Better Than A Hearing Aid? Better Hearing With Bone Conducted Sound

SOURCE

ScienceDaily (July 9, 2009) — New technology to hear vibrations through the skull bone has been developed at Chalmers University of Technology. Besides investigating the function of a new implantable bone conduction hearing aid, Sabine Reinfeldt has studied the sensitivity for bone conducted sound and also examined the possibilities for a two-way communication system that is utilizing bone conduction in noisy environments.

A new Bone Conduction Implant (BCI) hearing system was investigated by Sabine Reinfeldt. "This hearing aid does not require a permanent skin penetration, in contrast to the Bone-Anchored Hearing Aids (BAHAs) used today," she said.
Measurements showed that the new BCI hearing system can be a realistic alternative to the BAHA.
Sound is normally perceived through Air Conduction (AC), which means that the sound waves in the air enter the ear-canal and are transmitted to the cochlea in the inner ear. However, sound can also be perceived via Bone Conduction (BC). Vibrations are then transmitted to the cochleae through the skull bone from either one's own voice, the surrounding sound field, or a BC transducer.
In two-way communication systems, BC is believed to improve the sound quality when used in extremely noisy environments which require hearing protection devices in the ear-canals.
Several studies were performed to investigate the possibilities for a BC communication system and to increase the general knowledge of BC sound perception.
The low-frequency increase in perceived BC sound when wearing ear-plugs and/or ear-muffs is called the occlusion effect. This effect was studied by different methods and it was found that it is lower for deeper insertion of ear-plugs and for larger ear-muffs, and that it varies for different stimulations.
The difference in sensitivity of the BC and AC parts of one's own voice was estimated, showing that the BC component dominated for most sounds between 1 and 2 kHz. To be able to measure the BC component of a person's own voice, a large ear-muff was developed to attenuate the AC sound and to minimize the occlusion effect.
The study also showed that the sensitivity difference between the BC and AC parts of one's own voice were different for different kinds of sounds, depending on where in the mouth the sound is produced and on the influence from the vocal cords.
Also estimated was the difference in sensitivity between BC and AC sound from a surrounding sound field, demonstrating that the BC part was 40 to 60 dB lower than the AC part. This measure gives the maximum attenuation achievable with ordinary hearing protection devices, like ear-plugs and ear-muffs. It also shows the possible noise reduction from the surrounding noise by using a BC microphone, instead of an ordinary AC microphone in front of the mouth, to record one's own voice in a noisy environment.
Moreover, the amount of BC sound reaching the cochleae from different positions of the skull bone was examined with the conclusion that relative BC hearing can be estimated from ear-canal sound pressure and cochlear vibrations.
Adapted from materials provided by The Swedish Research Council, via AlphaGalileo.

Chemical In Common Consumer Products (Phthalates) May Play A Role In Pre-term Births

SOURCE

ScienceDaily (July 7, 2009) — A new study of expectant mothers suggests that a group of common environmental contaminants called phthalates, which are present in many industrial and consumer products including everyday personal care items, may contribute to the country's alarming rise in premature births.

