|A team of bioengineers at Brigham and Women’s Hospital (BWH), led by Ali Khademhosseini, PhD, and Nasim Annabi, PhD, of the Biomedical Engineering Division, has developed a new protein-based gel that, when exposed to light, mimics many of the properties of elastic tissue, such as skin and blood vessels. In a paper published in Advanced Functional Materials (“A Highly Elastic and Rapidly Crosslinkable Elastin-Like Polypeptide-Based Hydrogel for Biomedical Applications”), the research team reports on the new material’s key properties, many of which can be finely tuned, and on the results of using the material in preclinical models of wound healing.|
|Bioengineers have developed a new protein-based gel that, when exposed to light, mimics many of the properties of elastic tissue, such as skin and blood vessels. (Courtesy of Nasim Annabi, Brigham and Women’s Hospital)|
|“We are very interested in engineering strong, elastic materials from proteins because so many of the tissues within the human body are elastic. If we want to use biomaterials to regenerate those tissues, we need elasticity and flexibility,” said Annabi, a co-senior author of the study. “Our hydrogel is very flexible, made from a biocompatible polypeptide and can be activated using light.”|
|“Hydrogels – jelly-like materials that can mimic the properties of human tissue – are widely used in biomedicine, but currently available materials have limitations. Some synthetic gels degrade into toxic chemicals over time, and some natural gels are not strong enough to withstand the flow of arterial blood through them,” said Khademhosseini.|
|The new material, known as a photocrosslinkable elastin-like polypeptide-based (ELP) hydrogel, offers several benefits. This elastic hydrogel is formed by using a light-activated polypeptide. When exposed to light, strong bonds form between the molecules of the gel, providing mechanical stability without the need for any chemical modifiers to be added to the material.|
|The team reports that ELP hydrogel can be digested overtime by naturally-occurring enzymes and does not appear to have toxic effects when tested with living cells in the lab. The team also found that they could control how much the material swelled as well its strength, finding that the ELP hydrogel could withstand more stretching than experienced by arterial tissue in the body.|
|“Our hydrogel has many applications: it could be used as a scaffold to grow cells or it can be incorporated with cells in a dish and then injected to stimulate tissue growth,” said Annabi. “In addition, the material can be used as a sealant, sticking to the tissue at the site of injury and creating a barrier over a wound.”|
|The researchers found that it was possible to combine the gel with silica nanoparticles – microscopic particles previously found to stop bleeding – to develop an even more powerful barrier to promote wound healing.|
|“This could allow us to immediately stop bleeding with one treatment,” said Annabi. “We see great potential for use in the clinic. Our method is simple, the material is biocompatible, and we hope to see it solve clinical problems in the future.”|
|Further investigation in pre-clinical models will be needed to test the material’s properties and safety before approval for use in humans.|
|Source: Brigham and Women’s Hospital|
02 Jul 2015
|Instruments that measure the properties of light, known as spectrometers, are widely used in physical, chemical, and biological research. These devices are usually too large to be portable, but MIT scientists have now shown they can create spectrometers small enough to fit inside a smartphone camera, using tiny semiconductor nanoparticles called quantum dots.|
|Such devices could be used to diagnose diseases, especially skin conditions, or to detect environmental pollutants and food conditions, says Jie Bao, a former MIT postdoc and the lead author of a paper describing the quantum dot spectrometers in the July 2 issue of Nature (“A colloidal quantum dot spectrometer”).|
|In this illustration, the Quantum Dot (QD) spectrometer device is printing QD filters — a key fabrication step. Other spectrometer approaches have complicated systems in order to create the optical structures needed. Here in the QD spectrometer approach, the optical structure — QD filters — are generated by printing liquid droplets. This approach is unique and advantageous in terms of flexibility, simplicity, and cost reduction. (Image: Mary O’Reilly)|
|This work also represents a new application for quantum dots, which have been used primarily for labeling cells and biological molecules, as well as in computer and television screens.|
|“Using quantum dots for spectrometers is such a straightforward application compared to everything else that we’ve tried to do, and I think that’s very appealing,” says Moungi Bawendi, the Lester Wolfe Professor of Chemistry at MIT and the paper’s senior author.|
