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Brief Introduction To The Veterinary Applications Of Nanotechnology
By Dr. Jose Feneque - December 2003
For us in the veterinary community, this article describes some of the principal areas of nanotechnology currently being undertaken in the world of medicine. Because of the vast scope of the medical applications of nanotechnology, this article is not intended to be fully comprehensive nor cover every category of research. The main purposes of this article are to trigger the interest of discoveries of our profession in the field of nanotechnology and to provide a glimpse at potential important targets for nanotechnology in the field of veterinary medicine. Also it is important to mention that because nanotechnology is at a very early stage of development, it may take several years to perform the necessary research and conduct clinical trials for obtaining meaningful results, but as professionals we should begin to take note.
In the era of new health related technologies, Veterinary Medicine will enter a phase of new and incredible transformations. The major contributor to those changes is our recent ability to measure, manipulate and organize matter at the nanoscale level. Our understanding of the principles that rule the nanoscale world will be of great impact on veterinary research leading to new discoveries never before imagined.
Nanotechnology has the potential to impact not only the way we live, but also the way we practice veterinary medicine. Today scientists foresee that the progress in the field of nanotechnology could represent a major breakthrough in addressing some of our technical challenges not only in engineering but also in the fields of both human and veterinary medicine. Very soon engineers will develop tiny motors to power computers and appliances; and doctors will have miniature devices that aim to fight cancer on the molecular level at their disposal.
Veterinary health care is a highly visible and growing concern not only for pet owners, but also for our government. With an increasingly aging pet population, along with higher costs for medications and veterinary care, the need for new solutions is urgent. At this period of time the main objectives of Veterinary Medicine are to excel, according to the accepted standards of scientific excellence, in the creation of new knowledge and its translation into improved health for the other species with which we share our world, to create more effective veterinary services and products and to strengthen the veterinary education system.
For us in the veterinary community, this article describes some of the principal areas of nanotechnology research currently being undertaken in the world of medicine. Because of the vast scope of the medical applications of nanotechnology, this article is not intended to be fully comprehensive nor cover every category of research. The main purposes of this article are to trigger the interest of discoveries of our profession in the field of nanotechnology and to provide a glimpse of the potential important targets for nanotechnology in the field of veterinary medicine. Also it is important to mention that because nanotechnology is at a very early stage of development, it may take several years to perform the necessary research and conduct clinical trials for obtaining meaningful results, but as professionals we should begin to take note.
The most widely use definition of nanotechnology is provided by the United States Government's National Nanotechnology Initiative. According to them nanotechnology is defined as: "Research and technology development at the atomic, molecular and macromolecular levels at the scale of approximately 1 - 100 nanometer range, to provide a fundamental understanding of phenomena and materials at the nanoscale and to create and use structures, devices and systems that have novel properties and functions because of their small and / or intermediate size (1)". A simple definition of nanotechnology is the art of manipulating matter, atom by atom. This new area of science can provide us with the ability to assemble things from atomic and molecular blocks; the same way as today's industry assembles cars in factories from a set of predefined parts using robots. The term nano is derived from the Greek word dwarf and is usually combined with a noun to form words such as nanometer, nanobot and nanotechnology. A nanometer is defined as one-billionth of a meter. Since is not easy to visualize the scale of a nanometer, a comparison with concepts and objects of appreciable dimensions is helpful. To get a perspective of the scale used in nanotechnology, representative structures and materials found in nature are typically referenced to have the following dimensions:
EXAMPLES OF BIOLOGICAL STRUCTURES
DIMENSION IN NANOMETERS (nm)
1,000 - 10,000 nm
75 - 100 nm
While the word nanotechnology is increasing in popularity in scientific circles and the news; there is a word that since the beginning has been associated with the development of molecular manipulation. The term nanomedicine refers to the use of molecular machine systems (i.e.: nanobots) to address medical problems, and to the use of molecular knowledge to maintain and improve health at a molecular scale (1a). As a specialized field within nanotechnology, nanomedicine would work towards bodily repair through the use of engineered, in vivo probes and sensors that would operate, in a semi-permanent fashion, within the body. The development of nanomedicine will have extraordinary implications for the veterinary profession, because it will change the definition of disease and the way we do diagnosis and treatment of medical conditions.