Researchers at the University of Michigan School of Public Health found that women who deliver prematurely have, on average, up to three times the phthalate level in their urine compared to women who carry to term.
Professors John Meeker, Rita Loch-Caruso and Howard Hu of the SPH Department of Environmental Health Sciences and collaborators from the National Institute of Public Health in Mexico and the U.S. Centers for Disease Control and Prevention analyzed data from a larger study directed by Hu, which follows a cohort of Mexican women recruited during pre-natal visits at one of four clinics of the Mexican Institute of Social Security in Mexico City.
Meeker and colleagues looked at data from 60 women: 30 who carried to term and 30 who delivered prematurely (defined as less than 37 weeks gestation). They analyzed urine samples collected during the third trimester and compared them to the control group who carried to term. They found significantly higher phthalate metabolite levels in the women who delivered prematurely.
Premature birth is a significant risk factor for many health problems in childhood that can persist into adulthood, Meeker says. In the United States, premature births have increased by more than 30 percent since 1981 and by 18 percent since 1990. In 2004, premature births accounted for 12.8 percent of live births nationwide.
Premature births, he says, account for one-third of infant deaths in the United States, making it the leading cause of neonatal mortality. Being born too early can also lead to chronic health problems such as blindness, deafness, cerebral palsy, low IQ and more.
Phthalates are commonly used compounds in plastics, personal care products, home furnishings (vinyl flooring, carpeting, paints, etc.) and many other consumer and industrial products. The toxicity varies by specific phthalates or their breakdown products, but past studies show that several phthalates cause reproductive and developmental toxicity in animals.
A couple of human studies have reported associations between phthalates and gestational age, but this is the first known study to look at the relationship between phthalates and premature births, Meeker says.
"We looked at these commonly used compounds found in consumer products based on the growing amount of animal toxicity data and since national human data show that a large proportion of the population are unknowingly exposed," Meeker said. "One of the problems for consumers is that you don't know exactly which products contain phthalates because the products do not have to be labeled accordingly."
Meeker says the U-M study is a stepping stone to larger and more detailed studies examining the role of phthalates and premature births. The researchers hope to examine a larger population of pregnant women to corroborate these initial study findings, and conduct experimental lab studies to further explore the biological mechanisms of how phthalates work in the body.
Journal reference:
Meeker et al. Urinary phthalate metabolites in relation to preterm birth in Mexico City. Environmental Health Perspectives, 2009; DOI: 10.1289/ehp.0800522
Adapted from materials provided by University of Michigan.

Physics Research With Atomic Force Microscope Could Lead To Better Health Care

SOURCE

ScienceDaily (July 6, 2009) — Where biology, chemistry and physics intersect, a Kansas State University professor expects to find applications to improve human health.

Robert Szoszkiewicz, an assistant professor of physics at K-State, is continuing research on molecules both singularly and as a group. His study of proteins as a single molecule shows promise to help scientists understand the causes of diseases like some cancers. Meanwhile, his research on bunched molecules could lead to a more efficient way to identify antibodies in blood.
Szoszkiewicz's research on proteins began at Columbia University and some of it was published in June in Nature Chemistry. He and his former colleagues looked at the unexpected complexity in the dynamics of stretching and breaking of a single chemical bond between two atoms embedded in a protein. A cleavage of that particular bond has been precisely signaled by unfolding and elongation of a part of a protein.
"There is lots of potential for this research to really address issues of major importance in biology because this will be related to particular pathways through which some kinds of diseases, cancers and biological processes develop," he said. "And, we can study that on the very molecular level by studying the single proteins involved and stretching them and seeing how this contributes to the overall picture."
