New field of chemistry has potential for making drugs inside patients -- and more

The traditional way of making medicines from ingredients mixed together in a factory may be joined by a new approach in which doctors administer the ingredients for a medicine separately to patients, and the ingredients combine to produce the medicine inside patients' bodies.

That's one promise from an emerging new field of chemistry, according to the scientist who founded it barely a decade ago. Carolyn Bertozzi, Ph.D., spoke on the topic -- bioorthogonal chemistry -- in San Diego on March 27 in delivering the latest Kavli Foundation Innovations in Chemistry Lecture at the 243rd National Meeting & Exposition of the American Chemical Society (ACS).

Bertozzi explained that the techniques of bioorthogonal chemistry may fundamentally change the nature of drug development and diagnosis of disease, so that the active ingredients for medicines and substances to image diseased tissue are produced inside patients.

"Suppose a drug doesn't reach diseased tissue in concentrations high enough to work," Bertozzi said, citing one example of the potential of the new chemistry. "Maybe it is an oral drug that doesn't get absorbed very well into the blood through the stomach. You can imagine a scenario in which doctors administer two parts of the molecule that makes up the drug. The two units reach diseased tissue in large amounts or get absorbed through the stomach just fine. Then they recombine, producing the actual drug in the patient's body. Bioorthogonal chemistry is chemistry for life…literally!"

Bertozzi explained that bioorthogonal chemistry opens the door to creating new proteins, fats and sugars directly inside living cells without harming them. The field emerged from her frustration in the late 1990s with the lack of tools available to see sugars on the surfaces of living cells. Chains of these sugars, called glycans, sit on the surfaces of cells in the body and control the doorways through which different molecules enter. When a disease-causing virus enters and infects a cell, for instance, proteins on the virus's surface attach to certain glycans.

"To do that, we had to come up with a chemical reaction that would be really selective, only targeting the sugar of interest and the fluorescent probes that we delivered to it," said Bertozzi. The chemicals also couldn't stick to other biomolecules that the researchers didn't want to see.

That turned out to be a tall order, indeed. "We pulled all of our big textbooks off the shelves and flipped through them to see if there was something out there that fit our criteria," she said. Those criteria were essentially the conditions inside a living cell or living organism such as a mouse -- a reaction that could occur in water at pH 7 and at 98.6 degrees Fahrenheit. The reaction also couldn't interfere with all the other biomolecules in a cell or organism that keep it alive.

"It was a pretty restrictive set of conditions that a traditionally trained organic chemist like me never had to work within," she explained. That's because these types of reactions are usually performed in very clean, dry test tubes and flasks under conditions that the chemist can control. A living cell or organism, with all its water, proteins, fats, sugars and metabolites is very messy and uncontrollable by comparison.

Bertozzi and her team at the University of California, Berkeley, went on to develop a slew of reactions that can add fluorescent labels to biomolecules.

Now, the field is exploding, with her group and others reporting new bioorthogonal chemical reactions every year that help researchers see sugars, fats, proteins, and even DNA and RNA, that can't be seen using conventional methods. Researchers currently use the reactions not only to see where a biomolecule is within a living cell or organism, but also to determine when a biomolecule is made and what it binds to. Researchers also are using the methods to add things besides labels, like drugs, to various biomolecules. Some of the chemicals used for the reactions are currently available separately or in kits.

Several of Bertozzi's reactions are patented, and some are licensed to companies, including Redwood Bioscience, a company she co-founded with David Rabuka, Ph.D. The company is focused on bringing this technology to the clinic.

The scientists acknowledged funding from the National Institutes of Health and the Howard Hughes Medical Institute.

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The above story is reprinted from materials provided by American Chemical Society (ACS), via Newswise.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

To boldly go where no glass has gone before

Dr Castillo said the special glass will be the first QUT project to be launched into space.

"True ZBLAN glass fibres can only be made in the absence of gravity," he said.

"This glass contains a variety of heavy metals that upon cooling create internal stresses which leads to crystallization of the material, an undesired property for glass.

"The synthesis of this material in the absence of gravity has the ability to overcome this barrier."

It is believed the glass could revolutionise the way we make fibres for telecommunications and medical imaging tools.

Dr Castillo said the glass has the lowest theoretical attenuation loss of any glass yet known to man, which means little or no loss in signal occurs within the material.

"This special glass can be potentially drawn into a solid fibre and signals would be able to be transmitted over much great distances than in current silicate glass fibres," he said.

"The result of this is potentially eliminating power consuming amplifiers and repeaters while significantly increasing bandwidth.

"Although this glass has been made in a few places, no one has yet figured out how to draw it into a fibre."

Research will first be conducted at QUT's micro-gravity tower in an experiment that will see the glass undergo ~2.1 seconds of microgravity over a 21.3 meter drop inside a drag shield.

