Could focused ultrasound really be used to treat Alzheimer’s

via The Virginia Journal of Bioethics

Focused ultrasound is a safe and effective way to target and open areas of the blood-brain barrier, potentially allowing for new treatment approaches to Alzheimer’s disease, according to initial study results presented at the annual meeting of the Radiological Society of North America (RSNA).

There currently is no effective treatment for Alzheimer’s disease, the most common cause of dementia. The blood-brain barrier, a network of blood vessels and tissues that keeps foreign substances from entering the brain, presents a challenge to scientists researching treatments, as it also blocks potentially therapeutic medications from reaching targets inside the brain.

Studies on animals have shown that pulses of low-intensity focused ultrasound (LIFU) delivered under MRI guidance can reversibly open this barrier and allow for targeted drug and stem-cell delivery.

Researchers at three sites have been studying LIFU in humans for more than a year in a clinical trial led by Ali Rezai, M.D., director of the West Virginia University (WVU) Rockefeller Neuroscience Institute in Morgantown, W.Va. For the new study, researchers delivered LIFU to specific sites in the brain critical to memory in three women, ages 61, 72 and 73, with early-stage Alzheimer’s disease and evidence of amyloid plaques—abnormal clumps of protein in the brain that are linked with Alzheimer’s disease. The patients received three successive treatments at two-week intervals. Researchers tracked them for bleeding, infection and edema, or fluid buildup.

Post-treatment brain MRI confirmed that the blood-brain barrier opened within the target areas immediately after treatment. Closure of the barrier was observed at each target within 24 hours.

“The results are promising,” said study co-author Rashi Mehta, M.D., associate professor at WVU and research scholar at West Virginia Clinical and Translational Science Institute. “We were able to open the blood-brain barrier in a very precise manner and document closure of the barrier within 24 hours. The technique was reproduced successfully in the patients, with no adverse effects.”

MRI-guided LIFU involves placement of a helmet over the patient’s head after they are positioned in the MRI scanner. The helmet is equipped with more than 1,000 separate ultrasound transducers angled in different orientations. Each transducer delivers sound waves targeted to a specific area of the brain. Patients also receive an injection of contrast agent made up of microscopic bubbles. Once ultrasound is applied to the target area, the bubbles oscillate, or change size and shape.

“The helmet transducer delivers focal energy to specified locations in the brain,” Dr. Mehta said. “Oscillation of the microbubbles causes mechanical effects on the capillaries in the target area, resulting in a transient loosening of the blood-brain barrier.”

LIFU could help deliver therapeutic drugs into the brain to improve their effectiveness. Even without drugs, opening of the brain-blood barrier in animals has shown positive effects, Dr. Mehta said. These effects may be due to increased flow of the fluid that cleans the brain of toxic substances, from an immune response triggered by the opening, or by some combination of the two.

While the research so far has focused on the technique’s safety, in the future the researchers intend to study LIFU’s therapeutic effects.

“We’d like to treat more patients and study the long-term effects to see if there are improvements in memory and symptoms associated with Alzheimer’s disease,” Dr. Mehta said. “As safety is further clarified, the next step would be to use this approach to help deliver clinical drugs.”

Learn more: Focused Ultrasound May Open Door to Alzheimer’s Treatment



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Extending the functional life of cancer fighting circuitry in microbes with synthetic biology

A still image pulled from UC San Diego video from three-strain co-culture experiments of E. coli. The video the image is from demonstrates autonomous cycling of the researchers’ synchronized lysis circuit (SLC) that causes microbe population lysis once a threshold population density is reached. Image taken at 10X magnification. The three strains are mixed prior to loading into the microfluidic device. Strains compete until a single strain remains in each trap.

Bioengineers and biologists at the University of California San Diego have developed a method to significantly extend the life of gene circuits used to instruct microbes to do things such as produce and deliver drugs, break down chemicals and serve as environmental sensors.

