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A new way to deliver drugs with pinpoint targeting

A new way to deliver drugs with pinpoint targeting

Most pharmaceuticals must either be ingested or injected into the body to do their work. Either way, it takes some time for them to reach their intended targets, and they also tend to spread out to other areas of the body. Now, researchers at MIT and elsewhere have developed a system to deliver medical treatments that can be released at precise times, minimally-invasively, and that ultimately could also deliver those drugs to specifically targeted areas such as a specific group of neurons in the brain.

The new approach is based on the use of tiny magnetic particles enclosed within a tiny hollow bubble of lipids (fatty molecules) filled with water, known as a liposome. The drug of choice is encapsulated within these bubbles, and can be released by applying a magnetic field to heat up the particles, allowing the drug to escape from the liposome and into the surrounding tissue.

The findings are reported today in the journal Nature Nanotechnology in a paper by MIT postdoc Siyuan Rao, Associate Professor Polina Anikeeva, and 14 others at MIT, Stanford University, Harvard University, and the Swiss Federal Institute of Technology in Zurich.

“We wanted a system that could deliver a drug with temporal precision, and could eventually target a particular location,” Anikeeva explains. “And if we don’t want it to be invasive, we need to find a non-invasive way to trigger the release.”

Magnetic fields, which can easily penetrate through the body — as demonstrated by detailed internal images produced by magnetic resonance imaging, or MRI — were a natural choice. The hard part was finding materials that could be triggered to heat up by using a very weak magnetic field (about one-hundredth the strength of that used for MRI), in order to prevent damage to the drug or surrounding tissues, Rao says.

Rao came up with the idea of taking magnetic nanoparticles, which had already been shown to be capable of being heated by placing them in a magnetic field, and packing them into these spheres called liposomes. These are like little bubbles of lipids, which naturally form a spherical double layer surrounding a water droplet.

When placed inside a high-frequency but low-strength magnetic field, the nanoparticles heat up, warming the lipids and making them undergo a transition from solid to liquid, which makes the layer more porous — just enough to let some of the drug molecules escape into the surrounding areas. When the magnetic field is switched off, the lipids re-solidify, preventing further releases. Over time, this process can be repeated, thus releasing doses of the enclosed drug at precisely controlled intervals.

The drug carriers were engineered to be stable inside the body at the normal body temperature of 37 degrees Celsius, but able to release their payload of drugs at a temperature of 42 degrees. “So we have a magnetic switch for drug delivery,” and that amount of heat is small enough “so that you don’t cause thermal damage to tissues,” says Anikeeva, who holds appointments in the departments of Materials Science and Engineering and the Brain and Cognitive Sciences.

In principle, this technique could also be used to guide the particles to specific, pinpoint locations in the body, using gradients of magnetic fields to push them along, but that aspect of the work is an ongoing project. For now, the researchers have been injecting the particles directly into the target locations, and using the magnetic fields to control the timing of drug releases. “The technology will allow us to address the spatial aspect,” Anikeeva says, but that has not yet been demonstrated.

This could enable very precise treatments for a wide variety of conditions, she says. “Many brain disorders are characterized by erroneous activity of certain cells. When neurons are too active or not active enough, that manifests as a disorder, such as Parkinson’s, or depression, or epilepsy.” If a medical team wanted to deliver a drug to a specific patch of neurons and at a particular time, such as when an onset of symptoms is detected, without subjecting the rest of the brain to that drug, this system “could give us a very precise way to treat those conditions,” she says.

Rao says that making these nanoparticle-activated liposomes is actually quite a simple process. “We can prepare the liposomes with the particles within minutes in the lab,” she says, and the process should be “very easy to scale up” for manufacturing. And the system is broadly applicable for drug delivery: “we can encapsulate any water-soluble drug,” and with some adaptations, other drugs as well, she says.

One key to developing this system was perfecting and calibrating a way of making liposomes of a highly uniform size and composition. This involves mixing a water base with the fatty acid lipid molecules and magnetic nanoparticles and homogenizing them under precisely controlled conditions. Anikeeva compares it to shaking a bottle of salad dressing to get the oil and vinegar mixed, but controlling the timing, direction and strength of the shaking to ensure a precise mixing.