The research uses an atomic force microscope, a tool involving a cantilever with a sharp tip that under certain circumstances becomes attached to the protein molecule. The researchers stretch the molecules and measure precisely their tiny displacements.
"Any work that we do on the ground level of stretching any kind of chemical bonds is fundamentally important because it's the kind of knowledge no one has ever measured on this scale," he said. "Proteins constantly fold and unfold. A folded protein is the one that's biologically active and performing a function. So any problems during its folding and unfolding translate to some potential diseases like cancers."
Szoszkiewicz received a grant from K-State's Terry C. Johnson Center for Basic Cancer Research to use these techniques to stretch some proteins that are significant in breast cancer. He is collaborating with Anna Zolkiewska and Michal Zolkiewski, both K-State associate professors of biochemistry.
Another area of Szoszkiewicz's research began while at the Georgia Institute of Technology. It involves changing the properties of a surface at the very local scale by using an atomic force microscope in which the sharp cantilever tip can be heated up to between 500 degrees and 600 degrees Celsius.
When this heated tip is scraped across a surface, Szoszkiewicz said, the heat can -- under certain circumstances -- initiate a chemical reaction on that very surface. He and his colleagues have created patches of chemically changed surface only 10 to 15 nanometers across, but Szoszkiewicz thinks he will be able to change the surface just bunch of molecules at a time. This ability to pattern the surface, he said, could improve personalized medicine by allowing scientists to create tiny chips on which many tests can be run simultaneously.
"You could take a small sample of blood and screen it for any possible drug that could work for you," he said. "Ordinarily to do such a screening would require a humongous amount of testing material and antibodies. If you could prepare a surface that will selectively bind only one or two molecules of a kind and then see if you have bound or not, then you would need only a few milliliters of blood, and you could test it against millions of molecules. Of course, there are other factors involved and the particular interactions between single blood molecules and their antibodies might not be that simple. But this still remains to be seen."
Szoszkiewicz said that if scientists can pattern the surface in the way they like, another application might be tiny electric circuits and lenses that guide, respectively, electrons and photons. Also, using an atomic force microscope in this way, he said, physicists can not only change the chemical properties of the surface but they also can change the topography of a surface -- in other words, how the surface looks.
For example, Szoszkiewicz and colleagues have created and investigated the nature of nanoscale ripples created on polymers, or the "polymer dunes" at a nanoscale level. Using custom-made polymers, the researchers scratched them with the hot tip while using enough heat to indent within the polymer during scratching but not to destroy the polymer sample. Such research investigated how these tiny dunes created on polymers change with the application of heat. In this case, heat functions like wind would on real sand dunes. The researchers investigated under which conditions the dune gets pushed in the way they wanted it and forms a desired shape.
"This way you can prepare structures that can serve to sort materials at the nanoscale," he said. "Later on you virtually throw some other molecules on the surface, and maybe some of it will go into the grooves, depending on the chemistry."
The researchers were able to prepare several types of nanoscopic ripples -- these so-called tiny dunes -- with the most common type being the one in which the ripples organize in a roughly linear fashion. However, they also explored circular geometry. Their work has been published in the June issue of the journal Physical Review B.
"What we have proven in this paper is that, under certain conditions, by scanning continuously along these circles, you can make the ripples along your circular scanning path, and under certain circumstances to move them collectively and continuously," Szoszkiewicz said. "Measuring the collective velocities, we found that they would approach the velocities of shifting a big sand dune, just scaled down."
Szoszkiewicz's continuation of these projects in his lab at K-State include several other researchers: Heidi Martin, sophomore in physics from Junction City; Ashim Dey, doctoral student in physics, Manhattan; Neelam Khan, May 2009 doctoral graduate in physics; and Vera Okuneva, research assistant in biology.
Adapted from materials provided by Kansas State University.

