known as testing in vivo (literally “within the living”). In vivo tests have been conducted using various methods of administration, dosage, and measurement. Early experiments studying nanoparticles’ impact on health have frequently used carbon nanotubes—hollow tubes comprised only of carbon atoms that typically are less than 10 nm in length. These tubes are thought to present a danger to people in a manner similar to asbestos, which cuts and clogs the lungs of individuals who breathe the microfibers, causing inflammation that can lead to respiratory problems and cancer (Pichot 2). For example, a study completed in 2008 injected carbon nanotubes into mice to see what effect, if any, was observed. Some targeted mice were found to have internal swelling and cuts which are symptoms similar to those of asbestos damage (O’Mathuna 69).

Possibly more important than the confirmation that nanotubes can be hazardous is the finding that only certain shapes of carbon nanotubes caused harm. This realization further brings into relief that we are at such an early juncture in the nanotechnology revolution that it is not possible to know which particles may be dangerous and their adverse effects.

Another instance that illustrates the current lack of structure in nanoparticle testing is an experiment, done in 2008, that tracked carbon nanotubes injected into mice’s bloodstreams for over four months. Initial runs of the experiment saw a startling result; after four months of being symptom free, the mice’s livers and spleens were dissected and found to have large aggregations of the carbon nanotubes in them. However, subsequent trials failed to find this same accumulation (O’Mathuna 69).

These contradictory findings suggest two problems. The lack of reliability across the separate trials serves as a strong reminder that not enough is known about nanoparticles’ behavior in mice, let alone humans, to seriously consider using nanomedicine in patients. Second, and more disconcerting, is the realization that the administered nanoparticles gathered and remained in vital organs for over four months. While the lack of acute symptoms in the particle-harboring mice is puzzling, their long-term well-being remains unknown. Given that other, much larger particles, such as asbestos, result in cancer by gathering and remaining in vital organs, it is a plausible conclusion that nanoparticles, which can accumulate much more easily because of their smaller size, could certainly have a similarly harmful, inflammatory effect.

Nanoparticle Inhalation

While there is reasonable chance that nanoparticles in medicine could cause harm by collecting in a manner similar to asbestos, a major difference between the two is the route of exposure. In the study above the nanoparticles were intentionally injected into the mice. Asbestos, however, enters the body in an unintended fashion—through inhalation. Similarly nanoparticles, too, can be inhaled. They enter the atmosphere unintentionally as a result of industrial production, which includes the production of nanomedicine, providing another means of human exposure.

In nanoparticle literature industrial workers are the group most frequently mentioned as being at risk of hazardous inhalation, and while there is no denying they are likely to be the first victims of inhalation, they are not alone. The presence of nanoparticles in the atmosphere poses a risk for everyone. Further amplifying this point is the fact that nanoparticles are easily spread by wind, increasing their exposure to people (Clough 177). To understand how inhaled nanoparticles affect humans, early studies of nanoparticle inhalation have focused on the path and resting location of the inhaled particles and their potential toxicity to the inhabited organs.

During inhalation, air enters body through the nose and mouth, passes through the airways and comes to rest at the bottom of the lungs, where the alveoli are located. Respiration occurs and carbon dioxide, along with the remnants of the air originally inhaled, are now exhaled. When nanoparticles are inhaled they, too, follow this path. But, unlike clean air, nanoparticles do not undergo respiration nor are they all exhaled, meaning that once they are inhaled, they are most likely to remain in the respiratory tract.

The exact location of the particles’ resting place, however, is determined predominantly by their size. It has been shown that nanoparticles ranging from 10- 50 nm, the size of many biological molecules (Tsuda 2), end up in the alveoli while particles outside this range tend to rest in the upper respiratory tract (Hoet 77). The removal of the particle follows normal bodily procedures based upon their location; particles in the upper respiratory tract are taken out by the cilia which also push other solids, like phlegm, up to our mouth or nose to be expelled. Alveolar pollutants are not removed so easily, unfortunately, and require immune system intervention.

As such, nanoparticles represent a unique challenge to our body. Their unprecedentedly small size makes it harder for them to be removed by macrophages (Hoet 77). Macrophages have been revealed to play a part in proliferating cancer by releasing inflammatory compounds in the body, and if nanoparticles are not easily cleared by the macrophages they may lead to increased inflammation, similar to asbestos. For this reason nanoparticles are being investigated as possible carcinogens. With this in mind it is now understood that nanoparticles are doubly dangerous as atmospheric pollutants where they can enter the lungs undetected and, once there, can resist the body’s attempt to remove them.

Nanoparticle behavior inside of the lungs is unique in another way: they can translocate from one organ to another. For example, inhaled nanoparticles smaller than 6 nm have demonstrated the ability to cross through the lung tissue into the bloodstream, pass through the body and be excreted by the kidneys (Tsuda 2). Initially this sounds like a positive discovery but in reality it actually raises more troubling questions. What happens if the particle carries a molecular charge, like many deleterious free-radicals? As it passes through the body will it damage healthy cells? Other early findings offer little comfort, as these nomadic nanoparticles have been found to cause problems in blood clotting and, even more frighteningly, to enter the brain, prompting further investigation into the relationship between nanoparticles and neurological disorders (Hoet 78).

Clearly, nanomedicine represents a new frontier to researchers and doctors. The science is young to expect complete understanding of nanoparticle behavior in the human body. But with findings as startling as nanoparticles entering the brains simply by being inhaled currently unresolved, it is safe to say nanomedicine has many obstacles to overcome before it can safely be introduced to the public.