Most of the circuits that synthetic biologists insert into microbes break or vanish entirely from the microbes after a certain period of time—typically days to weeks—because of various mutations. But in the September 6, 2019 issue of the journal Science, the UC San Diego researchers demonstrated that they can keep genetic circuits going for much longer.

The key to this approach is the researchers’ ability to completely replace one genetic-circuit-carrying sub-population with another, in order to reset the mutation clock, while keeping the circuit running.

“We’ve shown that we can stabilize genetic circuits without getting into the business of fighting evolution,” said UC San Diego bioengineering and biology professor Jeff Hasty, the corresponding author on the study. “Once we stopped fighting evolution at the level of individual cells, we showed we could keep a metabolically-expensive genetic circuit going as long as we want.”

The circuit the UC San Diego researchers used in the Science study is one that this team, and others, are actively using to develop new kinds of cancer therapies.

“As synthetic biologists our goal is to develop gene circuits that will enable us to harness microorganisms for a wide range of applications. However, the reality today is that the gene circuits we insert into microbes are prone to fail due to evolution. Whether it be days, weeks, or months, even with the best circuit-stabilization approaches, it’s just a matter of time. And once you lose functionality in your genetic circuit, there is nothing to do but start over,” said Michael Liao, a UC San Diego bioengineering PhD student and the first author on the Science paper. “Our work shows there is another path forward, not just in theory, but in practice. We’ve shown that it’s possible to keep circuit-busting mutations at bay. We found a way to keep hitting reset on the mutation clock.”

If the team’s method can be optimized for living systems, the implications could be significant for many fields, including cancer therapy, bioremediation, and bioproduction of useful proteins and chemical components.

Rock Paper Scissors

To actually build a “reset button” for the mutation clock, the researchers focused on dynamics between strains of microbes, rather than trying to hold selective pressures at bay at the level of individual cells. The researchers demonstrated their community-level engineering system using three sub-populations of E. coli with a “rock-paper-scissors” power dynamic. This means that the “rock” strain can kill the “scissors” strain but will be killed by the “paper” strain.

Most published work tends to focus on stabilization strategies that act at the level of single cells. While some of these approaches may be sufficient in a given therapeutic context, evolution dictates that single cell approaches will naturally tend to stop working at some point. However, since the rock-paper-scissors (RPS) stabilization acts at a community level, it can also be coupled with any of the systems that act on a single cell level to drastically extend their lifespan.

Making Cancer Drugs and Delivering them to Tumors

In 2016 in Nature, UC San Diego researchers led by Hasty, along with colleagues at MIT, described a “synchronized lysis circuit” that could be used to deliver cancer-killing drugs that are produced by bacteria that accumulate in and around tumors.  This led the UC San Diego group to focus on the synchronized lysis platform for the experiments published in Science.

These coordinated explosions only occur once a predetermined density of cells has been reached, thanks to “quorum sensing” functionality also baked into the genetic circuitry. After the explosion, the approximately 10% of the bacterial population that did not explode starts growing again. When the population density once again reaches the predetermined density (more “quorum sensing”), another drug-delivering explosion is triggered and the process encoded by the researchers’ synchronized lysis circuit restarts.

The challenge, however, is that this cancer-killing genetic circuit – and other genetic circuits created by synthetic biologists – eventually stop working in the bacteria. The culprit. Mutations driven by the process of evolution.

“The fact that some bugs naturally grow in tumors and we can engineer them to produce and deliver therapies in the body is a game-changer for synthetic biology,” said Hasty. “But we have to find ways to keep the genetic circuits running. There is still work to do, but we’re showing that we can swap populations and keep the circuit running. This is a big step forward for synthetic biology.”

Biomedical Research Advances

One of the research teams working to further advance and implement the synchronized lysis circuit is run by Tal Danino, now a professor at Columbia University, who also published seminal work on the development of quorum sensing for synthetic biology as part of his Ph.D. at UC San Diego.