|The earliest spectrometers consisted of prisms that separate light into its constituent wavelengths, while current models use optical equipment such as diffraction gratings to achieve the same effect. Spectrometers are used in a wide variety of applications, such as studying atomic processes and energy levels in physics, or analyzing tissue samples for biomedical research and diagnostics.|
|Replacing that bulky optical equipment with quantum dots allowed the MIT team to shrink spectrometers to about the size of a U.S. quarter, and to take advantage of some of the inherent useful properties of quantum dots.|
|Quantum dots, a type of nanocrystals discovered in the early 1980s, are made by combining metals such as lead or cadmium with other elements including sulfur, selenium, or arsenic. By controlling the ratio of these starting materials, the temperature, and the reaction time, scientists can generate a nearly unlimited number of dots with differences in an electronic property known as bandgap, which determines the wavelengths of light that each dot will absorb.|
|However, most of the existing applications for quantum dots don’t take advantage of this huge range of light absorbance. Instead, most applications, such as labeling cells or new types of TV screens, exploit quantum dots’ fluorescence — a property that is much more difficult to control, Bawendi says. “It’s very hard to make something that fluoresces very brightly,” he says. “You’ve got to protect the dots, you’ve got to do all this engineering.”|
|Scientists are also working on solar cells based on quantum dots, which rely on the dots’ ability to convert light into electrons. However, this phenomenon is not well understood, and is difficult to manipulate.|
|On the other hand, quantum dots’ absorption properties are well known and very stable. “If we can rely on these properties, it is possible to create applications that will have a greater impact in the relative short term,” Bao says.|
|The new quantum dot spectrometer deploys hundreds of quantum dot materials that each filter a specific set of wavelengths of light. The quantum dot filters are printed into a thin film and placed on top of a photodetector such as the charge-coupled devices (CCDs) found in cellphone cameras.|
|The researchers created an algorithm that analyzes the percentage of photons absorbed by each filter, then recombines the information from each one to calculate the intensity and wavelength of the original rays of light.|
|The more quantum dot materials there are, the more wavelengths can be covered and the higher resolution can be obtained. In this case, the researchers used about 200 types of quantum dots spread over a range of about 300 nanometers. With more dots, such spectrometers could be designed to cover an even wider range of light frequencies.|
|“Bawendi and Bao showed a beautiful way to exploit the controlled optical absorption of semiconductor quantum dots for miniature spectrometers. They demonstrate a spectrometer that is not only small, but also with high throughput and high spectral resolution, which has never been achieved before,” says Feng Wang, an associate professor of physics at the University of California at Berkeley who was not involved in the research.|
|If incorporated into small handheld devices, this type of spectrometer could be used to diagnose skin conditions or analyze urine samples, Bao says. They could also be used to track vital signs such as pulse and oxygen level, or to measure exposure to different frequencies of ultraviolet light, which vary greatly in their ability to damage skin.|
|“The central component of such spectrometers — the quantum dot filter array — is fabricated with solution-based processing and printing, thus enabling significant potential cost reduction,” Bao adds.|
|Source: By Anne Trafton, MIT|
24 Jun 2015
The nanowires respond to an electromagnetic field generated by a separate device, which can be used to control the release of a preloaded drug. The system eliminates tubes and wires required by other implantable devices that can lead to infection and other complications, said team leader Richard Borgens, Purdue University’s Mari Hulman George Professor of Applied Neuroscience and director of Purdue’s Center for Paralysis Research.
“This tool allows us to apply drugs as needed directly to the site of injury, which could have broad medical applications,” Borgens said. “The technology is in the early stages of testing, but it is our hope that this could one day be used to deliver drugs directly to spinal cord injuries, ulcerations, deep bone injuries or tumors, and avoid the terrible side effects of systemic treatment with steroids or chemotherapy.”