The Danger of Nanoparticles In Water Sources

Nanomedicine poses a risk to more than just the patients who take it. Aside from not knowing exactly how nanoparticles behave within the body, it is also unclear how they behave in the environment. Industrially engineered nanoparticles can take a multitude of forms, many of which are used in nanomedical applications. The industrial production of nanomedicine has two primary means of impacting the environment: by contaminating water supplies and by polluting the air. Here is a discussion of the avenues nanoparticles use to enter the water supply, their behavior in water, and the lack of standardized environmental analysis, which inhibits the ability to make informed decisions about how to regulate nanoparticle use.

The most prominent way nanoparticles enter the environment is as a by-product of industrial production, where they can be transferred as industrial waste, through either the air or fluid waste streams. Other sources of nanopollution are consumer products, biological excretion, and destruction of nanoparticlecontaining infrastructure—also a common source of asbestos exposure now (Clough 177). Because of their unprecedentedly small size, nanoparticle transportation behavior en masse in the open environment resembles a gas more than it does microscale particulate matter (Clough 177). As such, given their ability to disperse so easily, nanoparticle concentration dwindles rapidly as they travel farther from the source of pollution. However, this dissipation may present more of a danger than a benefit. This dispersion creates a false sense of security, by implying that only areas very near the source of pollution may be afflicted, that overlooks the fact that nanopollution is indeed real, and, as scientists are discovering, rather difficult to characterize with reliable accuracy.

Once nanoparticles have been introduced to the water supply, either through waste streams or via rain after entering the atmosphere, they are no more predictable than they are in a living body. Like the in vivo experiments discussed above, nanoparticle behavior in water depends on a multitude of factors, some intrinsic to the particle itself, others contingent upon the aqueous environment, such as its pH level. While the research on nanopollution is still in its early stages, studies that have been performed so far have focused on a broad range of nanoparticle behavior, both in the field and the lab.

One study of note, funded by the National Center for Environmental Research (NCER), took place from 2004-2007. The study’s researchers examined how well contemporary methods of water purification would remove nanoparticles, specifically metal oxides, from commercial drinking water. The conclusion was that “removal of nanomaterials by coagulation, flocculation, and sedimentation processes was relatively difficult” (Henry 162). In fact, the drinking water still had over 20 percent of the original nanoparticles in it after purification. This finding is startling. Metal oxide nanoparticles are already being tested in medical applications, and if they are difficult to remove from water using current industrial purification techniques it stands to reason that their introduction to natural water sources could pose a serious problem to both regulators and the environment (Henry 162).

Similar experiments found that carbon nanotubes, which are averse to water and therefore should clump together in water for easy removal, bonded to “organic material that occurs naturally in river water,” and remained suspended in the water for over an entire month (Henry 162). Again, with results like these it is difficult to contend that enough is known about nanoparticle behavior to begin public use.

In conjunction with the problem of purification is the problem of nanoparticle deposition in the soil. As the carbon nanotube experiment above showed, some nanoparticles have a propensity to bond with other molecules in the water, including porous media i.e. soil. Normally particles in water are expected to travel through the saturated soil with a frequency proportional to the flow velocity of the stream or river. While some nanoparticles, like the metal oxides mentioned before, did indeed demonstrate this behavior, others like carbon nanotubes and carbon fullerenes (carbon-only molecules shaped like soccer balls) did not. Instead they ignored the flow rate, leading to increased deposition. It was also shown that fullerenes acted like magnets, where once one was deposited in soil it would attract other fullerenes, pulling them into the soil (Mackay 149). Yet another study saw increased nanoparticle deposition at certain pH levels, revealing the aqueous environment also plays a role in particle behavior (Mackay 150). Not only do nanoparticles resist removal from water via industrial purification techniques, they also evade removal by depositing themselves into the soil, making nanopollution in water a daunting challenge to overcome.

Given the lack of understanding about nanoparticle behavior in aqueous media, it seems the next logical step would be to establish a standardized system or protocol for testing nanoparticles’ behavior in water. Unfortunately, this has yet to be done. In part this systematic process is absent because nanoparticles are fairly new concepts and most attempts to generalize conclusions from one study to overall particle behavior have met with failure. The perplexing unpredictability of nanoparticles’ reactions in something as chemically fundamental as water has left researchers and regulatory agencies at a standstill. There simply isn’t enough collective understanding to accurately make protocols for the various classes of nanoparticles. Instead, Kim Henry, a hydrogeologist from Harvard University, accepts that “the fate and transport of nanomaterials must be considered on a case-by-case basis” (Mackay 151).

Balancing the Future of Nanomedicine

When considering nanomedicine it is essential to realize the significant paradigm shift it places. Nanotechnology is just now emerging from its infancy and is only beginning to be understood. It is important to bear in mind the fundamentally competing interests surrounding nanomedicine: doctors want to provide their patients with the best possible treatments but scientists seemingly want to study new technologies until details of their behavior is known before approving their public use in patients. Both parties are pursuing their best interest and professional security. In this way, science and medicine have a built-in checks and balances system.

Ideally every new medical treatment’s behavior in all environments would be easily characterized, allowing its introduction in a speedy manner. Unfortunately, as demonstrated by other discoveries during the 20th century, like DDT and asbestos, this is not always the case. Nanomedicine is currently in the midst of this “use now” versus “keep investigating” debate. Doctors, pharmaceutical CEOs, and patients are all clamoring for nanomedicine’s rapid adoption despite the fact that nanomedicine is simply not ready to be introduced to the public. Those same doctors, CEOs, and patients may not be quite so eager to push for nanomedicine’s public launch if they were more aware of how little is known about the potentially deleterious long-term effects of nanoparticles. Undeniably, society at large will only benefit from its successful incorporation into modern medicine. The continued research of nanomedicine before exposing it to the public is essential, so that science continues to help us, not harm us.

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