Dr Castillo, who has previously worked for space programs in the United States and Japan, will then board NASA's parabolic flight plane, dubbed the 'vomit comet', before launching the project into space via a United States Air Force suborbital satellite by mid next year.

"In order to stay at the leading edge of the synthesis of specialised glass, all traditional methods have to be abandoned," Dr Castillo said.

"I previously spent two years working in Japan trying to produce this glass via gas levitation and with a fibre pulling apparatus in zero gravity and was unsuccessful.

"Now I think we've been able to formulate very new and different techniques to that used by anyone in the world."

Provided by Queensland University of Technology (news : web)

A 24-karat gold key to unlock the immune system

Using nanoparticles made of pure gold, Dr. Dan Peer, head of Tel Aviv University's Laboratory of Nanomedicine at the Department of Cell Research and Immunology and the Center for Nanoscience and Nanotechnology, with a team including Drs. Meir Goldsmith and Dalit Landesman-Milo and in collaboration with Prof. Vincent Rotello and Dr. Daniel Moyano from the University of Massachusetts at Amherst, has developed a new method of introducing chemical residues into the immune system, allowing them to note the properties that incur the wrath of immune cells. Because the gold flecks are too small to be detected by the immune system, the immune system only responds when they are coated with different chemical residues.

This breakthrough could lead to an increased understanding of the properties of viruses and bacteria, better drug delivery systems, and more effective medications and vaccinations. Their study was published in the Journal of the American Chemical Society.

A tool for exploration

To begin probing the immune system, researchers used particles of gold, approximately two nanometers in diameter, and covered them with various chemical residues. Only when water-resistant residues were introduced did the immune system respond to their presence. That established a demonstrable link between hydrophobicity — the degree to which a molecule repels water — and the reaction of the immune system.

This idea has a basis in the normal functioning of the immune system, Dr. Peer explains. During cell death, the hydrophobic areas of the cell membrane become exposed. The immune system then realizes that damage has occurred and begins to alert neighboring cells.

The researchers discovered that the same principle held true for the chemicals added to the gold particles' surface. The more "water-hating" the particle is, the more actively the immune system will mobilize against it, he says.

Dr. Peer observes that this is only the first step in a long line of experiments. "We are using these gold particles to tackle the question of how the immune system recognizes different particles, which might include features such as geometry, charge, curvature, and so much more. Now that we know the tool works, we can build on it," he says.

Testing the "Danger Model"

Until now, scientists have developed theories about how the immune system functions, but have lacked the machinery to test these ideas. One such theory is the "Danger Model" by Prof. Polly Matzinger, which hypothesizes that cellular damage interacts with immune cells at the membrane level. Once they identify the foreign molecule as a "danger," the immune cells send signals throughout the immune system. Their initial experiment with hydrophobicity was designed to generate a toolbox for probing this theory, says Dr. Peer, whose investigations included both in vitro and in vivo experiments using mouse immune cells.

In the future, researchers will study various bacterial, viral, or damaged cells and to make the gold nanoparticles even more similar, thereby discovering which elements of dangerous particles are calling the body's immune system to arms. "We now have the capability of using nanomaterials to probe the immune system in a very accurate manner," says Dr. Peer, a breakthrough that could revolutionize the way we understand the immune system.

Provided by Tel Aviv University (news : web)

Study on swirls to optimize contacts between fluids

 A new model gives clues on how to optimize homogeneous feeding of cells in suspension from a liquid nutriments supply in a bioreactor.

Physicists who have studied the mixing between two incompatible fluids have found that it is possible to control the undercurrents of one circulating fluid to optimise its exposure to the other. This work, which is about to be published in EPJ E1, was performed by Jorge Peixinho from CNRS at Le Havre University, France, and his colleagues from the Benjamin Levich Institute, City University of New York, USA.

The authors compared quantitative experimental observations of a viscous fluid, similar to honey, with numerical simulations. They focused on a fluid, which partially filled the space between two concentric cylinders with the inner one rotating. This system was previously used to study roll coating and papermaking processes. To interpret this seemingly simple system, they factored in interface flows, film spreading, and the formation of free surface cusps -- a phenomenon relevant to fluid mixing, but which is not quantitatively captured by conventional numerical calculation.

The authors observed the presence of several flow eddies, stemming from fluid flowing past the inner cylinder, causing it to swirl, and the appearance of reverse currents including one orbiting around the rotating cylinder and a second underneath. They made the second eddy disappear by increasing the fluid filling or its velocity. This is akin to turning a spoon full of honey fast enough to prevent it from draining.

This model is based on a highly viscous oil combined with air as a top fluid. When combined with a light oil containing nutriments as a top fluid, it could also apply to a suspension of bioreactor cells typically used to produce biotech medicines. Ultimately, it could help identify the right parameters and adequate mixing time scales to ensure that nutriments feed all the cells homogeneously without segregation.