“Tal recently showed that synchronized lysis technology can be used to deliver an immunotherapy to tumors in mice. To my knowledge, they are the first to show that bacterial drug production and delivery within a treated tumor can modify the immune system to attack untreated tumors. The results are fascinating. They also highlight how important it is for us to figure out how to keep the lysis circuit running as long as possible,” said Hasty.

The current approach is not limited to a three-strain system. Individual sup-populations of microbes, for example, could each be programmed to produce different drugs, offering the potential of precise combination drug therapies to treat cancer, for example.

The researchers studied the dynamics of the populations using microfluidic devices that allow for controlled interactions between the different sub-populations. They also demonstrated the system is robust when tested in larger wells.

One next step will be to combine the approach with standard stabilizing approaches and demonstrate the system works in live animal models.

“We are converging on an extremely stable drug delivery platform with wide applicability for bacterial therapies,” said Hasty.

Hasty, Din, and Danino are co-founders of GenCirq, a company which seeks to transfer this and related work to the clinic.

Learn more: Synthetic Biologists Extend Functional Life of Cancer-Fighting Circuitry in Microbes


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Transforming proteins and antibodies into stable and highly functional drug transporters

The new technology enables a simple way of connecting the cytsteine residues (SH) of a tumor-sensing antibody (yellow) to toxic drug molecules. The emerging linker is highly stable during blood circulation and enables therefore a safe transport to the tumor side. (picture by Barth van Rossum/FMP)

Treating cancer more selectively and more effectively – this could be achieved with an innovative technology developed by teams of researchers at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and the Ludwig-Maximilians-Universität München (LMU). The process transforms proteins and antibodies into stable, highly functional drug transporters, with which tumor cells can be detected and killed.

Classic chemotherapy for the treatment of cancer is based on toxic substances that are particularly effective for rapidly dividing cells. However, since healthy tissue also depends on cell division, treatment with chemotherapeutic substances is often accompanied by severe side effects. A dose sufficient to completely remove the tumor, would in many cases be too toxic to administer to a diseased person. With more modern approaches, it is now possible to transport active agents (drugs) in the body selectively to the site of action, for example by linking a drug with an antibody that can differentiate cancer cells from healthy tissue through changes on the surface of the cell. Five such Antibody Drug Conjugates (ADCs) are already on the market.

However, these ADCs lose a large part of their “toxic cargo” en route to the cancer cell. The substances (drugs) are released into the bloodstream and dangerous side effects can occur. A stable link between drug and antibody would therefore be highly desirable. This is precisely what the researchers – a team led by Professor Christian Hackenberger from the FMP and Professor Heinrich Leonhardt from the LMU Biocenter – focused on. Their results have been published in the prestigious journal, Angewandte Chemie: In two consecutive articles, the development of methods and the application of these methods to selective drug transport are presented.

The new drug transporters enable lower doses and less severe side effects

“We have developed an innovative technology that makes it possible to link native proteins and antibodies to complex molecules, such as fluorescent dyes or drugs more easily and with better stability than ever before,” reports Marc-André Kasper, a researcher in Christian Hackenberger’s group. The researchers discovered the outstanding properties of unsaturated phosphorus (V) compounds and took advantage of those. These phosphonamidates connect a desired modification – for example, a cancer-fighting agent – exclusively to the amino acid cysteine, in a protein or antibody. Since cysteine is a very rare natural occurring amino acid, the number of modifications per protein can be controlled quite effectively, which is essential for the construction of drug conjugates. In addition, phosphonamidates can easily be incorporated into complex chemical compounds. “The greatest achievement of the new method, however, is that the resulting bond is also stable during blood circulation,” says Marc-André Kasper. The ADCs that are on the market cannot achieve this.

