Curtin researchers have developed a tiny electrical circuit that may enable an entirely new design of digital devices.
The electrical circuit is made from crystals of copper that are grown and electrically wired at nanoscale and may lead to digital devices that have increasing amounts of computational power packed into a smaller space.
In a paper published today in the leading nanotechnology journal ACS Nano, researchers used a single nanoparticle to create an ensemble of different diodes – a basic electronic component of most modern electronic devices, which functions by directing the flow of electric currents.
Lead researcher Ph.D. candidate Yan Vogel, from Curtin’s School of Molecular and Life Sciences and the Curtin Institute for Functional Molecules and Interfaces, said the research team used a single copper nanoparticle to compress in a single physical entity that would normally require many individual diode elements.
Mr Vogel said the research showed that each nanoparticle had an in-built range of electrical signatures and had led to something akin to ‘one particle, many diodes’, thereby opening up the concept of single-particle circuitry.
Mr Vogel said the breakthrough would enable new concepts and methods in the design of miniaturised circuitry.
“Instead of wiring-up a large number of different sorts of diodes, as is done now, we have shown that the same outcome is obtained by many wires landing accurately over a single physical entity, which in our case is a copper nanocrystal,” Mr Vogel said.
Team leader Dr. Simone Ciampi, also from Curtin’s School of Molecular and Life Sciences and the Curtin Institute for Functional Molecules and Interfaces, said the new research followed that published by himself and his Curtin colleague Dr. Nadim Darwish in 2017, when they created a diode out of a single-molecule, with a size of approximately 1 nanometer, and would help to continue the downsizing trend of electronic devices.
“Last year, we made a breakthrough in terms of the size of the diode and now we are building on that work by developing more tuneable diodes, which can potentially be used to make more powerful and faster-thinking electronic devices,” Dr. Ciampi said.
“Current technology is reaching its limit and molecular or nanoparticle diodes and transistors are the only way that we can continue the improvement of computer performances. We are trying to contribute to the development of the inevitable next generation of electronics.”
This research was co-authored by Dr. Darwish and Ms. Jinyang Zhang, also from Curtin’s School of Molecular and Life Sciences and the Curtin Institute for Functional Molecules and Interfaces.
A team of material researchers has succeeded in producing a composite material that is particularly suited for electrodes in lithium batteries. The nanocomposite material might help to significantly increase the storage capacity and lifetime of batteries as well as their charging speed.
Lithium-ion batteries are the ultimate benchmark when it comes to mobile phones, tablet devices, and electric cars. Their storage capacity and power density are far superior to other rechargeable battery systems. Despite all the progress that has been made, however, smartphone batteries only last a day and electric cars need hours to be recharged. Scientists are therefore working on ways to improve the power densities and charging rates of all-round batteries. “An important factor is the anode material,” explains Dina Fattakhova-Rohlfing from the Institute of Energy and Climate Research (IEK-1).
“In principle, anodes based on tin dioxide can achieve much higher specific capacities, and therefore store more energy, than the carbon anodes currently being used. They have the ability to absorb more lithium ions,” says Fattakhova-Rohlfing. “Pure tin oxide, however, exhibits very weak cycle stability — the storage capability of the batteries steadily decreases and they can only be recharged a few times. The volume of the anode changes with each charging and discharging cycle, which leads to it crumbling.”
One way of addressing this problem is hybrid materials or nanocomposites — composite materials that contain nanoparticles. The scientists developed a material comprising tin oxide nanoparticles enriched with antimony, on a base layer of graphene. The graphene basis aids the structural stability and conductivity of the material. The tin oxide particles are less than three nanometres in size — in other words less than three millionths of a millimetre — and are directly “grown” on the graphene. The small size of the particle and its good contact with the graphene layer also improves its tolerance to volume changes — the lithium cell becomes more stable and lasts longer.
