| Wed, 05/06/2015 George Hunka, American Friends of Tel Aviv University Water, when cooled below 32 F, eventually freezes—it's science known even to pre-schoolers. But some substances, when they undergo a process called "rapid-freezing" or "supercooling," remain in liquid form—even at below-freezing temperatures. The supercooling phenomenon has been studied for its possible applications in a wide spectrum of fields. A new Tel Aviv Univ. study published in Scientific Reports is the first to break down the rules governing the complex process of crystallization through rapid-cooling. According to the research, membranes can be engineered to crystallize at a specific time. In other words, it is indeed possible to control what was once considered a wild and unpredictable process—and it may revolutionize the delivery of drugs in the human body, providing a way to "freeze" the drugs at the exact time and biological location in the body necessary. The study was led jointly by Dr. Roy Beck of the Department of Physics at TAU's School of Physics and Astronomy and Prof. Dan Peer of the Dept. of Cell Research and Immunology at TAU's Faculty of Life Sciences, and conducted by TAU graduate students Guy Jacoby, Keren Cohen, and Kobi Barkai. Controlling a metastable process For the purpose of the study, the researchers conducted experiments on nanoscale drug vesicles (fluid-filled sacs that deliver drugs to their targets) to determine the precise dynamics of crystallization. The researchers used a state-of-the-art x-ray scattering system sensitive to nanoscale structures. "One key challenge in designing new nano-vesicles for drug delivery is their stability," said Dr. Beck. "On the one hand, you need a stable vesicle that will entrap your drug until it reaches the specific diseased cell. But on the other, if the vesicle is too stable, the payload may not be released upon arrival at its target." "Supercooled material is a suitable candidate since the transition between liquid and crystal states is very drastic and the liquid membrane explodes to rearrange as crystals. Therefore this new physical insight can be used to release entrapped drugs at the target and not elsewhere in the body's microenvironment. This is a novel mechanism for timely drug release." All in the timing "What was amazing was our ability to reproduce the results over and over again without any complicated techniques," said Dr. Beck. "We showed that the delayed crystallization was not sensitive to minor imperfection or external perturbation. Moreover, we found multiple alternative ways to 'tweak the clock' and start the crystallization process." The researchers are investigating an appropriate new nano-capsule capable of releasing medication at a specific time and place in the body. "The challenge now is to find the right drugs to exploit our insights for the medical benefit of patients," said Dr. Beck. Source: American Friends of Tel Aviv University
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quarta-feira, 6 de maio de 2015
A “super cool” way to deliver drugs
sábado, 25 de outubro de 2014
First protein microfiber engineered: New material advances tissue engineering and drug delivery
October 23, 2014
New York University Polytechnic School of Engineering
Researchers have broken new ground in the development of proteins that form specialized fibers used in medicine and nanotechnology. For as long as scientists have been able to create new proteins that are capable of self-assembling into fibers, their work has taken place on the nanoscale. For the first time, this achievement has been realized on the microscale -- a leap of magnitude in size that presents significant new opportunities for using engineered protein fibers.
Researchers at the New York University Polytechnic School of Engineering have broken new ground in the development of proteins that form specialized fibers used in medicine and nanotechnology. For as long as scientists have been able to create new proteins that are capable of self-assembling into fibers, their work has taken place on the nanoscale. For the first time, this achievement has been realized on the microscale -- a leap of magnitude in size that presents significant new opportunities for using engineered protein fibers.
Jin Kim Montclare, an associate professor of chemical and biomolecular engineering at the NYU School of Engineering, led a group of researchers who published the results of successful trials in the creation of engineered microfiber proteins in the journal Biomacromolecules.
Many materials used in medicine and nanotechnology rely on proteins engineered to form fibers with specific properties. For example, the scaffolds used in tissue engineering depend on engineered fibers, as do the nanowires used in biosensors. These fibers can also be bound with small molecules of therapeutic compounds and used in drug delivery.