Nanomaterials are structures created by nanotechnology research that range from 1 to 100 nanometers in size. Common examples of nanomaterials found in scientific literature are fullerenes, nanotubes, buckyballs, quatum dots, dendrimers and nanoshells. Nanomaterials can have very different properties than materials at the macro scale. They can be stronger, lighter, more electrically conductive, more porous and less corrosive than bulk materials. Nanomaterials have the potential to solve unique biological challenges not currently possible, such as having inorganic materials detect electrical changes from biological molecules and react in a manner that detects or treats a disease.
Fullerenes are pure carbon molecules composed of at least 60 atoms of carbon. Because a fullerene takes a shape similar to a soccer ball or a geodesic dome, it is sometimes referred as a buckyball after the inventor of the geodesic dome, Buckminster Fuller, for whom the fullerene is named (2).
Nanotubes are a sequence of nanoscale C60 atoms arranged in a long thin cylindrical structure (3). They are related to two other carbon crystal forms, graphite and diamonds. They are often described as looking like rolls of graphite chicken wire, but as member or the fullerene family they are essentially buckyballs expanded from the center into cylinders. Nanotubes are also called buckytubes in some references books.
By definition, Quantum dots are a nano-scale crystalline structure made from cadmium selenide that absorbs white light and then reemits it a couple of nanoseconds later in a specific color (4).
Dendrimers are synthetic, three-dimensional macromolecules formed using a nanoscale fabrication process (5). A dendrimer is built up from a monomer, with new branches added in steps until a tree-like structure is created. A dendrimer is technically a polymer.
Nanoshells are concentric sphere nanoparticles consisting of a dielectric (typically gold sulfide or silica) core and a metal (gold) shell (6). They are considered a very special kind of nanoparticle because they combine infrared optical activity with the uniquely biocompatible properties of gold colloid. In simple words, they can be described as spherical glass particles with an outer shell of gold. Their size is about 100 nanometers in diameter.
Nanotechnology can be viewed as a series of technologies that are used individually or in combination to make products and applications, and to better understand science (7). One way of characterizing nanotechnology is by "tools," "materials," "devices" and "intelligent materials or machines." Nanotechnology tools include microscopy techniques and equipment that permit the visualization and manipulation of items at the nanoscale level such as cells, bacteria, viruses and single molecules. The range of tools includes the atomic force microscope, scanning tunneling microscope, molecular modeling software and other technologies.
Nanotechnology materials can be grouped into three main areas: raw materials, nanostructured materials and the group composed by nanotubes and fullerenes. The raw material includes nanoparticles and nanocrystalline materials that are readily manufactured and substitute for less performing bulk materials. Nanostructured materials are typically processed forms of raw material that provide special shapes and functionality. Examples of nanostructured materials include the quantum dots and the dendrimers. Nanotubes and fullerenes can produce materials that are 100 times stronger than steel, more conductive than copper, and can be safely used in some medical applications.
Two classes of devices are commonly associated with nanotechnology. These are the micro devices and nano devices. Examples of micro devices are micro-electromechanical systems better know as MEMS, microfluidics and microarrays. Even thought they are not considered part of nanotechnology, these microtechnologies have diverse medical applications. Nano devices are those device technologies that are dimensioned at the nanoscale level. Nano devices are difficult to produce at this moment, but they are expected to have a brilliant future in the medical field.
The intelligent materials and machines are probably the most fascinating and controversial area of nanotechnology. It includes the concept of tiny artifacts, commonly known as nanobots or nanorobots, which can be injected into the body to attack infections or repair cells. So far, there are not serious research projects in this area. Many decades may pass before this area may be considered ready for commercialization.
One of the areas of veterinary medicine that would benefit most from the nanotechnology research is the field of pharmacology (8). The creation and manipulation of new synthetic molecules can provide us with new therapeutical compounds to treat diseases in our pet population. These new compounds - for example - would protect our patients from viral or bacterial infections and accelerate wound healing. Also these new compounds could carry drugs and genes into cells, making treatment of diseases more efficacious.