Three times more energy in one hour
“Enriching the nanoparticles with antimony ensures the material is extremely conductive,” explains Fattakhova-Rohlfing. “This makes the anode much quicker, meaning that it can store one-and-a-half times more energy in just one minute than would be possible with conventional graphite anodes. It can even store three times more energy for the usual charging time of one hour.”
“Such high energy densities were only previously achieved with low charging rates,” says Fattakhova-Rohlfing. “Faster charging cycles always led to a quick reduction in capacity.” The antimony-doped anodes developed by the scientists, however, retain 77 % of their original capacity even after 1,000 cycles.
“The nanocomposite anodes can be produced in an easy and cost-effective way. And the applied concepts can also be used for the design of other anode materials for lithium-ion batteries,” explains Fattakhova-Rohlfing. “We hope that our development will pave the way for lithium-ion batteries with a significantly increased energy density and very short charging time.”
Florian Zoller, Kristina Peters, Peter M. Zehetmaier, Patrick Zeller, Markus Döblinger, Thomas Bein, Zdeneˇk Sofer, Dina Fattakhova-Rohlfing. Making Ultrafast High-Capacity Anodes for Lithium-Ion Batteries via Antimony Doping of Nanosized Tin Oxide/Graphene Composites. Advanced Functional Materials, 2018; 28 (23): 1706529 DOI: 10.1002/adfm.201706529
Bioengineers may be able to use the unique mechanical properties of diseased cells, such as metastatic cancer cells, to help improve delivery of drug treatments to the targeted cells, according to a team of researchers at Penn State.
Many labs around the world are developing nanoparticle-based,drug delivery systems to selectively target tumors. They rely on a key-and-lock system in which protein keys on the surface of the nanoparticle click into the locks of a highly expressed protein on the surface of the cancer cell. The cell membrane then wraps around the nanoparticle and ingests it. If enough of the nanoparticles and their drug cargo is ingested, the cancer cell will die.
The adhesive force of the lock and key is what drives the nanoparticle into the cell, said Sulin Zhang, professor of engineering science and mechanics.
“It is almost universal that whenever there is a driving force for a process, there always is a resistive force,” Zhang said. “Here, the driving force is biochemical—the protein-protein interaction.”
The resistive force is the mechanical energy cost required for the membrane to wrap around the nanoparticle. Until now, bioengineers only considered the driving force and designed nanoparticles to optimize the chemical interactions, a targeting strategy called “chemotargeting.” Zhang believes they should also take into account the mechanics of the cells to design nanoparticles to achieve enhanced targeting, which forms a new targeting strategy called “mechanotargeting.”
“These two targeting strategies are complementary; you can combine chemotargeting and mechanotargeting to achieve the full potential of nanoparticle-based diagnostic and therapeutic agents,” Zhang said. “The fact is that targeting efficiency requires a delicate balance between driving and resistive forces. For instance, if there are too many keys on the nanoparticle surface, even though these keys only weakly interact with the nonmatching locks on normal cells, these weak, off-target interactions may still provide enough adhesion energy for the nanoparticles to penetrate the cell membrane and kill the healthy cells.”
On the other hand, if the adhesion energy is not high enough, the nanoparticle won’t get into the cell.
In “Mechanotargeting: Mechanics-dependent Cellular Uptake of Nanoparticles,” published online ahead of print in the journal Advanced Materials, Zhang and the team report the results of experiments on cancer cells grown on hydrogels of variable stiffness. On soft hydrogels the cells remained cohesive and benign and experienced a nearly constant stress that limited the uptake of the nanoparticles. But on stiff hydrogels the cells became metastatic and adopted a three-dimensional shape, offering more surface area for nanoparticles to adhere, and became less stressed. Under this condition, the cells took up five times the number of nanoparticles as the benign cells.
“The nanoparticles are fluorescent, so we count the number of nanoparticles that get into the cell by the fluorescence intensity. We found that in the malignant cells the intensity is five times higher,” Zhang said. “That proves that mechanotargeting works.”