The team tested the drug-delivery system in mice with compression injuries to their spinal cords and administered the corticosteroid dexamethasone. The study measured a molecular marker of inflammation and scar formation in the central nervous system and found that it was reduced after one week of treatment. A paper detailing the results will be published in an upcoming issue of the Journal of Controlled Release and is currently available online.
IMAGE: An image of a field of polypyrrole nanowires captured by a scanning electron microscope is shown. A team of Purdue University researchers developed a new implantable drug-delivery system using the… view more
Credit: (Purdue University image/courtesy of Richard Borgens)
The nanowires are made of polypyrrole, a conductive polymer material that responds to electromagnetic fields. Wen Gao, a postdoctoral researcher in the Center for Paralysis Research who worked on the project with Borgens, grew the nanowires vertically over a thin gold base, like tiny fibers making up a piece of shag carpet hundreds of times smaller than a human cell. The nanowires can be loaded with a drug and, when the correct electromagnetic field is applied, the nanowires release small amounts of the payload. This process can be started and stopped at will, like flipping a switch, by using the corresponding electromagnetic field stimulating device, Borgens said.
The researchers captured and transported a patch of the nanowire carpet on water droplets that were used used to deliver it to the site of injury. The nanowire patches adhere to the site of injury through surface tension, Gao said.
The magnitude and wave form of the electromagnetic field must be tuned to obtain the optimum release of the drug, and the precise mechanisms that release the drug are not yet well understood, she said. The team is investigating the release process.
The electromagnetic field is likely affecting the interaction between the nanomaterial and the drug molecules, Borgens said.
“We think it is a combination of charge effects and the shape change of the polymer that allows it to store and release drugs,” he said. “It is a reversible process. Once the electromagnetic field is removed, the polymer snaps back to the initial architecture and retains the remaining drug molecules.”
For each different drug the team would need to find the corresponding optimal electromagnetic field for its release, Gao said.
This study builds on previous work by Borgens and Gao. Gao first had to figure out how to grow polypyrrole in a long vertical architecture, which allows it to hold larger amounts of a drug and extends the potential treatment period. The team then demonstrated it could be manipulated to release dexamethasone on demand. A paper detailing the work, titled “Action at a Distance: Functional Drug Delivery Using Electromagnetic-Field-Responsive Polypyrrole Nanowires,” was published in the journal Langmuir.
Other team members involved in the research include John Cirillo, who designed and constructed the electromagnetic field stimulating system; Youngnam Cho, a former faculty member at Purdue’s Center for Paralysis Research; and Jianming Li, a research assistant professor at the center.
For the most recent study the team used mice that had been genetically modified such that the protein Glial Fibrillary Acidic Protein, or GFAP, is luminescent. GFAP is expressed in cells called astrocytes that gather in high numbers at central nervous system injuries. Astrocytes are a part of the inflammatory process and form a scar tissue, Borgens said.
A 1-2 millimeter patch of the nanowires doped with dexamethasone was placed onto spinal cord lesions that had been surgically exposed, Borgens said. The lesions were then closed and an electromagnetic field was applied for two hours a day for one week. By the end of the week the treated mice had a weaker GFAP signal than the control groups, which included mice that were not treated and those that received a nanowire patch but were not exposed to the electromagnetic field. In some cases, treated mice had no detectable GFAP signal.
Whether the reduction in astrocytes had any significant impact on spinal cord healing or functional outcomes was not studied. In addition, the concentration of drug maintained during treatment is not known because it is below the limits of systemic detection, Borgens said.
“This method allows a very, very small dose of a drug to effectively serve as a big dose right where you need it,” Borgens said. “By the time the drug diffuses from the site out into the rest of the body it is in amounts that are undetectable in the usual tests to monitor the concentration of drugs in the bloodstream.”