To test the applicability on targeted drug delivery, the researchers compared their technology directly with the FDA-approved ADC, Adcetris®. The medication was re-created as precisely as possible with the same antibody and active agent, the only difference was that the innovative phosphonamidate linkage was used. When applied to blood serum, the researchers observed that their modified ADC lost significantly less active ingredient over a period of days. They also used the new technology in experiments with mice to combat Hodgkin’s lymphoma. The preparation proved to be more effective than the conventional medication. “From our results, we conclude that phosphonamidate-linked drug transporters can be administered in lower doses, and that side effects can be further reduced. Thus the technology has great potential to replace current methods in order to develop more effective and safer ADCs in the future,” says FMP group leader Christian Hackenberger.

In the next step, the research groups will continue their efforts in the development of ADCs based on phosphonamidates. Preclinical studies, which are essential for the treatment of patients, are already underway. In this regard, the promising start-up company Tubulis, which was awarded the Leibniz Start-Up Prize last year, functions as a platform for the further development to market maturity.

Learn more: Bringing cancer medication safely to its destination


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Once a pharmacologist’s dream: Artificial DNA can control release of active ingredients from drugs

Prof. Oliver Lieleg and PhD student Ceren Kimna use balls and pipe cleaners in different colors to visualize how nanoparticles can be bound together by DNA fragments. Such connections may become the basis of drugs that release their active ingredients in sequence.
Image: Uli Benz / TUM

A drug with three active ingredients that are released in sequence at specific times: Thanks to the work of a team at the Technical University of Munich (TUM), what was once a pharmacologist’s dream is now much closer to reality. With a combination of hydrogels and artificial DNA, nanoparticles can be released in sequence under conditions similar to those in the human body.

It is becoming much more common for patients to be treated with several different medications. It is often necessary for the patient to take them at fixed intervals – a limitation that makes everyday life difficult and increases the risk of doses being skipped or forgotten.

Oliver Lieleg, Professor of Biomechanics and a member of the Munich School of BioEngineering at TUM, and doctoral candidate Ceren Kimna have now developed a process that could serve as the basis for medications containing several active ingredients that would reliably release them in the body in a pre-defined sequence at specified times. “For example, an ointment applied to a surgical incision could release pain medication first, followed by an anti-inflammatory drug and then a drug to reduce swelling,” explains Oliver Lieleg.

One active ingredient after the other
“Ointments or creams releasing their active ingredients with a time delay are not new in themselves,” says Oliver Lieleg. With the drugs currently in use, however, there is no guarantee that two or more active ingredients will not be released into the organism simultaneously.

To test the principle behind their idea, Oliver Lieleg and Ceren Kimna used nanometer-sized silver, iron oxide and gold particles embedded in a special gel-like substance known as a hydrogel. They then used a spectroscopic method to track the exit of the particles from the gel. The particles selected by the researchers have similar motion characteristics within the gel to the particles used to transport real active ingredients, but are easier and cheaper to make.

The special ingredient controlling the nanoparticles is artificial DNA. In nature, DNA is above all the carrier of genetic information. However, researchers are increasingly exploiting another property: The ability of DNA fragments to be combined with great accuracy, both in terms of the types of bonds and their strength, for example to build machines on a nanometer scale.

The DNA cascade: compress and then release at the right instant

The silver particles were released first. In the initial state, the particles were bound together by DNA fragments designed by Lieleg and Kimna using special software. The resulting particle clusters are so large that they are unable to move in the hydrogel. However, when a saline solution is added, they separate from the DNA. They can now move in the gel and drift to the surface. “Because the saline solution has approximately the same salinity as the human body, we were able to simulate conditions where the active ingredients would not be released until the medication is applied,” explains Ceren Kimna.

The mesh-like DNA structure surrounding the iron oxide particles consists of two types of DNA: The first has one end attached to the iron oxide particles. The second type is attached to the loose ends of the first type. These structures are not affected by the saline solution. The iron oxide particles can only be released when the first clusters have dissolved. This event releases not only the silver nanoparticles, but also DNA, which eliminates the “connection DNA” of the second cluster without forming connections itself. As a result, the iron oxide particles can separate. This releases DNA fragments which in turn act as the key to the third DNA-nanoparticle combination.