Montclare and her collaborators began their experiments with the intention of designing nanoscale proteins bound with the cancer therapeutic curcumin. They successfully created a novel, self-assembling nanoscale protein, including a hydrophobic pore capable of binding small molecules. To their surprise, after incubating the fibers with curcumin, the protein not only continued to assemble, but did so to a degree that the fibers crossed the diameter barrier from the nanoscale to the microscale, akin to the diameter of collagen or spider silk.
"This was a surprising and thrilling achievement," said Montclare, explaining that this kind of diameter increase in the presence of small molecules is unprecedented. "A microscale fiber that is capable of delivering a small molecule, whether it be a therapeutic compound or other material, is a major step forward."
Montclare explained that biomaterials embedded with small molecules could be used to construct dual-purpose scaffolds for tissue engineering or to deliver certain drugs more efficiently, especially those that are less effective in an aqueous environment. Using microscopy, the team was able to observe the fibers in three dimensions and to confirm that the curcumin, which fluoresces when bound to structural protein, was distributed homogeneously throughout the fiber.
Despite the enormity of the jump from nano- to microscale, the research team believes they can devise even larger fibers. The next step, Montclare says, is developing proteins that can assemble on the milliscale, creating fibers large enough to see with the naked eye. "It's even possible to imagine generating hair out of cell assembly," she says.
Researchers from three institutions collaborated on this work. In addition to Montclare, NYU School of Engineering doctoral candidate Jasmin Hume, graduate student Rudy Jacquet, and undergraduate student Jennifer Sun co-authored the paper. Richard Bonneau, an associate professor in NYU's Department of Biology and a member of the computer science faculty at NYU's Courant Institute of Mathematical Sciences, and postdoctoral scholar P. Douglas Renfrew also contributed, along with M. Lane Gilchrist, associate professor of chemical engineering at City College of New York and master's degree student Jesse A. Martin, also from City College. Their work was supported by the Army Research Office and the National Science Foundation.
Story Source:
The above story is based on materials provided by New York University Polytechnic School of Engineering. Note: Materials may be edited for content and length.
Journal Reference:
- Jasmin Hume, Jennifer Sun, Rudy Jacquet, P. Douglas Renfrew, Jesse A. Martin, Richard Bonneau, M. Lane Gilchrist, Jin Kim Montclare. Engineered Coiled-Coil Protein Microfibers. Biomacromolecules, 2014; 15 (10): 3503 DOI: 10.1021/bm5004948
quinta-feira, 2 de outubro de 2014
New drug-delivery capsule may replace injections
A schematic drawing of a microneedle pill with hollow needles. When the pill reaches the desired location in the digestive tract, the pH-sensitive coating surrounding the capsule dissolves, allowing the drug to be released through the microneedles.
Given a choice, most patients would prefer to take a drug orally instead of getting an injection. Unfortunately, many drugs, especially those made from large proteins, cannot be given as a pill because they get broken down in the stomach before they can be absorbed.
To help overcome that obstacle, researchers at MIT and Massachusetts General Hospital (MGH) have devised a novel drug capsule coated with tiny needles that can inject drugs directly into the lining of the stomach after the capsule is swallowed. In animal studies, the team found that the capsule delivered insulin more efficiently than injection under the skin, and there were no harmful side effects as the capsule passed through the digestive system.
"This could be a way that the patient can circumvent the need to have an infusion or subcutaneous administration of a drug," says Giovanni Traverso, a research fellow at MIT's Koch Institute for Integrative Cancer Research, a gastroenterologist at MGH, and one of the lead authors of the paper, which appears in the Journal of Pharmaceutical Sciences.
Although the researchers tested their capsule with insulin, they anticipate that it would be most useful for delivering biopharmaceuticals such as antibodies, which are used to treat cancer and autoimmune disorders like arthritis and Crohn's disease. This class of drugs, known as "biologics," also includes vaccines, recombinant DNA, and RNA.
"The large size of these biologic drugs makes them nonabsorbable. And before they even would be absorbed, they're degraded in your GI tract by acids and enzymes that just eat up the molecules and make them inactive," says Carl Schoellhammer, a graduate student in chemical engineering and a lead author of the paper.