Polypyrrole is an inert and biocompatable material, but the team is working to create a biodegradeable form that would dissolve after the treatment period ended, he said.
The team also is trying to increase the depth at which the drug delivery device will work. The current system appears to be limited to a depth in tissue of less than 3 centimeters, Gao said.
- Wen Gao, Richard Ben Borgens. Remote-controlled eradication of astrogliosis in spinal cord injury via electromagnetically-induced dexamethasone release from “smart” nanowires. Journal of Controlled Release, 2015; 211: 22 DOI: 10.1016/j.jconrel.2015.05.266
12 Jun 2015
Cornell Univ. engineers have created a functional, synthetic immune organ that produces antibodies and can be controlled in the lab, completely separate from a living organism. The engineered organ has implications for everything from rapid production of immune therapies to new frontiers in cancer or infectious disease research.
The immune organoid was created in the lab of Ankur Singh, assistant professor of mechanical and aerospace engineering, who applies engineering principles to the study and manipulation of the human immune system. The work was published online in Biomaterials and will appear later in print.
The synthetic organ is bio-inspired by secondary immune organs like the lymph node or spleen. It is made from gelatin-based biomaterials reinforced with nanoparticles and seeded with cells, and it mimics the anatomical microenvironment of lymphoid tissue. Like a real organ, the organoid converts B cells—which make antibodies that respond to infectious invaders—into germinal centers, which are clusters of B cells that activate, mature and mutate their antibody genes when the body is under attack. Germinal centers are a sign of infection and are not present in healthy immune organs.
The engineers have demonstrated how they can control this immune response in the organ and tune how quickly the B cells proliferate, get activated and change their antibody types. According to their paper, their 3-D organ outperforms existing 2-D cultures and can produce activated B cells up to 100 times faster.
The immune organ, made of a hydrogel, is a soft, nanocomposite biomaterial. The engineers reinforced the material with silicate nanoparticles to keep the structure from melting at the physiologically relevant temperature of 98.6 degrees.
When exposed to a foreign agent, such as an immunogenic protein, B cells in lymphoid organs undergo germinal center reactions. The image on the left is an immunized mouse spleen with activated B cells (brown) that produce antibodies. At right, top: a scanning electron micrograph of porous synthetic immune organs that enable rapid proliferation and activation of B cells into antibody-producing cells. At right, bottom: primary B cell viability and distribution is visible 24 hrs following encapsulation procedure. Images: Singh lab
The organ could lead to increased understanding of B cell functions, an area of study that typically relies on animal models to observe how the cells develop and mature.
What’s more, Singh said, the organ could be used to study specific infections and how the body produces antibodies to fight those infections—from Ebola to HIV.
“You can use our system to force the production of immunotherapeutics at much faster rates,” he said. Such a system also could be used to test toxic chemicals and environmental factors that contribute to infections or organ malfunctions.
The process of B cells becoming germinal centers is not well understood, and in fact, when the body makes mistakes in the genetic rearrangement related to this process, blood cancer can result.
“In the long run, we anticipate that the ability to drive immune reaction ex vivo at controllable rates grants us the ability to reproduce immunological events with tunable parameters for better mechanistic understanding of B cell development and generation of B cell tumors, as well as screening and translation of new classes of drugs,” Singh said.
Source: Cornell Univ.
With its high electrical conductivity, ability to store energy, and ultra-strong and lightweight structure, graphene has potential for many applications in electronics, energy, the environment, and even medicine.
Now a team of Northwestern University researchers has found a way to print three-dimensional structures with graphene nanoflakes. The fast and efficient method could open up new opportunities for using graphene printed scaffolds regenerative engineering and other electronic or medical applications.
Led by Ramille Shah, assistant professor of materials science and engineering at Northwestern’s McCormick School of Engineering and of surgery in the Feinberg School of Medicine, and her postdoctoral fellow Adam Jakus, the team developed a novel graphene-based ink that can be used to print large, robust 3-D structures.