Researchers have developed a process for creating ultrathin, self-assembling sheets of synthetic materials that can function like designer flypaper in selectively binding with viruses, bacteria, and other pathogens.
In this way the new platform, developed by a team led by scientists at the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab), could potentially be used to inactivate or detect pathogens.
The team, which also included researchers from New York University, created the synthesized nanosheets at Berkeley Lab’s Molecular Foundry, a nanoscale science center, out of self-assembling, bio-inspired polymers known as peptoids. The study was published earlier this month in the journal ACS Nano.
The sheets were designed to present simple sugars in a patterned way along their surfaces, and these sugars, in turn, were demonstrated to selectively bind with several proteins, including one associated with the Shiga toxin, which causes dysentery. Because the outside of our cells are flat and covered with sugars, these 2-D nanosheets can effectively mimic cell surfaces.
“It’s not just a ‘lock and key’ – it’s like Velcro, with a bunch of little loops that converge on the target protein together,” said Ronald Zuckermann, a scientist at the Molecular Foundry who led the study. “Now we can mimic a nanoscale feature that is ubiquitous in biology.”
He noted that numerous pathogens, from the flu virus to cholera bacteria, bind to sugars on cell surfaces. So picking the right sugars to bind to the peptoid nanosheets, in the right distributions, can determine which pathogens will be drawn to them.
“The chemistry we’re doing is very modular,” Zuckermann added. “We can ‘click on’ different sugars, and present them on a well-defined, planar surface. We can control how far apart they are from each other. We can do this with pretty much any sugar.”
The peptoid platform is also more rugged and stable compared to natural biomolecules, he said, so it can potentially be deployed into the field for tests of bioagents by military personnel and emergency responders, for example.
And peptoids – an analog to peptides in biology that are chains of amino acids – are cheap and easy-to-make polymers.
“The chemical information that instructs the molecules to spontaneously assemble into the sugar-coated sheets is programmed into each molecule during its synthesis,” Zuckermann said. “This work demonstrates our ability to readily engineer sophisticated biomimetic nanostructures by direct control of the polymer sequence.”
The sugar-coated nanosheets are made in a liquid solution. Zuckermann said if the nanosheets are used to protect someone from becoming exposed to a pathogen, he could envision the use of a nasal spray containing the pathogen-binding nanosheets.
The nanosheets could also potentially be used in environmental cleanups to neutralize specific toxins and pathogens, and the sheets could potentially be scaled to target viruses like Ebola and bacteria like E. coli, and other pathogens.
In the latest study, the researchers confirmed that the bindings with the targeted proteins were successful by embedding a fluorescent dye in the sheets and attaching another fluorescent dye on the target proteins. A color change indicated that a protein was bound to the nanosheet.
The intensity of this color change can also guide researchers to improve them, and to discover new nanosheets that could target specific pathogens.
Imagine that instead of switching on a lamp when it gets dark, you could read by the light of a glowing plant on your desk.
MIT engineers have taken a critical first step toward making that vision a reality. By embedding specialized nanoparticles into the leaves of a watercress plant, they induced the plants to give off dim light for nearly four hours. They believe that, with further optimization, such plants will one day be bright enough to illuminate a workspace.
“The vision is to make a plant that will function as a desk lamp—a lamp that you don’t have to plug in. The light is ultimately powered by the energy metabolism of the plant itself,” says Michael Strano, the Carbon P. Dubbs Professor of Chemical Engineering at MIT and the senior author of the study.
This technology could also be used to provide low-intensity indoor lighting, or to transform trees into self-powered streetlights, the researchers say.
MIT postdoc Seon-Yeong Kwak is the lead author of the study, which appears in the journal Nano Letters.