Anikeeva says that while her team has focused on neurological disorders, as that is their specialty, the drug delivery system is actually quite general and could be applied to almost any part of the body, for example to deliver cancer drugs, or even to deliver painkillers directly to an affected area instead of delivering them systemically and affecting the whole body. “This could deliver it to where it’s needed, and not deliver it continuously,” but only as needed.

Because the magnetic particles themselves are similar to those already in widespread use as contrast agents for MRI scans, the regulatory approval process for their use may be simplified, as their biological compatibility has largely been proven.

The team included researchers in MIT’s departments of Materials Science and Engineering and Brain and Cognitive Sciences, as well as the McGovern Institute for Brain Research, the Simons Center for Social Brain, and the Research Laboratory of Electronics; the Harvard University Department of Chemistry and Chemical Biology and the John A. Paulsen School of Engineering and Applied Sciences; Stanford University; and the Swiss Federal Institute of Technology in Zurich. The work was supported by the Simons Postdoctoral Fellowship, the U.S. Defense Advanced Research Projects Agency, the Bose Research Grant, and the National Institutes of Health.

Materials provided by Massachusetts Institute of Technology

Culture of rat brain cells

Researchers develop technology to control the brain cells with help of smartphone

A group of researchers in the United States and Korea have invented a device which can control neural circuits with the help of a small brain implant which is controlled by a smartphone. Scientists believe that this device can amplify the efforts to detect brain diseases like Alzheimer’s, Parkinson’s, migraine and depression. With the help of replaceable drug cartridges similar to LEGO and Bluetooth low-energy, this device can target the specific neurons for prolonged periods using drug and light. The study was published in Nature Biomedical Engineering journal.

Raza Qazi, a scientist with Korea Advanced Institute of Science and Technology (KAIST) and University of Colorado Boulder said that the wireless neural device enables optical and chemical neuromodulation which has been achieved for the first time. This technology overshadows the normal methods used by researchers which generally involve optical fibers and metal tubes for delivering light and drugs. It limits the subject’s movement due to physical connections with the heavy equipment and causes a lesion in soft brain tissue due to their rigid structure. Hence they are not suitable for long-term implantation. Efforts were put to mitigate the adverse tissue response with the incorporation of wireless platforms and soft probes however they could not deliver drugs for a prolonged time period.

For achieving chronic wireless drug delivery, researchers had to solve the challenge of evaporation and exhaustion of drugs. They invented a neural device having a replaceable drug cartridge that allowed to study the brain circuits without worrying about the factor of drug exhaustion. These drug cartridges were assembled for brain implantation in mice with an ultrathin probe which had microfluidic channels, LEDs for unlimited light delivery and drug doses.

Researchers controlled it with a user interface on a smartphone and could trigger any combination of light and drug deliveries in any implanted animal without being present in a laboratory. They could also set up automated animal studies where an animal’s behavior could affect other animals’ behavior due to the conditional triggering of drug and light delivery. This revolutionary equipment is possible due to complex electronics design and powerful nanoscale engineering. It would help scientists in several ways. It would also help to dissect the neural circuit basis of behavior and understand how neuromodulators control behavior in several ways. It would also help researchers develop therapeutics for emotional and addiction disorders.

KAIST researchers developed soft electronics for implantable devices and University of Washington scientists study brain circuits which are responsible for addiction, pain, stress. This global collaboration for three years made it possible to develop the powerful brain implant in mice which can speed up the detection of brain diseases. It was supported by grants from the National Research Foundation, Korea, National Institute of Health in the US, National Institute on Drug Abuse.

MIT Nanoemulsions

“Nanoemulsion” gels offer new way to deliver drugs through the skin

MIT chemical engineers have devised a new way to create very tiny droplets of one liquid suspended within another liquid, known as nanoemulsion. Such emulsions are similar to the mixture that forms when you shake an oil-and-vinegar salad dressing, but with much smaller droplets. Their tiny size allows them to remain stable for relatively long periods of time.

The researchers also found a way to easily convert the liquid nanoemulsion to a gel when they reach body temperature (37 degrees Celsius), which could be useful for developing materials that can deliver medication when rubbed on the skin or injected into the body.