“People have tried to print graphene before,” Shah said. “But it’s been a mostly polymer composite with graphene making up less than 20 percent of the volume.”
With a volume so meager, those inks are unable to maintain many of graphene’s celebrated properties. But adding higher volumes of graphene flakes to the mix in these ink systems typically results in printed structures too brittle and fragile to manipulate. Shah’s ink is the best of both worlds. At 60-70 percent graphene, it preserves the material’s unique properties, including its electrical conductivity. And it’s flexible and robust enough to print robust macroscopic structures. The ink’s secret lies in its formulation: the graphene flakes are mixed with a biocompatible elastomer and quickly evaporating solvents.
“It’s a liquid ink,” Shah explained. “After the ink is extruded, one of the solvents in the system evaporates right away, causing the structure to solidify nearly instantly. The presence of the other solvents and the interaction with the specific polymer binder chosen also has a significant contribution to its resulting flexibility and properties. Because it holds its shape, we are able to build larger, well-defined objects.”
Supported by a Google Gift and a McCormick Research Catalyst Award, the research is described in the paper “Three-dimensional printing of high-content graphene scaffolds for electronic and biomedical applications,” published in the April 2015 issue of ACS Nano. Jakus is the paper’s first author. Mark Hersam, the Bette and Neison Harris Chair in Teaching Excellence, professor of materials science and engineering at McCormick, served as coauthor.
An expert in biomaterials, Shah said 3-D printed graphene scaffolds could play a role in tissue engineering and regenerative medicine as well as in electronic devices. Her team populated one of the scaffolds with stem cells to surprising results. Not only did the cells survive, they divided, proliferated, and morphed into neuron-like cells.
“That’s without any additional growth factors or signaling that people usually have to use to induce differentiation into neuron-like cells,” Shah said. “If we could just use a material without needing to incorporate other more expensive or complex agents, that would be ideal.”
The printed graphene structure is also flexible and strong enough to be easily sutured to existing tissues, so it could be used for biodegradable sensors and medical implants. Shah said the biocompatible elastomer and graphene’s electrical conductivity most likely contributed to the scaffold’s biological success.
“Cells conduct electricity inherently — especially neurons,” Shah said. “So if they’re on a substrate that can help conduct that signal, they’re able to communicate over wider distances.”
The graphene-based ink directly follows work that Shah and her graduate student Alexandra Rutz completed earlier in the year to develop more cell-compatible, water-based, printable gels. As chronicled in a paper published in the January 2015 issue of Advanced Materials, Shah’s team developed 30 printable bioink formulations, all of which are compatible materials for tissues and organs. These inks can print 3-D structures that could potentially act as the starting point for more complex organs.
“There are many different tissue types, so we need many types of inks,” Shah said. “We’ve expanded that biomaterial tool box to be able to optimize more mimetic engineered tissue constructs using 3-D printing.”
- Adam E. Jakus, Ethan B. Secor, Alexandra L. Rutz, Sumanas W. Jordan, Mark C. Hersam, Ramille N. Shah. Three-Dimensional Printing of High-Content Graphene Scaffolds for Electronic and Biomedical Applications. ACS Nano, 2015; 9 (4): 4636 DOI: 10.1021/acsnano.5b01179
The latest version of a microfluidic device for capturing rare circulating tumor cells (CTCs) is the first designed specifically to capture clusters of two or more cells, rather than single cells. The new device, called the Cluster-Chip, was developed by the same Massachusetts General Hospital (MGH) research team that created previous microchip-based devices. Recent studies by MGH investigators and others have suggested that CTC clusters are significantly more likely to cause metastases than single circulating tumor cells.
13 May 2015
Photoacoustic imaging is a ground-breaking technique for spotting tumors inside living cells with the help of light-absorbing compounds known as contrast agents. A*STAR researchers have now discovered a way to improve the targeting efficacy and optical activity of breast-cancer-specific contrast agents using conjugated polymer nanoparticles.
