It's startling, isn't it, how quickly ideas become innovations become mundanities? In the early 1990s, most people would have put the likelihood of the proliferation of a vast information network...
It’s startling, isn’t it, how quickly ideas become innovations become mundanities? In the early 1990s, most people would have put the likelihood of the proliferation of a vast information network linking millions of computers worldwide somewhere between the lightsaber and “open the pod bay doors, HAL.” Four years later, every college freshman in America had an e-mail address. Ten years later, the Internet had become the foundation on which was built new forms of commerce, research, and communication. So it goes.
And so it seems likely to go with nanotechnology, a new approach to science and medicine poised to dramatically alter the faces of both fields. The term “nanotechnology” refers to the branch of science concerned with the creation of devices and materials used to manipulate matter on an extremely small scale (conveniently called the “nanoscale”). Nanoscale objects are those smaller than 100 nanometers (one nanometer equals one billionth of a meter) in diameter. Certain fundamental characteristics of matter, including color, melting point, and conductivity, are determined at the nanoscale; one of the chief advantages of nanotechnology in general is the ability to control these characteristics without changing the chemical composition of the subject matter. Every area of study and endeavor, from electronics to transportation, is expected to benefit from nanotechnology in some way. Nanoscale objects are roughly the same size as key biological components, such as proteins; the application of nanotechnology methods and devices might allow researchers to study and interact with “critical proteins and nucleic acids at the molecular level,” and thereby “provide a better understanding of the complex regulatory and signaling patterns that govern the behavior of cells in their normal state as well as the transformation into malignant cells,” according to the National Cancer Institute’s Alliance for Nanotechnology in Cancer.
Using therapeutic agents and devices at the smallest scale possible theoretically allows for the disruption of signaling patterns associated with carcinogenesis, the administration of drugs designed to kill cancer cells directly to those cells (reducing collateral damage to healthy tissue), and the identification of clustered malignant cells while those clusters are very, very small, and thus still manageable. Over time, researchers are certain to learn new things about the behavior of cancer at the molecular level; nanotechnology will allow the rapid creation of diagnostics, therapeutics, and preventives that take advantage of this new knowledge. The National Cancer Institute brochure entitled Going Small for Big Advances: Using Nanotechnology to Advance Cancer Diagnosis, Prevention, and Treatment claims that “Nanotechnology will change the very foundations of cancer diagnosis, treatment, and prevention.”
Small Medicine, Big Promise: Current Applications in Oncology
At first blush, some aspects of nanotechnology may seem rather more theoretical (or even fantastical) than practical (Robots! Tiny, cancer-fighting robots!), but real-world applications of this science are closer than you think. Nanotechnology researchers have thus far achieved some of their greatest progress in the diagnosis, evaluation, and novel treatment of cancer; research into cancer prevention is also ongoing, but thus far has produced somewhat less robust results.
Of Dots and Wires: Nanotechnology and Cancer Diagnosis
One of the most consistent challenges inherent in determining whether a given cancer has metastasized via the lymph system is locating the sentinel lymph node into which the tumor site first drains; these nodes are generally very tiny, and correspondingly difficult to find and remove. In December 2003, a team of researchers representing three institutions demonstrated a remarkable nanotech solution to this problem (Nature Biotechnology). So-called “quantum dots,” intensely fluorescent particles made of transition metals such as cadmium, selenium, or technetium, had first been described about five years earlier. Quantum dots are nanoscale spheres in which electrons and electron-negative areas are compressed and confined; energized electrons in this environment emit photons rather than heat as they relax.
The research team developed quantum dots small enough to pass through lymph ducts, but too large to pass through the nodes themselves; when these nanoparticles are introduced, they therefore become lodged in the lymph nodes. This causes the nodes to emit a green glow that is visible beneath the patient’s skin—through at least a centimeter of tissue. According to co-author Tomislav Mihaljevic, assistant professor of surgery at Brigham and Women’s Hospital, “With quantum dots, we have for the first time a method that can be used in real time with a high degree of sensitivity, and which can detect the smallest lymph nodes with exquisite precision.” Dots usable in human trials have not yet been developed—researchers must first explore the potential toxicity of the dots, which are made of heavy metals—but it seems clear that this method has the potential to generate vital information shortly following diagnosis.
Of course, nanotechnology also has potential applications even earlier in the diagnostic process. In October 2005, Harvard University researchers, reporting in the journal Nature Biotechnology, described “nanowires,” devices consisting of one or two tiny wires built on a nanoscale silicon grid and coated with antibodies to known tumor markers—PSA, mucin-1, and telomerase among them. When these markers interact with their antibodies on the nanowires, the result is a transient but measurable change in the conductivity of the device; this allows cancer to be detected in the presence of even modest marker activity. Ultimately, this might allow screening for cancer that detects much smaller tumors than is presently possible. See an animation illustrating how nanowires function, along with a host of references describing their utility in more detail.