“The pharmaceutical industry is hugely interested in nanoemulsions as a way of delivering small molecule therapeutics. That could be topically, through ingestion, or by spraying into the nose, because once you start getting into the size range of hundreds of nanometers you can permeate much more effectively into the skin,” says Patrick Doyle, the Robert T. Haslam Professor of Chemical Engineering and the senior author of the study.

In their new study, which appears in the June 21 issue of Nature Communications, the researchers created nanoemulsions that were stable for more than a year. To demonstrate the emulsions’ potential usefulness for delivering drugs, the researchers showed that they could incorporate ibuprofen into the droplets.

Seyed Meysam Hashemnejad, a former MIT postdoc, is the first author of the study. Other authors include former postdoc Abu Zayed Badruddoza, L’Oréal senior scientist Brady Zarket, and former MIT summer research intern Carlos Ricardo Castaneda.

Energy reduction

One of the easiest ways to create an emulsion is to add energy — by shaking your salad dressing, for example, or using a homogenizer to break down fat globules in milk. The more energy that goes in, the smaller the droplets, and the more stable they are.

Nanoemulsions, which contain droplets with a diameter 200 nanometers or smaller, are desirable not only because they are more stable, but they also have a higher ratio of surface area to volume, which allows them to carry larger payloads of active ingredients such as drugs or sunscreens.

Over the past few years, Doyle’s lab has been working on lower-energy strategies for making nanoemulsions, which could make the process easier to adapt for large-scale industrial manufacturing.

Detergent-like chemicals called surfactants can speed up the formation of emulsions, but many of the surfactants that have previously been used for creating nanoemulsions are not FDA-approved for use in humans. Doyle and his students chose two surfactants that are uncharged, which makes them less likely to irritate the skin, and are already FDA-approved as food or cosmetic additives. They also added a small amount of polyethylene glycol (PEG), a biocompatible polymer used for drug delivery that helps the solution to form even smaller droplets, down to about 50 nanometers in diameter.

“With this approach, you don’t have to put in much energy at all,” Doyle says. “In fact, a slow stirring bar almost spontaneously creates these super small emulsions.”

Active ingredients can be mixed into the oil phase before the emulsion is formed, so they end up loaded into the droplets of the emulsion.

Once they had developed a low-energy way to create nanoemulsions, using nontoxic ingredients, the researchers added a step that would allow the emulsions to be easily converted to gels when they reach body temperature. They achieved this by incorporating heat-sensitive polymers called poloxamers, or Pluronics, which are already FDA-approved and used in some drugs and cosmetics.

Pluronics contain three “blocks” of polymers: The outer two regions are hydrophilic, while the middle region is slightly hydrophobic. At room temperature, these molecules dissolve in water but do not interact much with the droplets that form the emulsion. However, when heated, the hydrophobic regions attach to the droplets, forcing them to pack together more tightly and creating a jelly-like solid. This process happens within seconds of heating the emulsion to the necessary temperature.

MIT chemical engineers have devised a way to convert liquid nanoemulsions into solid gels. These gels (red) form almost instantaneously when drops of the liquid emulsion enter warm water.

MIT chemical engineers have devised a way to convert liquid nanoemulsions into solid gels. These gels (red) form almost instantaneously when drops of the liquid emulsion enter warm water.

Tunable properties

The researchers found that they could tune the properties of the gels, including the temperature at which the material becomes a gel, by changing the size of the emulsion droplets and the concentration and structure of the Pluronics that they added to the emulsion. They can also alter traits such as elasticity and yield stress, which is a measure of how much force is needed to spread the gel.

Doyle is now exploring ways to incorporate a variety of active pharmaceutical ingredients into this type of gel. Such products could be useful for delivering topical medications to help heal burns or other types of injuries, or could be injected to form a “drug depot” that would solidify inside the body and release drugs over an extended period of time. These droplets could also be made small enough that they could be used in nasal sprays for delivering inhalable drugs, Doyle says.

For cosmetic applications, this approach could be used to create moisturizers or other products that are more shelf-stable and feel smoother on the skin.

Materials provided by Massachusetts Institute of Technology