Generating photoacoustic signals requires an ultrafast laser pulse to irradiate a small area of tissue. This sets off a series of molecular vibrations that produce ultrasonic sound waves in the sample. By ‘listening’ to the pressure differences created by the acoustic waves, researchers can reconstruct and visualize the inner structures of complex objects such as the brain and cardiovascular systems.
Diagnosing cancer with photoacoustic imaging requires contrast agents that deeply penetrate tissue and selectively bind to malignant cells. In addition, they need a high optical response to near-infrared laser light, a spectral region that is particularly safe to biological materials. Traditional contrast agents have been based on gold and silver nanostructures, but the complex chemical procedures needed to optically tune these nanocompounds have left researchers looking for alternatives.
Photoacoustic imaging of model breast cancer cells in mice reveals that a polymer-based contrast agent can illuminate tumor sites within one hour. Credit: Dove Medical Press Limited
Malini Olivo and her colleagues from the A*STAR Singapore Bioimaging Consortium and the A*STAR Institute of Materials Research and Engineering investigated different contrast agents based on conjugated polymers. These organic macromolecules, which contain alternating double and single carbon bonds, have delocalized electrons in their frameworks that can produce useful optical properties such as photoluminescence. The researchers identified a conjugated polymer known as PFTTQ—a compound with multiple aromatic rings, alkyl chains, sulfur and nitrogen atoms—as a promising in vivo photoacoustic agent because of its biocompatible structure and light absorption that peaks in the near-infrared range.
To direct this contrast agent to cancer cells, the team synthesized ‘dot’-like nanostructures with an inner core of PFTTQ surrounded by water-soluble polyethylene glycol chains, terminated by an outer layer of folate molecules—a vitamin that specifically binds to folate receptor proteins commonly expressed by breast cancer tumors. Experiments with MCF-7 model breast cancer cells implanted in mice revealed the merits of this approach: in just one hour after administering the folate–conjugated polymer dots, strong photoacoustic signals emerged from the tumor positions. The folate functionality played a critical role in this bioimaging procedure, quadrupling the photoacoustic signals compared to unmodified PFTTQ dots.
“The folate–PFTTQ nanoparticles have great potential for diagnostic imaging and other biomedical applications,” says Olivo. “We are working to expand the library of biocompatible polymers to use as molecular photoacoustic contrast agents.”
More information: “Molecular photoacoustic imaging of breast cancer using an actively targeted conjugated polymer.” International Journal of Nanomedicine 10, 387–397 (2015). dx.doi.org/10.2147/IJN.S73558
08 May 2015
Summary: Some substances, when they undergo a process called ‘rapid-freezing’ or ‘supercooling,’ remain in liquid form — even at below-freezing temperatures. A new study is the first to break down the rules governing the complex process of crystallization through rapid-cooling.
Its findings may revolutionize the delivery of drugs in the human body, providing a way to ‘freeze’ the drugs at an optimal time and location in the body.
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 University 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 Department 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
“We describe a supercooled material as ‘metastable,’ meaning it is very sensitive to any external perturbation that may transform it back to its stable low-temperature state,” Dr. Beck said. “We discovered in our study that it is possible to control the process and harness the advantages of the fluid/not-fluid transition to design a precise and effective nanoscale drug encapsulating system.”
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
The researchers found that the membranes were able to remain stable for tens of hours before collectively crystallizing at a predetermined time.
“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.
- Guy Jacoby, Keren Cohen, Kobi Barkan, Yeshayahu Talmon, Dan Peer, Roy Beck. Metastability in lipid based particles exhibits temporally deterministic and controllable behavior. Scientific Reports, 2015; 5: 9481 DOI: 10.1038/srep09481
08 May 2015
But because the blood containing the drug travels all round your body only a small percentage of the initial dose actually reaches the desired location.
For over-the-counter drugs like paracetamol or ibuprofen, with very few side-effects, this doesn’t matter too much.