Plant nanobionics, a new research area pioneered by Strano’s lab, aims to give plants novel features by embedding them with different types of nanoparticles. The group’s goal is to engineer plants to take over many of the functions now performed by electrical devices. The researchers have previously designed plants that can detect explosives and communicate that information to a smartphone, as well as plants that can monitor drought conditions.
Lighting, which accounts for about 20 percent of worldwide energy consumption, seemed like a logical next target. “Plants can self-repair, they have their own energy, and they are already adapted to the outdoor environment,” Strano says. “We think this is an idea whose time has come. It’s a perfect problem for plant nanobionics.”
To create their glowing plants, the MIT team turned to luciferase, the enzyme that gives fireflies their glow. Luciferase acts on a molecule called luciferin, causing it to emit light. Another molecule called co-enzyme A helps the process along by removing a reaction byproduct that can inhibit luciferase activity.
The MIT team packaged each of these three components into a different type of nanoparticle carrier. The nanoparticles, which are all made of materials that the U.S. Food and Drug Administration classifies as “generally regarded as safe,” help each component get to the right part of the plant. They also prevent the components from reaching concentrations that could be toxic to the plants.
The researchers used silica nanoparticles about 10 nanometers in diameter to carry luciferase, and they used slightly larger particles of the polymers PLGA and chitosan to carry luciferin and coenzyme A, respectively. To get the particles into plant leaves, the researchers first suspended the particles in a solution. Plants were immersed in the solution and then exposed to high pressure, allowing the particles to enter the leaves through tiny pores called stomata.
Particles releasing luciferin and coenzyme A were designed to accumulate in the extracellular space of the mesophyll, an inner layer of the leaf, while the smaller particles carrying luciferase enter the cells that make up the mesophyll. The PLGA particles gradually release luciferin, which then enters the plant cells, where luciferase performs the chemical reaction that makes luciferin glow.
The researchers’ early efforts at the start of the project yielded plants that could glow for about 45 minutes, which they have since improved to 3.5 hours. The light generated by one 10-centimeter watercress seedling is currently about one-thousandth of the amount needed to read by, but the researchers believe they can boost the light emitted, as well as the duration of light, by further optimizing the concentration and release rates of the components.
Previous efforts to create light-emitting plants have relied on genetically engineering plants to express the gene for luciferase, but this is a laborious process that yields extremely dim light. Those studies were performed on tobacco plants and Arabidopsis thaliana, which are commonly used for plant genetic studies. However, the method developed by Strano’s lab could be used on any type of plant. So far, they have demonstrated it with arugula, kale, and spinach, in addition to watercress.
For future versions of this technology, the researchers hope to develop a way to paint or spray the nanoparticles onto plant leaves, which could make it possible to transform trees and other large plants into light sources.
“Our target is to perform one treatment when the plant is a seedling or a mature plant, and have it last for the lifetime of the plant,” Strano says. “Our work very seriously opens up the doorway to streetlamps that are nothing but treated trees, and to indirect lighting around homes.”
The researchers have also demonstrated that they can turn the light off by adding nanoparticles carrying a luciferase inhibitor. This could enable them to eventually create plants that shut off their light emission in response to environmental conditions such as sunlight, the researchers say.
Source: National Institute of Biomedical Imaging and Bioengineering
Summary: Researchers have developed a synergistic cancer nanovaccine packing DNA and RNA sequences that modulate the immune response, along with anti-tumor antigens, into one small nanoparticle.
(Above) Large particles (left) containing the DNA and RNA components are coated with electronically charged molecules that shrink the particle. The tumor-specific neoantigen is then complexed with the surface to complete construction of the nanovaccine. Upper left: electron micrograph of large particle. Credit: Zhu, et al. Nat Comm.
Scientists are using their increasing knowledge of the complex interaction between cancer and the immune system to engineer increasingly potent anti-cancer vaccines. The nanovaccine produced an immune response that specifically killed tumor tissue, while simultaneously inhibiting tumor-induced immune suppression to block lung tumor growth in a mouse model of metastatic colon cancer.