“The consistency of ointments makes them the most obvious solution for a hydrogel-based approach. However, this principle also has the potential to be used in tablets that could release several effective ingredients in the body in a specific order,” explains Prof. Lieleg.

Learn more: One at a time


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Drug delivery inside the human body using “submarines” that don’t need external stimulus

An artist’s representation of ‘micro-submarines’ transporting their medical cargo through capillaries among red blood cells. Picture: UNSW

UNSW engineers have shown that micro-submarines powered by nano-motors could navigate the human body to provide targeted drug delivery to diseased organs without the need for external stimulus.

Cancers in the human body may one day be treated by tiny, self-propelled ‘micro-submarines’ delivering medicine to affected organs after UNSW Sydney chemical and biomedical engineers proved it was possible.

In a paper published in Materials Today, the engineers explain how they developed micrometre-sized submarines that exploit biological environments to tune their buoyancy, enabling them to carry drugs to specific locations in the body.

Corresponding author Dr Kang Liang, with both the School of Biomedical Engineering and School of Chemical Engineering at UNSW, says the knowledge can be used to design next generation ‘micro-motors’ or nano-drug delivery vehicles, by applying novel driving forces to reach specific targets in the body.

“We already know that micro-motors use different external driving forces – such as light, heat or magnetic field – to actively navigate to a specific location,” Dr Liang says.

“In this research, we designed micro-motors that no longer rely on external manipulation to navigate to a specific location. Instead, they take advantage of variations in biological environments to automatically navigate themselves.”

What makes these micro-sized particles unique is that they respond to changes in biological pH environments to self-adjust their buoyancy. In the same way that submarines use oxygen or water to flood ballast points to make them more or less buoyant, gas bubbles released or retained by the micro-motors due to the pH conditions in human cells contribute to these nanoparticles moving up or down.

This is significant not just for medical applications, but for micro-motors generally.

“Most micro-motors travel in a 2-dimensional fashion,” Dr Liang says.

“But in this work, we designed a vertical direction mechanism. We combined these two concepts to come up with a design of autonomous micro-motors that move in a 3D fashion. This will enable their ultimate use as smart drug delivery vehicles in the future.”

Dr Liang illustrates a possible scenario where drugs are taken orally to treat a cancer in the stomach or intestines. To give an idea of scale, he says each capsule of medicine could contain millions of micro-submarines, and within each micro-submarine would be millions of drug molecules.

“Imagine you swallow a capsule to target a cancer in the gastrointestinal tract,” he says.

“Once in the gastrointestinal fluid, the micro-submarines carrying the medicine could be released. Within the fluid, they could travel to the upper or bottom region depending on the orientation of the patient.

“The drug-loaded particles can then be internalised by the cells at the site of the cancer. Once inside the cells, they will be degraded causing the release of the drugs to fight the cancer in a very targeted and efficient way.”

For the micro-submarines to find their target, a patient would need to be oriented in such a way that the cancer or ailment being treated is either up or down – in other words, a patient would be either upright or lying down.

Dr Liang says the so-called micro-submarines are essentially composite metal-organic frameworks (MOF)-based micro-motor systems containing a bioactive enzyme (catalase, CAT) as the engine for gas bubble generation. He stresses that he and his colleagues’ research is at the proof-of-concept stage, with years of testing needing to be completed before this could become a reality.

Dr Liang says the research team – comprised of engineers from UNSW, University of Queensland, Stanford University and University of Cambridge – will be also looking outside of medical applications for these new multi-directional nano-motors.

“We are planning to apply this new finding to other types of nanoparticles to prove the versatility of this technique,” he says.

Learn more: ‘Submarines’ small enough to deliver medicine inside human body


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