But when it comes to cancer drugs, which can affect healthy cells just as much as cancer cells, this process can cause big problems.
Partly because drugs are diluted in their blood, cancer patients need to take these drugs in particularly high doses – and this can cause seriously unpleasant side effects.
But Professor Sonia Trigueros, co-director of the Oxford Martin Programme on Nanotechnology, is inching closer to developing a nano-scale drug delivery system with the aim of specifically targeting cancer cells.
Working with a team of chemists, engineers and physicists, Trigueros has embarked on an ambitious mission to tackle cancer at the ‘nano’ level – less than 100 nanometers wide. For context, this is super-tiny: a nanometre is a thousandth of a thousandth of a millimetre.
There’s still a long way to go, but Trigueros is making decent headway, and has recently tackled a major problem of working at a nano level. And at this year’s Wired Health conference – which looked at the future of health care, wellbeing and genomics – she told us about her recent progress, and her visions for the future.
At the nano level
Some of us will remember the periodic table displayed in our science classrooms which told us about the properties of each element. But working on a nano level everything changes, and elements behave completely differently.
Elements have different properties at the nano level than they do at the micro level, explained Prof Trigueros to the Wired Health 2015 audience.
This poses big problems for researchers trying to make nano-scale devices, which can be made out of a number of different materials, including gold, silver and carbon. All these materials are highly unstable at the nano level.
“After you make the nanostructures you only have minutes to a couple of days to work,” she said. They are really unstable, especially when you put them in water.”
This isn’t ideal, considering our bodies are made up mostly of water.
Trigueros’ recent work has focused on trying to stabilise tiny tubes made of carbon, called carbon nanotubes, which hold drugs inside the tube so they can be delivered into cancer cells.
She has now found a way of keeping them stable for more than two years and in temperatures up to 42ºC.
To do this, she wraps DNA around the structures, like a tortilla wraps around the fillings of a burrito.
While this accomplishes the goal of keeping the nanostructures stable inside the body this doesn’t do much good if the DNA can’t unwrap to deliver the drugs. But, according to Trigueros, she has shown that, once inside a cell, the DNA easily unwinds and releases its payload.
Truly targeted drug delivery
So how does it all work? How do the drugs get into the cancer cells? Trigueros’s nanotubes exploit the differences between cancer cells and healthy cells – in this case, differences in the membranes that hold them together.
“Cancer cells are more permeable than normal cells so the nanotubes can get through the cell membrane. And once they are in, they unwrap and deliver drug,” explained Trigueros.
Exploiting differences in their permeability is one way to target the cancer cells, but Trigueros explains that there is more than one way to create a truly targeted drug delivery system.
“We can attach whatever we want on DNA,” she said. “So you can attach a protein that recognises cancer cells”.
From theory to reality
While this all sounds great in theory, will it actually work in reality?
Trigueros has now started preliminary tests on laboratory grown lung cancer cells, she told us during an interview. And this has shown tentative promise, she says, citing unpublished data on their effectiveness at killing these cells in the lab.
Others are cautiously optimistic. “This is a really exciting prospect,” says Professor Duncan Graham, nanotechnology expert and advisor to Cancer Research UK.
“A common concern with carbon nanotubes is toxicity, but when coated with DNA this concern could be removed,” he explains, “and it also addresses a fundamental issue, which is that they collect into clusters that become a solid mass and so are unable to leave the body.”
In theory, once Trigueros’s nanotubes have finished their job they are tiny enough (50 nanometres) to be excreted through urine.
This isn’t the first time carbon nanotubes have been used in cancer research: a US research team has used them, for example, to target and collect images of tumours in mice. But the combination of drug delivery and cancer-specific targeting is what interests Professor Graham.
“Unlike previous work using carbon nanotubes, this approach is set to target the tumour specifically, potentially meaning fewer side effects and a lower dosage. I look forward to seeing this in animal models which is where the real proof of activity lies,” he said.
