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The main purpose of this article is to introduce pet owners and the veterinary community to the fascinating world of nanotherapeutics. I will also discuss the potential applications of new molecular structures known as "nanopharmaceuticals," especially as they apply to the field of veterinary medicine.
Today, with the help of nanotechnology, we are creating a better future for ourselves and our beloved pets. While many of the promises of nanotechnology seem to belong to the world of science fiction, it is only a matter of years before people and their pets began to receive direct benefits from these new and fascinating technologies. All around the country, scientists are developing synthetic materials that form tiny structures, or nanodevices, to perform medically important tasks. These devices are so small that they can slip inside cells without being recognized by the immune system. These materials provide us with opportunities to address specific problems and to tailor therapies in order to restore normal cellular function. Nanomaterials are thousands of times smaller than the cells that make up our pet's body. They are very complex to manufacture and analyze, but their potential benefits are truly remarkable. One day most of our pet's diseases will be addressed by nanotherapeutics.
Probably the first trials to incorporate nanomaterials in medicine came from 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 todays drugs are made. Buckyballs are nanoscale in size, and perfectly smooth and round. They are also inert, nontoxic, and because of their size, 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 (1). And since they are excreted intact, the radiation is removed from the body, reducing the complications related to radiation toxicity.
Scientists also have begun to look to 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. These nanotubes are formed by self-assembled stacking of cyclic peptides having an even number of alternating D- and L-amino acids. They insert themselves readily into bacterial cell membranes and act as potent and selective antibacterial agents, both in cell cultures and in studies on mice (2). 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 physical; when the oil nanodrops contact the membranes of bacteria or they envelope viruses, the drop's surface tension forces a merger with the membrane, blowing it apart and killing the pathogen. One very important characteristic of the nanoemulsion is that it doesn't affect the cell structures of higher organisms, which make it ideal to use in animals and humans. The nanoemulsion is entirely safe when applied externally; unfortunately scientists have discovered that the oil droplets can also destroy red blood cells 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 cannot be used intravenously. If the research continues showing promising results, in the near future we may see bactericidal and viricidal products that can be used topically in animals and humans.
By definition, Quantum dots are "a nano-scale crystalline structure made from cadmium selenide that absorbs white light and then re-emits it a couple of
nanoseconds later in a specific color" (3). Quantum 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 dot technology is 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 the last century, researchers have used florescent dyes to tag cells. However, that technique can be 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 a tendency to blend together. And they can only be "lit up" for short periods of time after a light source is applied - usually just a few seconds.
Instead of depending on dyes, quantum dots offer the advantage of color-change by varying the size of the crystal; the smaller the quantum dot, the brighter the color. They stay lit for much longer than dyes - often hours or days. Similar to florescence, they allow us to tag different biological components, like proteins or strands of DNA, 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 pores of tiny plastic beads that are tagged with a molecular probe (a protein or DNA sequence that binds 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 quantum dots with ultraviolet light. Current techniques may allow researchers to create over 10,000 distinguishable quantum dot labels. With each label corresponding to a particular gene or protein, researchers may be able to detect tens of molecules at once.
Some scientists envision the possibility of injecting quantum dots into the animal's bodies. Once injected, they may detect cells that are not working normally. Because they respond to the effects of 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 of light, and heat up enough to destroy cancerous cells.
Quantum dots offer many technical advantages over traditional florescent 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 will 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.
One of the most important and promising areas of medical research today is the study of nanomaterials known as "dendrimers." Dendrimers 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 surface 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 importantly, 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 diagnosis, treatment and eradication of malignant tumors that commonly affect the geriatric population of our beloved pets. They can serve as a delivery vehicle for drugs or radioactive isotopes (directly into a tumor's microvasculature), which may be considered as an alternative to direct irradiation of tumors, with fewer side-effects. Medical researchers envision that one day dendrimers may execute a five-step task when treating tumors: they may be able to find tumor cells throughout the body by looking for tumor receptors, then bind to and pass through cell membranes, then perform a chemical analysis inside the cells to inform veterinarians what type of tumor is present, then release chemotherapy or radioactive agents inside the tumor's cell and finally, confirm via chemical analysis that the procedure killed the cells. The same principles are applied to the treatment of hyperthyroid cats (as an example of how versatile these nanomaterials can be).
Along with targeting tumor cells and drug delivery systems, dendrimers have shown promising results as tools for MRI imaging (4-6) and gene transfer techniques. Also, dendrimer-based nanocomposites are being studied as possible antimicrobial agents to fight Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli (7).
In the twenty first century, nanotechnology may offer a vast number of breakthroughs that will advance the practice of clinical veterinary medicine. The
creation of new pharmacological compounds and novel treatment protocols are going to have a huge impact on the health and quality-of-life in companion
animals. Today, the creation of public awareness about the impact of these technologies - not only in our daily lives but also in the life of our pets - are more important than ever. It is absolutely necessary that the veterinary community became more involved in nano- and biotechnology research. Changes in the curriculum of veterinary schools around the world are going to be necessary to introduce the concepts of nanotechnology to the next generation of veterinarians.
It may be a couple of years before we see the use of products and treatment protocols based in the nanopharmacological research. While much work remains to be done in this area, the veterinary community - along with the general public - needs to share the enthusiasm that comes from exploring these new medical frontiers, for the sake of our pets and the future of humanity.
(1) L. J. Wilson, "Medical Applications Of Fullerenes And Metallofullerenes". Interface, 8 (1999): 24-28.
(2) Fernandez-Lopez Sara, Granja J.R., Ghadiri M.R. and others. "Antibacterial Agents Based On The Cyclic D-, L- Alpha Peptide Architecture". Nature (412); 452-455 (26 Jul 2001.
(3) Quantum dot definition: http://www.webopedia.com/TERM/Q/quantum_dot.html
(4) Wu, C.; Breshbiel, M. W. : Kozack, R. W.; Gansow, O. A. Biorganic and Medicinal Chemistry letters, 1994, 4(3), 449.
(5) Margerum, L. D.; Campion, B. K.; Koo, M.; Shargill, N.; Lai, J; Marumoto, A.; Sontum, P. C. J. Alloys Comp. 1997, 249 (1-2), 185.
(6) Kim, Yoonkyung; Zimmerman, Steven C. Curr.Opin.Chem. Biol. 1998, 2(6), 733-742.
(7) Balogh, L.; Bielinska, A.; Eichman, J.D.; Valluzzi, R. and others. Dendrimer Nanocomposites in Medicine. The University of Michigan Center for Biologic Nanotechnology, Tuff Biotechnology Center and Department of Radiation Oncology at The University of Michigan.
Dr. Jose Feneque practices as senior associate veterinarian at Crossroads Animal Hospital in Miami, Florida, and is the Director of Nanomedicine Forum, for the The Nano Computer Dream Team. He can be reached at (305) 279-2000 or by email at firstname.lastname@example.org
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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