One of the most promising and productive areas of nanotechnology are the nanopharmaceuticals. Most of our pet diseases one day will be addressed by the use of nanopharmaceuticals (9). Research in the area of nanopharmaceuticals would provide new advances in the area of drug delivery systems. These systems have an impact on the rate of absorption, distribution, metabolism, and excretion of drugs or other substances in the body. They must allow the drug to bind to its target receptor and influence the receptor's action. Drug delivery systems have severe restrictions on the materials and production process that can be used. The drug delivery material must be compatible and bind easy with the drug, and be bioresorbable. The production process must respect stringent conditions on processing and chemistry that won't degrade the drug, and still provide a cost effective product.
One of the major classes of drug delivery systems are materials that encapsulate drugs to protect them during transit through the body. When encapsulation materials are produced from nanoparticles in the 1 to 100 nanometer size range instead of bigger micro particles (commonly in use at this moment), they have a larger surface area for the same volume, smaller pore size, improved solubility, and different structural properties. This can improve both the diffusion and degradation characteristics of the encapsulation material.
Another class of drug delivery system is nanomaterials that can carry drugs to their destination sites and also have functional properties. Certain nanostructures can be controlled to link with a drug, a molecule or an imaging agent, then attract specific cells and release their payload when required. Because of their size, nanostructures have the ability to enter cells, as cells will typically internalize materials below 100 nanometers.
Probably the first trials to incorporate nanomaterials in the world of medicine came from those studying the physical characteristics and behavior of buckyballs, a novel form of carbon discovered by researchers many years ago. Some have compared buckyballs to the discovery of benzene, another carbon molecule, from which 40 percent of today drugs are made. Buckyballs are only a nanometer long, perfectly smooth and round. They are also inert, nontoxic and because of their size, they can interact easily with cells, proteins and viruses. In addition, they are hollow inside, so it is very easy to put pharmacological agents inside them. Besides delivering medicine more efficiently to the inside of cells, buckyballs may have a promising future in the area of diagnostic imaging. It is feasible to put radioactive agents inside the buckyballs so they can travel through the bloodstream as they emit radiation (10). But since they are excreted intact, they will completely remove the radiation from the body after the procedure, reducing the complications related to radiation toxicity.
Scientists also have begun to look into the potential applications of nanotubes as pharmacological agents. The antibacterial properties of nanotubes are being studied, specifically the ones designed by chemistry professor M. Reza Ghadiri and coworkers at Scripps Research Institute. The nanotubes are formed by self-assembled stacking of cyclic peptides having an even number of alternating D- and L-aminoacids. The nanotubes insert themselves readily into bacterial cell membranes and act as potent and selective antibacterial agents, both in cell cultures and in studies on mice (11). Both nanomaterials - buckyballs and nanotubes - will undoubtedly become an important part of the total pharmaceutical tool kit over the next few years.
Soybean oil in its standard form has very few to no medical applications. But once it is emulsified with detergents to form nanodrops with measurements less than 600 nanometers, it can act as a very potent destroyer of pathogens. Its mode of action is not chemical, but a physical one. When the oil nanodrops contact the membranes of bacteria or envelope viruses, the drops surface tension forces a merger with the membrane, blowing it apart and killing the pathogen. One very important characteristic of the nanoemulsion is that they don't affect cell structures of higher organisms, which make it ideal to use in animals and humans. While the nanoemulsion is entirely safe when applied externally, unfortunately scientists had discovered that the oil droplets can also destroy erythrocytes and sperm cells. The reason seems to be that both types of cells lack the support structures that make other cells invulnerable to the effects of the nanodrops. This means that the nanoemulsion can't be use intravenously. If nanoemulsion research continues showing promising results, in the near future we may see bactericidal and viricidal products that can be use topically in animals and humans.
