While the concept of shrinking humans is quite fantastic and unrealistic, scientists have already developed tiny vessels that can hunt down diseased cells and deliver precise drug doses.
“Man is the center of the universe. We stand in the middle of infinity between outer and inner space, and there’s no limit to either.”
-Fantastic Voyage, 1966
In 1959, physicist Richard Feynman gave a talk at Caltech titled “There’s Plenty of Room at the Bottom,” wherein he first introduced the concept of creating devices at the molecular level by manipulating individual atoms and molecules. It wasn’t until years later that the term “nanotechnology” was coined to refer to this concept, yet its principles had invoked imaginations everywhere, including Hollywood, and, in 1966, the film Fantastic Voyage was released. In the movie, a submarine with a medical team onboard is shrunk to become microscopic and injected into a scientist with the intention of treating his life-threatening blood clot. Since its release over 40 years ago, countless references to this film have been made in literature, television, and cinema, and a remake is slated to be released in 2010, which will perhaps spark interest in nanotech among future generations.
While the concept of shrinking humans is quite fantastic and unrealistic (at least for the foreseeable future), scientists have already developed tiny vessels that can hunt down diseased cells and deliver precise drug doses. These tiny vessels are called nanocapsules or nanoparticles, and Russell Mumper, PhD, UNC Center for Nanotechnology in Drug Delivery, UNC Lineberger Comprehensive Cancer Center, has used them to overcome chemoresistance in mouse models. Dr. Mumper and his team found that when doxorubicin or paclitaxel were delivered using lipid nanocapsules, the growth of multidrug-resistant ovarian cancer lesions stopped completely in the mouse models that they examined, whereas these drugs were found to be ineffective when administered through conventional means. His research is published in the May 1, 2009 issue of Cancer Research, and he took the time to answer some of our questions on his findings and share his thoughts on nanotechnology and its medical applications.
Overcoming chemoresistance: A conversation with Dr. Mumper
How do you think nanotechnology will impact medicine over the next decade—do you see this as the next frontier?
Nanotechnology is not new. In fact, it has been around for decades and arguably for much longer; however, it has more recently captured the imagination and interest of scientists and lay people alike. As of 2007, there were about 200 companies focusing on the use of nanotechnology to address medical issues. There are already over 40 nanomedicine products on the market with sales exceeding $7 billion annually. The use of nanotechnology for drug delivery captures the largest percentage of this market, about 78% of sales. I believe it is one of two next frontiers, those being the really small (nanotechnology) and the really large (outer space).
How do nanocapsules work?
Our laboratory has been focused over the past decade on trying to put very potent cancer drugs in nanoparticles so that these small carriers can be injected into the body and potentially targeted to tumors. This endeavor has been challenging for many labs, including ours, since the task is multifaceted and there are many obstacles. We have discovered a very simple process to make oil-filled nanocapsules. Unlike nanoparticles that are solid throughout, these nanocapsules have a shell with a liquid oil on the inside. The engineering process to make the nanocapsules is rapid, cost-effective, and can be completed in a few minutes in one vessel. All of the materials used to make them are already in pharmaceutical products. The oil on the inside of the nanocapsules can dissolve the cancer drugs in high concentration, and the drugs remain stable in the vial or when injected into the bloodstream. Over time, the drug is released from the nanocapsules and the oil in the nanocapsules is actually metabolized by the body and used as nutrients.
What were some of the key outcomes of your study?
Many types of cancers develop mechanisms to become resistant to otherwise potent cancer drugs. The most well-known mechanism of resistance is where a protein on the surface of the cells or sometimes in the cells can quickly and extensively pump the drug out of the cell. Resistance is a significant problem and leads to recurrence. The only solution is to choose a different drug and hope that the new drug can provide benefit before the tumor becomes resistant to it.