Nitrates May Be Environmental Trigger For Alzheimer’s, Diabetes And Parkinson's Disease

SOURCE

ScienceDaily (July 6, 2009) — A new study by researchers at Rhode Island Hospital have found a substantial link between increased levels of nitrates in our environment and food with increased deaths from diseases, including Alzheimer's, diabetes mellitus and Parkinson's. The study was published in the Journal of Alzheimer's Disease.

Led by Suzanne de la Monte, MD, MPH, of Rhode Island Hospital, researchers studied the trends in mortality rates due to diseases that are associated with aging, such as diabetes, Alzheimer's, Parkinson's, diabetes and cerebrovascular disease, as well as HIV. They found strong parallels between age adjusted increases in death rate from Alzheimer's, Parkinson's, and diabetes and the progressive increases in human exposure to nitrates, nitrites and nitrosamines through processed and preserved foods as well as fertilizers. Other diseases including HIV-AIDS, cerebrovascular disease, and leukemia did not exhibit those trends. De la Monte and the authors propose that the increase in exposure plays a critical role in the cause, development and effects of the pandemic of these insulin-resistant diseases.
De la Monte, who is also a professor of pathology and lab medicine at The Warren Alpert Medical School of Brown University, says, "We have become a 'nitrosamine generation.' In essence, we have moved to a diet that is rich in amines and nitrates, which lead to increased nitrosamine production. We receive increased exposure through the abundant use of nitrate-containing fertilizers for agriculture." She continues, "Not only do we consume them in processed foods, but they get into our food supply by leeching from the soil and contaminating water supplies used for crop irrigation, food processing and drinking."
Nitrites and nitrates belong to a class of chemical compounds that have been found to be harmful to humans and animals. More than 90 percent of these compounds that have been tested have been determined to be carcinogenic in various organs. They are found in many food products, including fried bacon, cured meats and cheese products as well as beer and water. Exposure also occurs through manufacturing and processing of rubber and latex products, as well as fertilizers, pesticides and cosmetics.
Nitrosamines are formed by a chemical reaction between nitrites or other proteins. Sodium nitrite is deliberately added to meat and fish to prevent toxin production; it is also used to preserve, color and flavor meats. Ground beef, cured meats and bacon in particular contain abundant amounts of amines due to their high protein content. Because of the significant levels of added nitrates and nitrites, nitrosamines are nearly always detectable in these foods. Nitrosamines are also easily generated under strong acid conditions, such as in the stomach, or at high temperatures associated with frying or flame broiling. Reducing sodium nitrite content reduces nitrosamine formation in foods.
Nitrosamines basically become highly reactive at the cellular level, which then alters gene expression and causes DNA damage. The researchers note that the role of nitrosamines has been well-studied, and their role as a carcinogen has been fully documented. The investigators propose that the cellular alterations that occur as a result of nitrosamine exposure are fundamentally similar to those that occur with aging, as well as Alzheimer's, Parkinson's and Type 2 diabetes mellitus.
De la Monte comments, "All of these diseases are associated with increased insulin resistance and DNA damage. Their prevalence rates have all increased radically over the past several decades and show no sign of plateau. Because there has been a relatively short time interval associated with the dramatic shift in disease incidence and prevalence rates, we believe this is due to exposure-related rather than genetic etiologies."
The researchers recognize that an increase in death rates is anticipated in higher age groups. Yet when the researchers compared mortality from Parkinson's and Alzheimer's disease among 75 to 84 year olds from 1968 to 2005, the death rates increased much more dramatically than for cerebrovascular and cardiovascular disease, which are also aging-associated. For example, in Alzheimer's patients, the death rate increased 150-fold, from 0 deaths to more than 150 deaths per 100,000. Parkinson's disease death rates also increased across all age groups. However, mortality rates from cerebrovascular disease in the same age group declined, even though this is a disease associated with aging as well.
De la Monte notes, "Because of the similar trending in nearly all age groups within each disease category, this indicates that these overall trends are not due to an aging population. This relatively short time interval for such dramatic increases in death rates associated with these diseases is more consistent with exposure-related causes rather than genetic changes." She also comments, "Moreover, the strikingly higher and climbing mortality rates in older age brackets suggest that aging and/or longer durations of exposure have greater impacts on progression and severity of these diseases."
The researchers graphed and analyzed mortality rates, and compared them with increasing age for each disease. They then studied United States population growth, annual use and consumption of nitrite-containing fertilizers, annual sales at popular fast food chains, and sales for a major meat processing company, as well as consumption of grain and consumption of watermelon and cantaloupe (the melons were used as a control since they are not typically associated with nitrate or nitrite exposure).
The findings indicate that while nitrogen-containing fertilizer consumption increased by 230 percent between 1955 and 2005, its usage doubled between 1960 and 1980, which just precedes the insulin-resistant epidemics the researchers found. They also found that sales from the fast food chain and the meat processing company increased more than 8-fold from 1970 to 2005, and grain consumption increased 5-fold.
The authors state that the time course of the increased prevalence rates of Alzheimer's, Parkinson's and diabetes cannot be explained on the basis of gene mutations. They instead mirror the classical trends of exposure-related disease. Because nitrosamines produce biochemical changes within cells and tissues, it is conceivable that chronic exposure to low levels of nitrites and nitrosamines through processed foods, water and fertilizers is responsible for the current epidemics of these diseases and the increasing mortality rates associated with them.
De la Monte states, "If this hypothesis is correct, potential solutions include eliminating the use of nitrites and nitrates in food processing, preservation and agriculture; taking steps to prevent the formation of nitrosamines and employing safe and effective measures to detoxify food and water before human consumption."
Other researchers involved in the study with de la Monte include Alexander Neusner, Jennifer Chu and Margot Lawton, from the departments of pathology, neurology and medicine at Rhode Island Hospital and The Warren Alpert Medical School of Brown University.
The study was funded through grants from the National Institutes of Health. Two subsequent papers have been accepted for publication in the near future that demonstrate experimentally that low levels of nitrosamine exposure cause neurodegeneration, NASH and diabetes.
Journal reference:
De la Monte, Suzanne M., Alexander Neusner, Jennifer Chu and Margot Lawton. Epidemilogical Trends Strongly Suggest Exposures as Etiologic Agents in the Pathogenesis of Sporadic Alzheimer's Disease, Diabetes Mellitus, and Non-Alcoholic Steatohepatitis. Journal of Alzheimer's Disease, 17:3 (July 2009) pp 519-529
Adapted from materials provided by Lifespan, via EurekAlert!, a service of AAAS.