One of the most important and promising areas of medical research of today is the study of nanomaterials known as dendrimers. They are synthetic polymers, a thousand times smaller than cells. Dendrimers can be synthesized in various predetermined sizes and can interact with biological agents by modifying their surfaces properties. Three very important properties of dendrimers make them an excellent candidate as pharmacological agents. First, they can hold a drug's molecules in their structure and serve as a delivery vehicle. Second, they can enter cells very easily and release drugs right on target. Third and most important, dendrimers don't trigger immune system responses.
Dendrimers have a lot to offer to the field of Veterinary Medicine. In the future one of the major contributions of these synthetic nanomaterials will be the diagnoses, treatment and eradication of malignant tumors that commonly affect the small animal geriatric population. They can serve as a drug delivery vehicle for drugs or radioactive isotopes directly into a tumor microvasculature, which may be considered as an alternative to direct irradiation of tumors with less side effects. Medical researchers envision that one day dendrimers may execute a five step task when dealing with the treatment of tumors: (i) dendrimers may be able to find tumors cells through the body by looking for tumor receptors, (ii) bind and pass through cell membranes, (iii) perform a chemical analysis inside the cells to inform veterinarians what type of tumors is present in the animal's body, (iv) release chemotherapy or radioactive agents inside the tumor cells and (v) confirm via chemical analysis that the procedure killed the cells. As an example of how versatile these nanomaterials may be, the same principles may one day be applied to the treatment of hyperthyroid cats.
Besides targeting tumor cells and drug delivery systems, dendrimers have demonstrated promising results as tools for MRI imaging (12-14) and gene transfer techniques (15). Also dendrimer-based nanocomposites are been studied as possible antimicrobial agents against Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli.
Another area that probably would benefit from nanotechnology research is the production of vaccines. The most recent studies indicate that synthetic oligodeoxynucleotides and antigens in biodegradable nanospheres can be use as an alternative approach for immunization (16). A better immune response seems to be obtained with biodegradable nanospheres then with vaccines produced by conventional methods.
Nanotechnology can bring to our veterinary hospitals cheaper, faster and more precise diagnostic tools. Diagnostic tests that are usually sent to outside laboratories and can take from hours to days to provide us with results may be considered obsolete sooner than we expected.
Quatum dot particles are tiny crystals which are a ten-millionth of an inch in size. These particles enable powerful new approaches to genetic analysis, drug discovery and disease diagnostics. Today quantum dots are considered an important advancement in our understanding of how genes work. Scientists believe that in a couple of years these particles will be instrumental in allowing researchers to monitor reactions of cells to certain drugs or viruses.
Since the beginning of last century researchers have used fluorescent dyes to tag cells. These techniques however can problematic. Each dye molecule requires a source of light of the same color to cause it to illuminate. For instance, when using a green dye, a source of light emitting the wavelength of the green color is needed to be able to see the dye. The dyes are also imprecise and have the tendency to blend together. They can only be lit up for a short period of time, usually just a few seconds after a light source is applied.
Instead of depending of dyes, quantum dots offer the advantage that varying the size of the crystal can cause a rainbow of colors to fluoresce. The smaller the quantum dots, the brighter the color. They stay lit for much longer periods of time than dyes, often for hours or days. Similar to fluorescence, they allow us to tag different biological components, like proteins or DNA strands, with specific colors. For us in the veterinary profession, it means that quantum dots could be used in a blood sample to quickly screen for certain proteins that may indicate a higher propensity for certain diseases.
To use quantum dots as molecular labels, researchers coax the nanocrystals into the pores of tiny plastic beads that are tagged with a molecular probe (a protein or DNA sequence) that bind strongly to the molecule of interest. After the probe binds to its molecular target in a cell or other biological sample, it is possible to visualize the location or abundance of the molecule by lighting up the dots with ultraviolet light. Current techniques may allow researchers to create over 10,000 distinguishable labels. With each label corresponding to a particular gene or protein, researchers may be able to detect tens of molecules all at once.
Some scientists envision the possibility of injecting quatum dots into animal bodies. Once injected into the body they may detect cells that are not working normally. Because they respond to light, it may be possible to affect the behavior of the dot once it is inside the cell. For example, they may be able to respond to a flash and heat up enough to destroy cancerous cells.