Our studies have shown that the nanocapsules can significantly enhance the intracellular drug concentrations in resistant cancer cells. We showed that an ingredient in the nanocapsules that is used to engineer them can inhibit the protein pump in several resistant cancer cells and reduce the energy level in the cell. The cumulative effect is that a much higher concentration of the cancer drug gets into the cancer cells, and is therefore able to kill these cells. This has now been shown in resistant ovarian and breast cancers and melanoma, and we are testing it on other types of cancer as well.
Why do you think the nanocapsules were able to overcome chemotherapy resistance in your mouse model?
We have shown that the nanocapsules carrying the cancer drug paclitaxel are able to completely prevent the growth of resistant ovarian tumors in mice carrying human ovarian tumors. The nanocapsules are injected into the bloodstream and are able to deliver drug to solid tumors. The commercially available form of paclitaxel, Taxol®, was completely ineffective in reducing tumor growth even at almost lethally high doses to the mice. Even more encouraging was that the mice that failed Taxol treatment had their tumors shrink when they were treated with the nanocapsules.
What further investigations have your team planned?
Tumors that do not respond to chemotherapy, or that develop resistance, very often metastasize and spread to other organs in the body. Metastatic cancer, and not the primary tumor, is frequently the cause of death. The ‘holy grail’ of nanotechnology-based drug delivery is to seek out and destroy tumor cells that have metastasized or broken away from the primary tumor; however, if these metastatic cells are now resistant, this may be difficult to do. We think our nanocapsules can be targeted to these metastatic tumor cells and may be able to overcome the resistance when they find these cells.
Nonmedical nanotech may spawn medical advancements
While there are numerous medicines on the market that already employ nanotechnology, as noted by Dr. Mumper, some of the advancements on the medical front may come from nanotechnologies that are not specifically focused on the medical industry. Gregory Rutledge, PhD, Lammot du Pont Professor, department of chemical engineering, MIT, Cambridge, has developed unique electrospun nanofibers that may eventually have medical applications. These nanofibers have a diameter roughly a thousand times smaller than that of a human hair, and while they may not appear to be any different (apart from their size) from regular fibers macroscopically, they can be developed to contain unique and highly useful properties. Dr. Rutledge and his team have developed several textiles that incorporate functional materials into the electrospun membranes. One such material, recently described in the journal Polymer, incorporated chlorhexidine, a chemical antiseptic that can kill both grampositive and gram-negative bacteria. This technology holds much promise for a wide range of applications, and one day protective clothing and drug delivery mechanisms may just be comprised of some very unique nanofibers. Dr. Rutledge discussed his work on electospinning and nanofibers with us, including his observations on how these may eventually be applied to medicine.
Protection at the nanoscale: A conversation with Dr. Rutledge
How did you come to work on electrospinning and nanofibers?
I have a long-standing interest in high-performance fibers, dating back to my days as a graduate student. In the mid-90s, I attended a scientific presentation where the author claimed to make 30 nm diameter fibers from a hard-to-process, high-performance polymer. It turned out that those fibers could not be produced continuously, but I was fascinated by the unusual behavior of the electrospinning jet. As a polymer scientist, I knew these fibers had to have very different molecular organization and properties from the more conventional, micrometerdiameter fibers I was familiar with—we just didn’t know what those different properties would be. When we first launched into this area, it was curiosity-driven, “blue sky” research.
How does electrospinning work?
“Electrospinning” is a popular term for an electrostatic jetting phenomenon that leads to the formation of solid, continuous fibers. It is closely related to the electrospray technology used in inkjet printers and in ionization methods for mass spectrometry, a technique that earned its developers the Nobel Prize in Chemistry in 2002. Electrospinning works by charging a viscoelastic liquid to a high potential, on the order of 10 to 40 kV. Under such conditions, the free surface of the fluid becomes unstable and emits one or more jets of charged fluid. If the jet is further introduced into an electric field, typically around 1 kV/cm, the charge on the jet accelerates it downfield, causing it to thin as it goes. When the jet become thin enough, it starts to whip back and forth in the electric field; it is this whipping motion that is largely responsible for reducing the diameter of the jet by another 1 to 2 orders of magnitude, to less than 1 micrometer. With such small diameters, these jets dry very rapidly, so that solid fibers can be collected.