Safe and effective delivery
Scientists have tried designing microparticles and nanoparticles that can deliver biologics, but such particles are expensive to produce and require a new version to be engineered for each drug.
Schoellhammer, Traverso, and their colleagues set out to design a capsule that would serve as a platform for the delivery of a wide range of therapeutics, prevent degradation of the drugs, and inject the payload directly into the lining of the GI tract. Their prototype acrylic capsule, 2 centimeters long and 1 centimeter in diameter, includes a reservoir for the drug and is coated with hollow, stainless steel needles about 5 millimeters long.
Previous studies of accidental ingestion of sharp objects in human patients have suggested that it could be safe to swallow a capsule coated with short needles. Because there are no pain receptors in the GI tract, patients would not feel any pain from the drug injection.
To test whether this type of capsule could allow safe and effective drug delivery, the researchers tested it in pigs, with insulin as the drug payload. It took more than a week for the capsules to move through the entire digestive tract, and the researchers found no traces of tissue damage, supporting the potential safety of this novel approach.
They also found that the microneedles successfully injected insulin into the lining of the stomach, small intestine, and colon, causing the animals' blood glucose levels to drop. This reduction in blood glucose was faster and larger than the drop seen when the same amount of glucose was given by subcutaneous injection.
"The kinetics are much better, and much faster-onset, than those seen with traditional under-the-skin administration," Traverso says. "For molecules that are particularly difficult to absorb, this would be a way of actually administering them at much higher efficiency."
"This is a very interesting approach," says Samir Mitragotri, a professor of chemical engineering at the University of California at Santa Barbara who was not involved in the research. "Oral delivery of drugs is a major challenge, especially for protein drugs. There is tremendous motivation on various fronts for finding other ways to deliver drugs without using the standard needle and syringe."
Further optimization
This approach could also be used to administer vaccines that normally have to be injected, the researchers say.
The team now plans to modify the capsule so that peristalsis, or contractions of the digestive tract, would slowly squeeze the drug out of the capsule as it travels through the tract. They are also working on capsules with needles made of degradable polymers and sugar that would break off and become embedded in the gut lining, where they would slowly disintegrate and release the drug. This would further minimize any safety concern.
Story Source:
The above story is based on materials provided by Massachusetts Institute of Technology. The original article was written by Anne Trafton. Note: Materials may be edited for content and length.
Journal Reference:
- Giovanni Traverso, Carl M. Schoellhammer, Avi Schroeder, Ruby Maa, Gregory Y. Lauwers, Baris E. Polat, Daniel G. Anderson, Daniel Blankschtein, Robert Langer. Microneedles for Drug Delivery via the Gastrointestinal Tract. Journal of Pharmaceutical Sciences, 2014; DOI: 10.1002/jps.24182
quarta-feira, 1 de outubro de 2014
High-speed drug screen developed
Mehmet Fatih Yanik.
MIT engineers have devised a way to rapidly test hundreds of different drug-delivery vehicles in living animals, making it easier to discover promising new ways to deliver a class of drugs called biologics, which includes antibodies, peptides, RNA, and DNA, to human patients.
In a study appearing in the journal Integrative Biology, the researchers used this technology to identify materials that can efficiently deliver RNA to zebrafish and also to rodents. This type of high-speed screen could help overcome one of the major bottlenecks in developing disease treatments based on biologics: It is challenging to find safe and effective ways to deliver them.
"Biologics is the fastest growing field in biotech, because it gives you the ability to do highly predictive designs with unique targeting capabilities," says senior author Mehmet Fatih Yanik, an associate professor of electrical engineering and computer science and biological engineering. "However, delivery of biologics to diseased tissues is challenging, because they are significantly larger and more complex than conventional drugs."
"By combining this work with our previously published high-throughput screening system, we are able to create a drug-discovery pipeline with efficiency we had never imagined before," adds Tsung-Yao Chang, a recent MIT PhD recipient and one of the paper's lead authors.