Quantum dots offer many technical advantages over traditional fluorescent dyes, which are commonly used to detect and track biological molecules. They not only can stay lit for a prolonged period of time, they are also brighter and easier to visualize than organic dyes. They can be very helpful in visualizing cell pathways, which is essential for our understanding of how certain drugs are going to behave in an animal's body. In addition to their usefulness in identifying and tracking molecules, they promise faster, more flexible, and less costly tests for clinical analysis.
Those who work in the veterinary field are familiar with immunoassay testing. Immunoassay technology capitalizes on the characteristic way that antibodies attach themselves to invading pathogens in the body. Antibodies recognize and bind to antigens with great specificity. One of the diagnostic applications of this behavior is the conventional immunoassay. In a routine immunoassay test we expose a solution, such as blood plasma for example, to a tray containing antibodies that bind with a specific antigen under investigation. When the antibodies bind to the antigen, the test changes color. This system is used to identify and diagnose various conditions that afflict the animal population.
Unfortunately, we haven't produced a fast and reliable whole blood immunoassay yet, in part because blood is so viscous and murky that it interferes with the chemical reactions in the test solution and make it difficult to get accurate readings. Instead, clinicians must purify the blood to remove these contaminants before proceeding with the immunoassay, a time consuming step that typically takes an hour or more. Nanotechnology research may have found a way to overcome the problems with whole blood immunoassays. Nanotechnology researchers have developed a new method of testing whole blood using optically active gold-coated glass particles commonly known as gold nanoshells (17).
In laboratory tests, the nanoshells immunoassay was capable of detecting less than one billionth of a gram of IgG per milliliter of whole blood. This may be the first whole-blood immunoassay to report sensitivities on this order under 30 minutes. The nanoshells immunoassay overcome the obstacles commonly attributed to whole-blood immunoassay coupling antibodies to nanoshells that absorb near-infrared light. Nanoshells are layered colloids that consist of a core of non-conducting material covered by a thin metallic shell. By varying the thickness of the metal shell, researchers can precisely tune the color of light to which the nanoshells respond. Because near infrared light penetrates whole blood very well, it is an optimal wavelength for a whole blood immunoassay. When the antibody-nanoshells particles are placed into a solution of whole blood containing the test molecule, the antibody-nanoshells bind to the test molecule, which causes slight changes in the optical properties of the nanoshells. By monitoring these changes, researchers are able to monitor very slight concentrations of antigens in the blood, without any time consuming sample preparation.
Nanoshells are also being tested as a noninvasive way to detect tumors. Since they are gold coated, nanoshells would not trigger an immunity response. Scientists have found that they can attach to the shells antibodies that would lock onto specific tumor cells. The nanoshells are then injected into the body of a laboratory animal, a light source is turned on (a laser or infrared light for example) and they observe if and where the nanoshells accumulate. But nanoshells are more than a marker, it turns out. It has been found that they could be used to destroy tumors as well (18). Like a magnifying glass, nanoshells concentrate light beamed at them and heat up. Their studies showed the shells killed tumor cells without harming skin or nearby healthy tissue. While more studies with this novel optical material need to be done, we can say today that nanoshells will play an important role in the future of veterinary care.
Clearly, the profession of Veterinary Medicine will be substantially different in 25 years from that of today. It can be hoped that nanotechnology, in addition to contributing to the creation of changes in our profession, will also be one of the technologies that help practitioners stay abreast of and manage these developments. Because nanotechnology is not in the mainstream quite yet, most of us in the veterinary community are simply unaware of it's potential. In order to appreciate the advantages of this technology, the veterinary profession needs to understand it's basic concepts and contributions. This may require that everyone involved in our profession spend some time educating themselves. The best way to begin is trying to understand the definitions of nanotechnology, nanomedicine, etc…. Whatever our specialty is, we should ask ourselves the following questions: If I could do this at a molecular level, how would things be changed? As a group we need to coordinate efforts to create a generation of veterinarians that will understand nanotechnology.