New Evidence That Vinegar May Be Natural Fat-fighter

SOURCE

ScienceDaily (July 7, 2009) — Researchers in Japan are reporting new evidence that the ordinary vinegar — a staple in oil-and-vinegar salad dressings, pickles, and other foods — may live up to its age-old reputation in folk medicine as a health promoter. They are reporting new evidence that vinegar can help prevent accumulation of body fat and weight gain.

Tomoo Kondo and colleagues note in the new study that vinegar has also been used as a folk medicine since ancient times. People have used it for a range of ills. Modern scientific research suggests that acetic acid, the main component of vinegar, may help control blood pressure, blood sugar levels, and fat accumulation.
Their new study showed that laboratory mice fed a high-fat diet and given acetic acid developed significantly less body fat (up to 10 percent less) than other mice.
Importantly, the new research adds evidence to the belief that acetic acid fights fat by turning on genes for fatty acid oxidation enzymes. The genes churn out proteins involved in breaking down fats, thus suppressing body fat accumulation in the body.
Journal reference:
Kondo et al. Acetic Acid Upregulates the Expression of Genes for Fatty Acid Oxidation Enzymes in Liver To Suppress Body Fat Accumulation. Journal of Agricultural and Food Chemistry, 2009; 090609114939008 DOI: 10.1021/jf900470c
Adapted from materials provided by American Chemical Society.

Why Some Tumors Don't Respond To Radiation And Chemotherapy

SOURCE

ScienceDaily (July 7, 2009) — A tightly controlled system of checks and balances ensures that a powerful tumor suppressor called p53 keeps a tight lid on unchecked cell growth but doesn't wreak havoc in healthy cells. In their latest study, scientists at the Salk Institute for Biological Studies suggest just how finely tuned the system is and how little it takes to tip the balance.