But he’s cautious, stressing that Trigueros’s work has not yet been peer-reviewed and published.
Next Trigueros is aiming towards starting animal trials and, eventually, she wants to begin clinical trials in patients – that is if everything goes well.
She hopes to focus on how nanostructures could be used to cross the blood-brain barrier – the brain’s highly selective ‘bouncer’ that only lets certain molecules across. This has been notoriously difficult to get past, making targeting cancers in the brain more difficult.
But there is a still a long way to go and a lot of problems to tackle. In the shorter term, we’ll be keeping an eager eye on her drug delivery research, as her ideas continue to develop.
Explore further: Nano packages for anti-cancer drug delivery
30 Apr 2015
The group works with the precious metal to create nanoscale silver clusters with unique fluorescent properties. These properties are important for a variety of sensing applications including biomedical imaging.
The team’s latest research is published in a featured article in this month’s issue of ACS Nano, a journal of the American Chemical Society. The scientists positioned silver clusters at programmed sites on a nanoscale breadboard, a construction base for prototyping of photonics and electronics. “Our ‘breadboard’ is a DNA nanotube with spaces programmed 7 nanometers apart,” said lead author Stacy Copp, a graduate student in UCSB’s Department of Physics.
“Due to the strong interactions between DNA and metal atoms, it’s quite challenging to design DNA breadboards that keep their desired structure when these new interactions are introduced,” said Gwinn, a professor in UCSB’s Department of Physics. “Stacy’s work has shown that not only can the breadboard keep its shape when silver clusters are present, it can also position arrays of many hundreds of clusters containing identical numbers of silver atoms — a remarkable degree of control that is promising for realizing new types of nanoscale photonics.”
The results of this novel form of DNA nanotechnology address the difficulty of achieving uniform particle sizes and shapes. “In order to make photonic arrays using a self-assembly process, you have to be able to program the positions of the clusters you are putting on the array,” Copp explained. “This paper is the first demonstration of this for silver clusters.”
The colors of the clusters are largely determined by the DNA sequence that wraps around them and controls their size. To create a positionable silver cluster with DNA-programmed color, the researchers engineered a piece of DNA with two parts: one that wraps around the cluster and the other that attaches to the DNA nanotube. “Sticking out of the nanotube are short DNA strands that act as docking stations for the silver clusters’ host strands,” Copp explained.
The research group’s team of graduate and undergraduate researchers is able to tune the silver clusters to fluoresce in a wide range of colors, from blue-green all the way to the infrared — an important achievement because tissues have windows of high transparency in the infrared. According to Copp, biologists are always looking for better dye molecules or other infrared-emitting objects to use for imaging through a tissue.
“People are already using similar silver cluster technologies to sense mercury ions, small pieces of DNA that are important for human diseases, and a number of other biochemical molecules,” Copp said. “But there’s a lot more you can learn by putting the silver clusters on a breadboard instead of doing experiments in a test tube. You get more information if you can see an array of different molecules all at the same time.”
The modular design presented in this research means that its step-by-step process can be easily generalized to silver clusters of different sizes and to many types of DNA scaffolds. The paper walks readers through the process of creating the DNA that stabilizes silver clusters. This newly outlined protocol offers investigators a new degree of control and flexibility in the rapidly expanding field of nanophotonics.
The overarching theme of Copp’s research is to understand how DNA controls the size and shape of the silver clusters themselves and then figure out how to use the fact that these silver clusters are stabilized by DNA in order to build nanoscale arrays.
“It’s challenging because we don’t really understand the interactions between silver and DNA just by itself,” Copp said. “So part of what I’ve been doing is using big datasets to create a bank of working sequences that we’ve published so other scientists can use them. We want to give researchers tools to design these types of structures intelligently instead of just having to guess.”
The paper’s acknowledgements include a dedication to “those students who lost their lives in the Isla Vista tragedy and to the courage of the first responders, whose selfless actions saved many lives.”