Peng Shi, a former MIT postdoc who is now an assistant professor at the University of Hong Kong, is the paper's other lead author.
Fish on the fly
Zebrafish are commonly used to model human diseases, in part because their larvae are transparent, making it easy to see the effects of genetic mutations or drugs.
In 2010, Yanik's team developed a technology for rapidly moving zebrafish larvae to an imaging platform, orienting them correctly, and imaging them. This kind of automated system makes it possible to do large-scale studies because analyzing each larva takes less than 20 seconds, compared with the several minutes it would take for a scientist to evaluate the larvae by hand.
For this study, Yanik's team developed a new technology to inject RNA carried by nanoparticles called lipidoids, previously designed by Daniel Anderson, an associate professor of chemical engineering, member of the Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, and an author of the new paper. These fatty molecules have shown promise as delivery vehicles for RNA interference, a process that allows disease-causing genes to be turned off with small strands of RNA.
Yanik's group tested about 100 lipidoids that had not performed well in tests of RNA delivery in cells grown in a lab dish. They designed each lipidoid to carry RNA expressing a fluorescent protein, allowing them to easily track RNA delivery, and injected the lipidoids into the spinal fluid of the zebrafish.
To automate that process, the zebrafish were oriented either laterally or dorsally once they arrived on the viewing platform. Once the larvae were properly aligned, they were immobilized by a hydrogel. Then, the lipidoid-RNA complex was automatically injected, guided by a computer vision algorithm. The system can be adapted to target any organ, and the process takes about 14 seconds per fish.
A few hours after injection, the researchers imaged the zebrafish to see if they displayed any fluorescent protein in the brain, indicating whether the RNA successfully entered the brain tissue, was taken up by the cells, and expressed the desired protein.
The researchers found that several lipidoids that had not performed well in cultured cells did deliver RNA efficiently in the zebrafish model. They next tested six randomly selected best- and worst-performing lipidoids in rats and found that the correlation between performance in rats and in zebrafish was 97 percent, suggesting that zebrafish are a good model for predicting drug-delivery success in mammals.
"The ability to identify useful drug delivery nanoparticles using this miniaturized system holds great potential for accelerating our discovery process," Anderson says.
"The lipidoid material screen is just an example demonstrated in this article; a similar strategy can be readily extended to other libraries or other organ systems," Peng adds.
Jeff Karp, an associate professor of medicine at Harvard Medical School who was not part of the research team, says this work is "an excellent example of harnessing a multidisciplinary team to partner complementary technologies for the purpose of solving a unified problem. Yanik and colleagues, who have extensive expertise with high-throughput screening in zebrafish and other small animals, have teamed up with Anderson et al., who are leading experts in RNA delivery, to create a new platform for rapidly screening biologics and methods to deliver them. This approach should have utility across multiple disease areas."
New leads
The researchers are now using what they learned about the most successful lipidoids identified in this study to try to design even better possibilities. "If we can pick up certain design features from the screens, it can guide us to design larger combinatorial libraries based on these leads," Yanik says.
Yanik's lab is currently using this technology to find delivery vehicles that can carry biologics across the blood-brain barrier -- a very selective barrier that makes it difficult for drugs or other large molecules to enter the brain through the bloodstream.
The research was funded by the National Institutes of Health, the Packard Award in Science and Engineering, Sanofi Pharmaceuticals, Foxconn Technology Group, and the Hertz Foundation.
Story Source:
The above story is based on materials provided by Massachusetts Institute of Technology. The original article was written by Anne Trafton. Note: Materials may be edited for content and length.
Journal Reference:
- Tsung-Yao Chang, Peng Shi, Joseph D. Steinmeyer, Itthi Chatnuntawech, Paul Tillberg, Kevin T. Love, Peter M. Eimon, Daniel G. Anderson, Mehmet Fatih Yanik. Organ-targeted high-throughput in vivo biologics screen identifies materials for RNA delivery. Integr. Biol., 2014; 6 (10): 926 DOI: 10.1039/C4IB00150H