We as an organized profession should have some influence in public policies about nanotechnology and other new fields or research. Our profession needs to be more vocal about issues arrising from new technologies such as cloning and stem cell research. It is the responsibility of the veterinary community to maintain awareness of these technologies and the benefits they can bring to our patients. One way we can prepare our profession for changes due to new technologies is to advise academic and commercial organizations about our needs. Support of those involved in new technological research such as nanotechnology is very important. Despite initial success, the veterinary applications of nanotechnology are in its infancy, and a number of hurdles remain prior to bringing these therapies into the clinical arena. Encouraging commercial organizations to make good and useful products based on these technologies can be crucial for the ultimate benefit of our profession. The real challenge to veterinary medicine is to understand and apply these technologies in a way that will provide maximum benefits to our patient's health. I am confident that once our colleagues and clients begin to realize the great benefits of nanotechnology, especially in terms of pet healthcare, there will be no problem generating the enthusiasm needed to make nanotechnology an important and vital tool for the enhancement of our profession. Nanotechnology will raise our technological capabilities to a new level, improving pet health care and quality of life. It will also increase our standard of living and it will drive futher economic expansion into the veterinary profession. We as members of the veterinary community have an unique opportunity to become major players in the development of nanotechnological applications in the fields of animal and human medicine. We need to create significant momentum while the field is still emerging in order to later collect the fruits of our actions.
(1) Nanotechnology definition: National Nanotechnology Initiative. February 2000.
(1a) Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities,
Landes Bioscience, Georgetown, TX, 1999; link
(2) Fullerenes definition: link
(3) Nanotubes definition: link
(4) Quantum dot definition: link
(5) Dendrimer definition: link
(6) Avaritt R. D. et al.: Plasmon resonance shifts of Au-coated Au 25 nanoshells: insight into multicomponent nanoparticle growth. Phys Rev Lett. 78: 4217-20. 1997.
(7) Gordon, N.; Sagman, U.: Nanomedicine taxonomy: briefing paper. Canadian Nanobusiness Alliance. February 2003. link
(8) Feneque, J.: Nanotechnology: a new challenge for veterinary medicine. The Pet Tribune. 6 (5): 16. 2000.
(9) Feneque, J.: The future of nanopharmaceuticals in veterinary medicine. link
(10) Wilson, L. J.: Medical applications of fullerenes and metallofullerenes.
Interface. 8: 24-28. 1999.
(11) Fernandez-Lopez, S.; et al: Antibacterial agents based on the cyclic D-, L- alpha
peptide architecture. Nature. (412): 452-455. (26 Jul 2001).
(12) Wu, C.; et al. Bioorganic And Medicinal Chemistry Letters. 4(3): 449. 1994.
(13) Margerum, L.D.; et al. J Alloys Comp. 249 (1-2): 185. 1997.
(14) Kim, Y.; Zimmerman, S.C.: Curr Opin Chem Biol. 2(6): 733-742. 1998.
(15) Balogh, L.; et al. Dendrimer nanocomposites in medicine. Chimica Oggi.
20 (5): 35. May 2002.
(16) Diwan, M.; et al. Enhancement of immune responses by co-delivery of A CpG
oligodeoxynucleotide and tetanus toxoid in biodegradable nanospheres. J Control
Release. 85(1-3): 247-62. Dec 13, 2002.
(17) L. R. Hirsch; et al. A whole blood immunoassay using gold nanoshells.
Analytical Chemistry. 75 (10): 2377- 2381. 2003.
(18) L.R. Hirsch; et al. Nanoshell mediated near infrared photo dermal tumor
therapy. Summer Bioengineering Conference, Key Biscayne, Florida. 2003
Dr. Jose Feneque graduated from The University of Georgia College of Veterinary Medicine in 1996. He practices as an associate veterinarian at Crossroads Animal Hospital in Miami, Florida. He can be contact by phone at (305) 279-2000.
Jose' Feneque, DVM
Nanomedicine Forum http://nanocomputer.org
Nanomedicine Egroup http://www.egroups.com/group/nanomed
Nano Veterinary Medicine http://www.topica.com/lists/nanovetmedicine
Reprinted with premission.
Copyright Dr. Jose Feneque.
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