Now researchers at the National Institute of Biomedical Imaging and Bioengineering (NIBIB) have developed a synergistic nanovaccine packing DNA and RNA sequences that modulate the immune response, along with anti-tumor antigens, into one small nanoparticle. The nanovaccine produced an immune response that specifically killed tumor tissue, while simultaneously inhibiting tumor-induced immune suppression. Together this blocked lung tumor growth in a mouse model of metastatic colon cancer.
The molecular dance between cancer and the immune system is a complex one and scientists continue to identify the specific molecular pathways that rev up or tamp down the immune system. Biomedical engineers are using this knowledge to create nanoparticles that can carry different molecular agents that target these pathways. The goal is to simultaneously stimulate the immune system to specifically attack the tumor while also inhibiting the suppression of the immune system, which often occurs in cancer patients. The aim is to press on the gas pedal of the immune system while also releasing the emergency brake.
A key hurdle is to design a system to reproducibly and efficiently create a nanoparticle loaded with multiple agents that synergize to mount an enhanced immune attack on the tumor. Engineers at the NIBIB report the development and testing of such a nanovaccine in the November issue of Nature Communications.
Making all the parts fit
Guizhi Zhu, Ph.D., a post-doctoral fellow in the NIBIB Laboratory of Molecular Imaging and Nanomedicine (LOMIN) and lead author on the study, explains the challenge. “We are very excited about putting multiple cooperating molecules that have anti-cancer activity into one nanovaccine to increase effectiveness. However, the bioengineering challenge is fitting everything in to a small particle and designing a way to maintain its structural integrity and biological activity.”
Zhu and his colleagues have created what they call a “self-assembling, intertwining DNA-RNA nanocapsule loaded with tumor neoantigens.” They describe it as a synergistic vaccine because the components work together to stimulate and enhance an immune attack against a tumor.
The DNA component of the vaccine is known to stimulate immune cells to work with partner immune cells for antitumor activation. The tumor neoantigens are pieces of proteins that are only present in the tumor; so, when the DNA attracts the immune cells, the immune cells interact with the tumor neoantigens and mount an expanded and specific immune response against the tumor. The RNA is the component that inhibits suppression of the immune system. The engineered RNA binds to and degrades the tumor’s mRNA that makes a protein called STAT3. Thus, the bound mRNA is blocked from making STAT3, which may suppress the immune system. The result is an enhanced immune response that is specific to the tumor and does not harm healthy tissues.
In addition to engineering a system where the DNA, RNA and tumor neoantigens self-assemble into a stable nanoparticle, an important final step in the process is shrinking the particle. Zhu explains: “Shrinking the particle is a critical step for activating an immune response. This is because a very small nanoparticle can more readily move through the lymphatic vessels to reach the parts of the immune system such as lymph nodes. A process that is essential for immune activation.”
The method for shrinking also had to be engineered. This was achieved by coating the particle with a positively charged polypeptide that interacts with the negatively charged DNA and RNA components to condense it to one-tenth of its original size.
Testing the nanovaccine
To create a model of metastatic colon cancer, the researchers injected human colon cancer cells into the circulation of mice. The cells infiltrate different organs and grow as metastatic colon cancer. One of the prime sites of metastasis is the lung.
The nanovaccine was injected under the skin of the mice 10, 16, and 22 days after the colon cancer cells were injected. To compare to the nanovaccine, two control groups of mice were analyzed; one group was injected with just the DNA and the neoantigen in solution but not formed into a nanovaccine particle, and the second control group was injected with an inert buffer solution.
At 40 days into the experiment, lung tumors from the nanovaccine-treated and the control groups were assessed by PET-CT imaging, and then removed and weighed. In mice treated with the nanovaccine, tumors were consistently one tenth the size of the tumors that were found in mice in both control groups.