What are some of the most interesting nanofibers that you’ve spun?
Beauty is in the eyes of the beholder. I am fascinated by many of the nanofibers we’ve made—each is beautiful in its own way. A particularly interesting recent example is a family of nanofibers we’ve made that look, on the inside, like several embedded, concentric cylinders, each about 25 nm thick; in cross-section, the fibers look a bit like a target used in archery. These fibers are made from block copolymers. Each cylindrical domain can be imbued with different properties, and we can vary the number and thickness of the cylindrical domains. This could be useful for a variety of applications, from wave guides to sensors and drug delivery.
How do you think nanofibers may be used in the future by the medical industry?
The two most popular applications currently under development are tissue engineering and drug delivery. The nanofibers formed by electrospinning are about the same size as, and have comparable mechanical properties to, the collagen fibrils that make up the extracellular matrix (ECM) of many tissues, so it seems natural to consider them for applications requiring a synthetic mimic of the ECM. In drug delivery, the combination of high surface area, short diffusive length, and ease of handling of the fibrous membrane give electrospun nanofibers a drug-release profile that is difficult to achieve by other methods. In our own work, we have used electrospun fiber membranes as synthetic replacements for membranes used in wound healing and the repair of severed tendons and nerves.
When do you think nanotechnologies, such as nanofibers, will be commercialized and/or readily adopted?
As it turns out, in the filtration industry nanofiber technologies have been used in commercial products for decades. However, these were largely practiced as trade secret, so the full potential of these technologies was hardly appreciated. This has been changing in the past several years. Numerous small start-ups have formed around the use of electrospun nanofibers for specific applications or commercialization of proprietary process technologies. Large multinational chemical and medical supply companies have also become involved. I think this trend toward commercialization will continue to grow for years to come. Not all applications are winners, but the unique features of these materials promise to support a broad range of applications beyond filtration.
What does the future hold?
Recognizing the vast revenue-generating potential of nanotechnology, the United States National Nanotechnology Initiative was established in 2001 to coordinate federal nanotechnology research and development to foster the transfer of new technologies into products for commercial and consumer use. In 2007, the global market for goods incorporating nanotechnology totaled $147 billion, and this number is estimated to grow to $3.1 trillion by 2015. Clearly, nanotechnology is here to stay, and its impact will become more pronounced as research continues and more products incorporating these technologies and materials are produced. The ultimate ramifications of this molecular manufacturing, however, are unclear, as the long-term impact of nanomaterials on human health and the environment is unknown. Even seemingly innocuous nanotechnologies may have a negative effect on health and the environment. One study found that silver nanoparticles added to socks and other athletic wear to kill odor-causing bacteria may be released into waste water during washing, resulting in these nanoparticles ending up in waste treatment plants, where they may destroy the very bacteria that are used to render the waste harmless. Furthermore, a study published in Nature Nanotechnology found that carbon nanofibers, which are commercially available, mimicked asbestos when injected into mice. This study raises concern that exposure to nanofibers could result in an increased risk of cancer, such as mesothelioma.
Several groups, including the Center for Responsible Nanotechnology, have arisen to raise awareness about the potential dangers of nanotechnology. These groups have advocated government regulation of these technologies, and on December 10, 2008, the US National Research Council released a report calling for more regulation of nanotechnology.
Some proponents of nanotech indicate that such regulation would halt scientific research and the development of pharmacotherapies and other innovations that could greatly impact the quality of life for humankind. Although risk is clearly there, so is promise, and nanotech may just help patients with a life-threatening illness such as cancer beat the odds and continue on their fantastic voyage.