Story Source:

The above story is reprinted from materials provided by Springer Science+Business Media, via AlphaGalileo.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Peixinho J., Mirbod M. and Morris J.F. Free surface flow between two horizontal concentric cylinders. European Physical Journal E, 2012 DOI: 10.1140/epje/i2012-12019-8 2

'Noodle gels' or 'spaghetti highways' could become tools of regenerative medicine

Samuel I. Stupp, Ph.D., who presented an ACS plenary lecture, explained that the synthetic pasta-like objects actually are major chemistry advances for regenerative medicine that his research team has accomplished. Regenerative medicine is an emerging field that combines chemistry, biology and engineering. It focuses on the regeneration of tissues and organs for the human body, to repair or replace those damaged through illness, injury, aging or birth defects. Those tissues range from cartilage in joints damaged by arthritis to heart muscle scarred by a heart attack and nerves severed in auto accidents.

"A graying of the population is underway in industrialized countries," Stupp said. "In the U.S., we have the 'baby boom' generation — 75 million people born between 1946 and 1964, who now are reaching their mid-60s. At the same time, people are living longer — into their 80s, 90s and even 100s. With that comes an expectation of a better quality of life. It's also an economic issue because with lifespan rising, we're going to have to think about how to provide healthcare and keep people functional for longer periods of time, perhaps to keep them in the workforce longer."

Stupp explained that advances in regenerative medicine also hold promise to improve people's lives at any age. For example, a young person could survive a car accident, but emerge with a spinal cord injury and be paralyzed. Also, cardiovascular disease and heart attacks are a leading cause of premature death around the world. Cartilage wears away and does not regenerate on its own in the body, leading to painful osteoarthritis. Some bones do not mend correctly. And the millions of people with diabetes face complications, including blocked blood vessels that result in an increased risk of heart attacks and limb amputations. Regenerative medical techniques could coax cells to grow and repair all of these types of damage, said Stupp, who is with Northwestern University. He is Board of Trustees Professor of Chemistry, Materials Science and Engineering, and Medicine and director of the Institute for BioNanotechnology in Medicine.

One type of spaghetti-like filament developed by Stupp's team is a nanostructure of small bits of protein that glue themselves together spontaneously. These nanofilaments are so small that more than 50,000 would fit across the width of a human hair, and they can serve as smart scaffolds for many uses. For example, Stupp attached to these fibers signaling substances that mimic a powerful substance called VEGF that can promote the formation of new blood vessels. The VEGF-mimic caused new blood vessels to form in mice (stand-ins for humans) with blood vessel damage.

"When VEGF itself was used in clinical trials on humans, it didn't work, despite a lot of laboratory research that suggested otherwise," said Stupp. "The problem was that VEGF was quickly broken down in the body. The nanofilament scaffold, however, lasts in the body for weeks, which allows the VEGF-mimic more time to grow vessels." Eventually, the nanofilaments break down and disappear, leaving only the new blood vessels behind.

In other research, his group developed so-called "noodle gels," which are nanofibers that form long, noodle-like gels when they are heated, cooled and then squeezed out from a pipette (much like frosting from a piping bag) into salty water. These gels can be more than half an inch long and are visible with the naked eye.

These noodle gels are a potential solution to a long-standing problem in regenerative medicine. It involves delivering proteins, biological signals and stem cells in a specific direction to target precisely the damaged parts of the heart, brain, spinal cord or other organs. Noodle gels can align stem cells in the linear fashion needed for proper repair of damaged tissue. Those strings could also serve as "spaghetti highways" to guide cells in our bodies to a specific location where repair is needed. Alternatively, the noodle gels containing aligned filaments could deliver signaling proteins and other beneficial substances to diseased locales.

Many of Stupp's innovations are in the preclinical stage of testing by various companies, including his own company called Nanotope. These include materials for spinal cord, cartilage, blood vessel and bone regeneration. He predicts that some of these could be in clinical trials within the next five years. Eventually, the nanofibers and gels might someday allow doctors to simply "fix" damage that is currently impossible to treat, improving the quality of life for millions of people with devastating injuries and conditions.

More information:
Abstract
Regeneration of human tissues and organs can have extraordinary impact on quality of life and the cost of health care, both issues of critical importance when the average lifespan of world populations continues to rise. As the relevant biological pathways become better understood, chemistry can play a key role in implementing novel therapies. This lecture describes strategies that utilize supramolecular self-assembly to create bioactive, biomimetic, and biodegradable nanoscale filaments, virus-like objects, or cell-like microcapsules that function as an artificial extracellular matrix to trigger regeneration. The supramolecular chemistry of these nanostructures allows them to interact directly with cell receptors, activate or mimic growth factors, recruit endogenous proteins, or interact with intracellular targets. The lecture will discuss their use in spinal cord injury, Parkinson's disease, rapid growth of blood vessels for myocardial infarction or peripheral arterial disease, as well as their use in bone and cartilage regeneration.

Provided by American Chemical Society (news : web)