Other diagnostic approaches abound. One team used a “naturally occurring nanoparticle” (the protein albumin) to bind with low-molecular-weight molecules, allowing the detection of the nuclear protein BRCA2, which has been linked to increased cancer susceptibility. There is also the possibility that fluorescent nanoparticles—similar to quantum dots—could be modified to bind directly to cancer cells; this might allow previously invisible cancers to be seen. “Nanotech gives us the opportunity to detect cancer tumors at 1,000 cells, whereas we’re now seeing them at 1 million cells. By the time you detect some cancers today, there’s no option of curing them, only of prolonging life,” Sri Sridhar of Northeastern University told Wired News in November 2005.
An even more recent development is designed to help physicians track metastasis when and if it does occur, and to elucidate the biochemical systems underlying the movement of tumor cells. Investigators developed a “microfluidic chamber,” containing multiple inlets each of which is capable of dispensing different concentrations of epidermal growth factor (EGF). They found that when concentration of EGF drops sharply from one side of the chamber to another, breast cancer cells move en masse and very quickly toward high concentrations of EGF; when the concentration gradient was less drastic, only some cells migrated toward higher EGF concentrations. Researchers were also able to show that adding an inhibitory antibody to EGF caused random, rather than directed, movement of tumor cells through the chamber.
Little Wrecking Crews: Nanotechnology and Cancer Treatment
Nanotech approaches to cancer treatment generally fall into one of two categories: (1) devices/particles designed to directly attack malignant cells; and (2) those intended to serve as targeted carriers for therapeutic agents. The rationale for delivering anticancer agents in nanoscale packages is twofold. First, it allows compounds that would otherwise be too toxic to be safely administered without danger to the patient. Sadik Esener, professor of electrical and computer engineering at UC San Diego refers to a nanoscale package of this sort as a “mother ship.” According to Esener, “You can put multifunctional particles on it, like an aircraft carrier transports choppers and planes. It goes into the body, and if it encounters a suspicious region, it finds out what that area is about and delivers the therapeutics.”
Nanoscale packages are also intended to deliver therapeutic agents or genes directly to cancer cells, while sparing healthy tissue. Antibodies or receptor ligands are attached to the nanoscale construct that can bind to molecules specific to the surface of cancer cells. For example, one team of investigators attached folate to a nanoparticle called a dendrimer, a spherical polymer of uniform molecular weight housing either methotrexate or paclitaxel. Folate bonds with the high-affinity folate receptors found on the surface of cancer cells (cancer cells require more folate than other cells, and thus have a greater number of folate receptors on their surfaces). In vivo and in vitro experiments using mice both showed that methotrexate and paclitaxel were delivered directly to cells positive for folate receptors (ie, cancer cells).
In June 2005, scientists at the University of Michigan reported on the use of a dendrimer with attached folate to deliver methotrexate to laboratory mice with cancer. The treatment worked precisely as planned, they reported; “folate molecules on the nanoparticle bind to receptors on tumor cell membranes and the cell immediately internalizes it, because it thinks it’s getting the vitamin it needs. But while it’s bringing folate across the cell membrane, the cell also draws in the methotrexate that will poison it.” This method proved 10 times more effective in delaying tumor growth than methotrexate administered alone and was associated with less toxicity. “Effectively, we achieved a 30-day tumor growth delay,” equivalent to about three years for a human subject, the authors reported.
Nanotechnology is also at the heart of a breakthrough new formulation of paclitaxel (marketed as Abraxane by American Pharmaceutical Partners and American BioScience). Like all taxanes, paclitaxel functions by disrupting the microtubule network in a cancer cell, thus preventing cell growth and mitosis. In the new formulation of paclitaxel, nanoparticle albumin-bound paclitaxel or Nab-paclitaxel, the drug itself is bound to the protein albumin, which is non-toxic, thereby allowing paclitaxel to be delivered without side effects. In January 2005, the FDA approved Nab-paclitaxel for the treatment of advanced breast cancer among women who had previously undergone chemotherapy or who had relapsed within six months of post-surgical chemotherapy. The FDA decision came on the heels of research findings demonstrating that Nab-paclitaxel was more likely to target cancer cells alone, generated a higher tumor response rate and time until tumor growth resumes, obviated the need for pretreatment steroids, required a shorter infusion time, and was associated with less risk of neutropenia.