Further testing revealed that mice receiving the nanovaccine had a significant increase in circulating cytotoxic T lymphocytes (CTLs) that specifically targeted the neoantigen on the colon cancer cells. CTLs are cells that attack and kill virus-infected cells and those damaged in other ways, such as cancerous cells.
An important aspect of the nanovaccine approach is that it mounts an anti-tumor immune response that circulates through the system, and therefore is particularly valuable for finding and inhibiting metastatic tumors growing throughout the body.
The researchers view their nanovaccine as an important part of eventual therapies combining immunotherapy with other cancer killing approaches.
Guizhi Zhu, Lei Mei, Harshad D. Vishwasrao, Orit Jacobson, Zhantong Wang, Yijing Liu, Bryant C. Yung, Xiao Fu, Albert Jin, Gang Niu, Qin Wang, Fuwu Zhang, Hari Shroff, Xiaoyuan Chen. Intertwining DNA-RNA nanocapsules loaded with tumor neoantigens as synergistic nanovaccines for cancer immunotherapy. Nature Communications, 2017; 8 (1) DOI: 10.1038/s41467-017-01386-7
Tumor-targeting nanoparticles loaded with a drug that makes cancer cells more vulnerable to chemotherapy’s toxicity could be used to treat an aggressive and often deadly form of endometrial cancer, according to new research by the University of Iowa College of Pharmacy.
For the first time, researchers combined traditional chemotherapy with a relatively new cancer drug that attacks chemo-resistant tumor cells, loaded both into tiny nanoparticles, and created an extremely selective and lethal cancer treatment. Results of the three-year lab study were published today in the journal Nature Nanotechnology.
The new treatment could mean improved survival rates for the roughly 6,000 U.S. women diagnosed with type II endometrial cancer every year and also represents an important step in the development of targeted cancer therapies. In contrast to chemotherapy, the current standard in cancer treatment that exposes the entire body to anti-cancer drugs, targeted treatments deliver drugs directly to the tumor site, thereby protecting healthy tissue and organs and enhancing drug efficacy.
“In this particular study, we took on one of the biggest challenges in cancer research, which is tumor targeting,” said Kareem Ebeid, a UI pharmacy science graduate student and lead researcher on the study. “And for the first time, we were able to combine two different tumor-targeting strategies and use them to defeat deadly type II endometrial cancer. We believe this treatment could be used to fight other cancers, as well.”
In their effort to create a highly selective cancer treatment, Ebeid and his team started with tiny nanoparticles. In recent years, there has been increased interest in using nanoparticles to treat cancer, in large part because of their small size. Tumors grow quickly, and the blood vessels they create to feed their growth are defective and full of holes. Nanoparticles are small enough to slip through the holes, thereby allowing them to specifically target tumors.
Researchers then fueled the nanoparticles with two anti-cancer drugs: paclitaxel, a type of chemotherapy used to treat endometrial cancer, and nintedanib, or BIBF 1120, a relatively new drug used to restrict tumor blood vessel growth. However, in the UI study, the drug was used for a different purpose. Besides limiting blood vessel growth, nintedanib also targets tumor cells with a specific mutation. The mutation, known as Loss of Function p53, interrupts the normal life cycle of tumor cells and makes them more resistant to the lethal effects of chemotherapy.
Chemotherapy kills cells when they are in the process of mitosis, or cell division, and tumor cells with the Loss of Function p53 mutation often are stuck in a limbo state that slows this process. Cancers that are resistant to chemotherapy are much harder to treat and have less favorable outcomes.
Nintedanib attacks tumor cells with the Loss of Function p53 mutation and compels them to enter mitosis and divide, at which point they are more easily killed by chemotherapy. Ebeid says this is the first time that researchers have used nintedanib to force tumor cells into mitosis and kill them—a phenomenon scientists refer to as “synthetic lethality.”