When unprovoked, at least two negative regulators—the related proteins Mdm2 and Mdmx—prevent p53 from unleashing its power to kill. But just slightly increasing the amount of available Mdmx, which grips p53 and renders it inactive, the Salk researchers discovered, made mice remarkably resistant to the harmful effects of radiation but very susceptible to the development of oncogene-induced lymphomas.
"Our experiments emphasize how subtle and precarious the balance is," says postdoctoral researcher and first author Yunyuan V. Wang. "A slight shift of balance and the mice survive the equivalent of Chernobyl but are in big trouble when an oncogene is activated."
Their findings, to be published in the July issue of the journal Cancer Cell, could explain why some tumors don't respond to radiation or chemotherapy, and provide novel routes for the development of new anti-cancer therapies.
As a powerful tumor suppressor, p53 turns on genes that either halt cell division to allow time for repair of damaged DNA or, when all rescue attempts prove futile, to prevent cells with genetic defects from dividing, as this would fuel the development of cancer. Consequently, before any tumor cell can start proliferating willfully, it needs to escape from p53's iron fist.
"One way or another, p53 function is compromised in all cancers. Either p53 itself is mutated or there is a problem with one of the proteins that regulate p53's activity," says the study's leader Geoffrey M. Wahl, Ph.D., a professor in the Gene Expression Laboratory. "Our hope is that we can develop small molecule drugs that will activate p53 in those tumors where it is still functional but inactivated by one of its negative regulators."
In an earlier study, Wahl and his team discovered that Mdm2 and Mdmx cooperate to prevent p53 from being activated, with Mdm2 being primarily responsible for degrading p53, while Mdmx is more effective at preventing p53 from turning on genes. But how p53 shakes off its negative regulators when cells experience one of the myriad stresses that activate p53 has been the topic of much discussion.
One view holds that after DNA damage occurs, enzymes directly modify p53 and that those modifications change the structure of p53 in such a way that neither Mdm2 nor Mdmx are able to bind. In an alternative scenario the same enzymes—kinases that attach phosphate groups to proteins—modify the negative regulators, accelerating their degradation and freeing p53 of their antagonists. Of course, it may well be that both views are correct, but the extent to which each contributes to p53 control remains an important unanswered question.
To get to the bottom of the dispute, Wang genetically engineered mice to eliminate three key phosphorylation sites in Mdmx. "The mutations stabilize Mdmx and as a result we saw consistently lower basal activity of p53. Surprisingly, we observed no increase in spontaneous tumor formation " she says. "In the absence of catastrophic DNA damage these low levels of p53 were enough to suppress tumorigenesis."
But in order to put cells on notice or commandeer them to commit suicide in the face of irreparable damage, these animals need to activate p53, which in turn activates a whole range of target genes. "Levels of active p53 still go up," says Wang, "but they never reach the critical threshold that's required to elicit a biological response."
As a result, these animals became very resistant to the deleterious effects of high doses of radiation. When blasted with 10 Gy of irradiation—enough to wipe out all blood stem cells in the bone marrow of normal mice—mutant mice that were unable to fully activate p53 experienced only a modest blood count drop. The other noticeable effect was a premature graying of their coat.
"Both radiation and chemotherapy are commonly used for the treatment of cancer and act by inducing DNA damage and subsequent cell death through p53. As such, tumors that retain normal p53 are more likely to respond to treatment while tumors carrying a defective p53 pathway are often less responsive ," says Wahl. Ideally, we want to find a therapeutic target, such as MDM2 or MDMX, that would increase p53 activity in tumor cells while minimally impacting other vital functions such as hematopoiesis."
Since p53 also protects against wayward cell proliferation caused by oncogenes such as c-myc, the researchers permanently activated c-myc in the B cell lineage to mimic human endemic Burkitt's lymphomas. They observed that mice with defective Mdmx developed very aggressive lymphomas at a very young age. Thus, control by Mdmx is critical to balance the severity of the response to DNA damaging agents, while also preventing induction of cancer by activated oncogenes.
Researchers who contributed to the work include staff scientist Mathias Leblanc, Ph.D. and postdoctoral researcher Mark Wade, Ph.D., in the Gene Expression Laboratory and professor Aart G. Jochemsen, Ph.D. at the Leiden University Medical Center, The Netherlands.
This work was supported by grants from the National Cancer Institute.
Adapted from materials provided by Salk Institute.

Prostate Cancer 'Homing Device' Created For Drug Delivery

SOURCE

ScienceDaily (July 7, 2009) — A new prostate cancer "homing device" could improve detection and allow for the first targeted treatment of the disease.