There is, of course, a more direct approach to cancer treatment: send in the robots and start killing cancer cells. Of course, in some cases, the robots are actually tiny bits of precious metal. Researchers at Rice University and MD Anderson Cancer Center, working jointly, have encountered success using “nanospheres,” nanoscale silica particles plated with a layer of gold 10 nanometers thick, which are designed to absorb infrared light and convert it into heat. These nanospheres are injected directly into a tumor, and then bombarded with infrared light; they heat nearby tumor cells to above the “kill line” of 55ºC, destroying them.
The same research group, led by Rice University’s Jennifer West, has also modified the nanospheres by attaching antibodies that bind only to cancer cells; this allows the spheres to be injected into the bloodstream, from where they find and attach to malignant tissue on their own. Accordingly, suggests West, nanospheres should be “able to treat very small metastases [that have] not [been] detected yet. For example, if you had genes predisposing you to breast cancer, you could have this done on a periodic basis” to eliminate possibly undetectable clusters of cancer cells. Early mice studies have been encouraging, with nanosphere injection resulting in complete destruction of tumors and halting of tumor growth at 150 days. Human studies are ongoing.
The Future of Nanotechnology: Did We Mention the Tiny Robots?
The entity most responsible for guiding the US development of nanotechnology in the immediate future is the aforementioned NCI Alliance for Nanotechnology in Cancer, a “comprehensive, systematized initiative encompassing the public and private sectors, designed to accelerate the application of the best capabilities of nanotechnology to cancer.” The Alliance recently unveiled an elaborate plan in support of these aims, for which $144.3 million has been allocated over five years. The NCI Plan calls for research emphasizing six major areas of study:
1. Imaging/Early Detection
Will include further investigation of nanowires and other devices able to detect small and/or rare indicators of malignancy, as well as the creation of techniques for analyzing genetic mutations in a given cell and distinguishing normal from cancerous cells. Nanoscale devices designed to assess exposure to environmental risk factors for cancer will also be developed and tested.
2. Prevention and Control
Efforts to detect markers of cancer susceptibility and/or cells likely to lead to cancer, and reverse carcinogenic processes before they progress to full-blown disease.
3. Multifunctional Therapeutics
Refers to the development of devices packaging diagnostic and therapeutic functionality. A nanoscale object containing a therapeutic agent could be attached to a targeted agent (such as folate), and be made fluorescent to aid in imaging. Such devices could make it possible to deliver multiple interventions in a specified order or in multiple locations throughout the body.
Includes efforts to detect tumors at a much smaller scale than possible with contemporary technology, via improved targeting of cancer cells and generation of a larger imaging signal. The overall goal would be to allow clinicians “to more carefully monitor the disease-free status of patients who have undergone treatment or individuals susceptible to cancer because of various risk factors.”
5. Reporters of Efficacy
Refers to the creation of particles or devices able to assess the effectiveness of various forms of therapy. May include the development of devices able to recognize the biochemical signals associated with cancer apoptosis, thus assessing the efficacy of chemotherapy. Treatment efficacy could also be measured by creating nanoscale particles that would bind irreversibly to cancer cells, only released into the bloodstream upon the death of those cells; the presence of these particles in the patient’s urine would thus signal successful treatment. Nanotechnology might also be used to more accurately establish the margins of a tumor prior to surgical resection or track metastasis throughout the lymph system.
6. Research Enablers
Comprises the development of tools, such as tiny “nanolabs” capable of studying and manipulating individual cells or molecular harvesting devices, which will aid in the overall study and monitoring of cancer.
Beyond these efforts, well... no one can say what the future holds for nanotechnology in medicine, but anyone can speculate. The ultimate goal of this line of inquiry is the creation of a truly “smart” nanodevice, a literal robot that, placed in the human bloodstream, could easily and reliably find and identify malignant cells wherever they occur. The proposed device would then attach to the cells and destroy them—via chemotherapeutic drug, radiation, heat, or another method—and then report back via wireless connection the results of the mission. Such devices might initially be used only among at-risk individuals but could ultimately be used to stamp out early signs of cancer in every patient. Similar devices might also detect genetic changes associated with cancer development, aiding in preventive efforts. Still more useful would be a device that could fingerprint a given cancer cell for type and growth stage and then select an appropriate treatment from a range of choices and administer it at the ideal moment in the cell’s life cycle. This sort of highly individualized medicine, carried out at the cellular level, would vastly increase the ability of oncologists to ensure that patients receive the optimal treatment for their particular circumstances.
It is worth noting that the vast majority of the devices and methods described above are still only theoretical, or very early in development and may not see the light of day for years to come. All the same, it seems likely that—like the Internet—nanotech could become an essential component of oncology much more quickly than you might think. So keep watching, and remember: think small.