“Basically, we are taking advantage of the tumor cells‘ Achilles heel—the Loss of Function mutation—and then sweeping in and killing them with chemotherapy,” Ebeid says. “We call this a synthetically lethal situation because we are creating the right conditions for massive cell death.”
The treatment—and cellular death that it incites—could be used to treat other cancers as well, including types of ovarian and lung cancers that also carry the Loss of Function p53 mutation.
“We believe our research could have a positive impact beyond the treatment of endometrial cancer,” says Aliasger K. Salem, professor of pharmaceutical sciences at the UI and corresponding author on the study. “We hope that since the drugs used in our study have already been approved for clinical use, we will be able to begin working with patients soon.”
Incidence and mortality rates for endometrial cancer have been on the rise in the U.S. in recent years, especially in Iowa. Type I endometrial cancer, which feeds on the hormone estrogen, accounts for about 80 percent of new cases annually. Type II endometrial cancer is less common, accounting for roughly 10 percent to 20 percent of cases, but is much more aggressive, resulting in 39 percent of total endometrial cancer deaths every year.
“For two decades, the standard therapy for type II endometrial cancer has been chemotherapy and radiation,” says Kimberly K. Leslie, professor and chair of the Department of Obstetrics and Gynecology at the UI Roy J. and Lucille A. Carver College of Medicine. “The possibility of a new treatment that is both highly selective and highly effective is incredibly exciting.”
What might sound like the set-up to a joke actually has a clinical answer: Both groups can face health risks when injected with metal-containing agents sometimes needed to enhance the color contrast — and diagnostic value — of MRIs.
But a new metal-free nanoparticle developed by the University of Nebraska-Lincoln and MIT could help circumvent these health- and age-related barriers to the powerful diagnostic tool, which physicians use to investigate or confirm a broad range of medical issues.
The team’s nanoparticle contains a non-metallic molecule that enhances MRI contrast to help distinguish among bodily tissue, a task typically performed by contrast agents containing gadolinium or other metals (ACS Central Science, “Nitroxide-Based Macromolecular Contrast Agents with Unprecedented Transverse Relaxivity and Stability for Magnetic Resonance Imaging of Tumors”).
It also survived long enough to congregate around tumors in mice, suggesting the nanoparticle could help detect cancers as well as its metallic counterparts while eliminating concerns about the long-term accumulation of metal in the body.
MRIs of a mouse before (first and third rows) and 20 hours after being injected with a low dose (second row) and high dose (fourth row) of a new metal-free contrast agent developed by Nebraska and MIT. The yellow arrow indicates the location of a tumor. (click on image to enlarge)
Contrast in styles
The molecules residing in the team’s nanoparticle belong to a family known as the nitroxides, which are among the most promising alternatives to the metallic agents often injected into patients prior to undergoing MRIs.
But antioxidants in the body typically begin breaking down nitroxides within minutes, limiting how long they can enhance the contrast of an MRI. And the team’s molecule of interest — a so-called organic radical — has just a single electron, a fact that normally inhibits how much contrast it can produce.
Gadolinium and other metals possess multiple electrons that help them influence how the magnetic waves produced by an MRI interact with water molecules in tissue. This magnetic influence, or relaxivity, ultimately dictates the strength of contrast signals that get converted into the familiar multicolored MRIs.
So Nebraska chemist Andrzej Rajca began collaborating with colleagues at MIT to design a metal-free nanoparticle that would exhibit stability and relaxivity comparable to gadolinium’s. Rajca previously designed a nitroxide that, when embedded within relatively small nanoparticles, displayed a relaxivity several times greater than its predecessors.
This time around, MIT researchers incorporated Rajca’s nitroxide into a large nanoparticle known as a brush-arm star polymer. The process involved assembling polymers into a spherical structure with a water-attracting core and water-repelling shell, then squeezing multitudes of nitroxide molecules between that core and shell.
The team found that packing so many nitroxides into such tight quarters effectively multiplied their individual relaxivity values, resulting in a nanoparticle with a relaxivity about 40 times higher than a typical nitroxide.