A team of Purdue University researchers has synthesized a molecule that finds and penetrates prostate cancer cells and has created imaging agents and therapeutic drugs that can link to the molecule and be carried with it as cargo.
A radioimaging application used for body scans is expected to enter clinical trials this fall, and an optical imaging application used to measure prostate cancer cells in blood samples is already in clinical trials.
Philip Low, the Ralph C. Corley Distinguished Professor of Biochemistry who led the team, said a targeted treatment could be much more effective in treating cancer and would greatly reduce the harmful side effects associated with current treatments.
"Currently none of the drugs available to treat prostate cancer are targeted, which means they go everywhere in the body as opposed to only the tumor, and so are quite toxic for the patient," said Low, who is a member of the Purdue Cancer Center. "By being able to target only the cancer cells, we could eliminate toxic side effects of treatments. In addition, the ability to target only the cancer cells can greatly improve imaging of the cancer to diagnose the disease, determine if it has spread or is responding to treatment."
Prostate cancer is the most common cancer, other than skin cancers, and is the second leading cause of cancer death in American men, according to the American Cancer Society. It is estimated that about 192,280 new cases will be diagnosed and 27,360 men will die of prostate cancer in the United States this year.
The molecule Low's team created attaches to prostate-specific membrane antigen, or PSMA, a protein that is found on the membrane of more than 90 percent of all prostate cancers. It also is found on the blood vessels of most solid tumors and could provide a way to cut off the tumor blood supply, Low said.
"A lot of new drugs are being designed to destroy the vasculature of solid tumors, and, if they could be linked to this new targeting molecule, we could have a two-pronged attack for prostate cancer," he said. "We could not only kill the prostate cancer cells directly, we could also destroy the vasculature that feeds the tumors."
There also is potential for the targeting molecule to be used to attack the vasculature of solid tumors of other types of cancers, Low said.
Two papers detailing the work of the Purdue team were published in the June 1 issue of Molecular Pharmaceutics. Endocyte Inc. funded the work.
The team's animal study data shows an ability to eliminate human prostate cancer cells in mice with no evidence of collateral toxicity in normal tissue.
Sumith Kularatne, a graduate student in Purdue's chemistry department and first author of both papers, compared the targeting molecule to a homing device.
"The molecule acts like a homing device for prostate cancer," he said. "PSMA, which is found only on prostate cancer cells and tumor blood vessels, acts as the homing signal that the molecule targets. The molecule and its cargo go only to cancerous tissue, leaving healthy tissue unharmed."
Once the molecule reaches the PSMA protein, it binds to it. The molecule is designed with a specific shape that fits with the protein like a key to a lock, Kularatne said. The molecule and its cargo are then carried inside the cell with the protein as it goes through its normal cycle.
In 1995 Low developed a similar method to infiltrate cancer cells by attaching treatments to the vitamin folate, which many cancers rapidly consume. This method provided a "Trojan Horse" entry of large treatment molecules that otherwise would not be able to enter cancer cells.
Low was inspired to find a similar way to target prostate cancer, which does not have the same appetite for folate, he said.
A clinical trial of the radioimaging application is expected to begin at the Indiana University Medical Center in the fall through a collaboration between the Purdue Cancer Center and the Indiana University Cancer Center with additional support from Endocyte Inc.
A radioimaging agent linked to the targeting molecule will be injected into prostate cancer patients and pictures will be taken using a special camera that detects radioactivity. The pictures show where the cancer is present to help doctors determine if it has metastasized, or spread, to any other areas of the body. It also will help doctors decide on the best course of treatment, Low said.
There is currently only one radioimaging agent for prostate cancer approved by the Food and Drug Administration.
"The current imaging capabilities available for prostate cancer are very poor," Low said. "The existing imaging agent is limited because of its large size, which is difficult to get into a solid tumor. Also it seeks out a target located inside the cancer cell and is only able to mark injured cells that are falling apart as opposed to actively growing cancer cells."
The targeting molecule and radioimaging agent combination designed by Low's group is more than 150 times smaller than the existing agent and has much easier penetration through a solid tumor to reach all of the cells inside, he said. It also has the advantage of targeting an area of PSMA exposed on the outside of cancer cells.
Already in clinical trials is an optical imaging application that involves attaching a fluorescent dye to the targeting molecule and mixing it with a patient's blood sample. Circulating prostate cancer cells in the sample fluoresce and are easily measured to help in diagnosing patients with prostate cancer. Researchers also are investigating whether this could be used to evaluate a patient's response to therapy, Low said.
Low's research group modeled the targeting molecule after a naturally occurring molecule that strongly binds to PSMA, called DUPA. Several alterations were necessary to create a molecule that fit the needs of a homing device and delivery vehicle, Kularatne said. The team created an area on the molecule that would link to various imaging or therapeutic agents to bring them along as cargo and created a spacer that would stretch the molecule so that its cargo would not keep it from properly fitting into the binding site. The spacer also was designed to improve binding of the targeting molecule to PSMA.
In addition to Low and Kularatne, co-authors of the papers include Endocyte researchers Kevin Wang and Hari-Krishna R. Santhapuram, graduate student in medicinal chemistry Zhigang Zhou, graduate student in chemistry Jun Yang, and professor of medicinal chemistry and molecular pharmacology Carol B. Post.
Low is the chief science officer for Endocyte, a Purdue Research Park-based company that develops receptor-targeted therapeutics for the treatment of cancer and autoimmune diseases. Endocyte holds the license to many of Low's drug-targeting technologies.
Journal reference:
Kularatne et al. Prostate-Specific Membrane Antigen Targeted Imaging and Therapy of Prostate Cancer Using a PSMA Inhibitor as a Homing Ligand. Molecular Pharmaceutics, 2009; 6 (3): 780 DOI: 10.1021/mp900069d
Adapted from materials provided by Purdue University.