“You don’t need much of the (new) contrast agent to see a good image,” said Rajca, Charles Bessey Professor of chemistry.
The nanoparticle’s polymer shell also helped slow the advance of the disruptive antioxidants enough to prolong the nitroxides’ lifespan from roughly two hours to 20. By injecting mice with their agent, the researchers showed that the nanoparticle’s longevity and large size allow it to reach tumors and differentiate them from normal tissue. Even in doses larger than those typically needed for MRIs, the team’s contrast agent showed no signs of toxicity in human cells or mice.
The Marble Center for Cancer Nanomedicine’s faculty is made up of Koch Institute members who are committed to fighting cancer with nanomedicine through research, education, and collaboration. Top row (l-r) Sangeeta Bhatia, director; Daniel Anderson; and Angela Belcher. Bottom row: Paula Hammond; Darrell Irvine; and Robert Langer. Photo: Koch Institute Marble Center for Cancer Nanomedicine
Koch Institute – July 2017
Marking its first anniversary, the Koch Institute’s Marble Center for Cancer Nanomedicine goes full steam ahead.
This summer, the Koch Institute for Integrative Cancer Research at MIT marks the first anniversary of the launch of the Marble Center for Cancer Nanomedicine, established through a generous gift from Kathy and Curt Marble ’63.
Bringing together leading Koch Institute faculty members and their teams, the Marble Center for Cancer Nanomedicine focuses on grand challenges in cancer detection, treatment, and monitoring that can benefit from the emerging biology and physics of the nanoscale.
These challenges include detecting cancer earlier than existing methods allow, harnessing the immune system to fight cancer even as it evolves, using therapeutic insights from cancer biology to design therapies for previously undruggable targets, combining existing drugs for synergistic action, and creating tools for more accurate diagnosis and better surgical intervention.
Koch Institute member Sangeeta N. Bhatia, the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, serves as the inaugural director for the center.
”A major goal for research at the Marble Center is to leverage the collaborative culture at the Koch Institute to use nanotechnology to improve cancer diagnosis and care in patients around the world,” Bhatia says.
The Marble Center joins MIT’s broader efforts at the forefront of discovery and innovation to solve the urgent global challenge that is cancer. The concept of “convergence” — the blending of the life and physical sciences with engineering — is a hallmark of MIT, the founding principle of the Koch Institute, and at the heart of the Marble Center’s mission.
“The center galvanizes the MIT cancer research community in efforts to use nanomedicine as a translational platform for cancer care,” says Tyler Jacks, director of the Koch Institute and a David H. Koch Professor of Biology. “It’s transformative by applying these emerging technologies to push the boundaries of cancer detection, treatment, and monitoring — and translational by promoting their development and application in the clinic.”
The center’s faculty — six prominent MIT professors and Koch Institute members — are committed to fighting cancer with nanomedicine through research, education, and collaboration. They are:
Sangeeta Bhatia (director), the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science;
Daniel G. Anderson, the Samuel A. Goldblith Professor of Applied Biology in the Department of Chemical Engineering and the Institute for Medical Engineering and Science;
Angela M. Belcher, the James Mason Crafts Professor in the departments of Biological Engineering and Materials Science and Engineering;
Paula T. Hammond, the David H. Koch Professor of Engineering and head of the Department of Chemical Engineering;
Darrell J. Irvine, professor in the departments of Biological Engineering and Materials Science and Engineering; and
Extending their collaboration within the walls of the Institute, Marble Center members benefit greatly from the support of the Peterson (1957) Nanotechnology Materials Core Facility in the Koch Institute’s Robert A. Swanson (1969) Biotechnology Center. The Peterson Facility’s array of technological resources and expertise is unmatched in the United States, and gives members of the center, and of the Koch Institute, a distinct advantage in the development and application of nanoscale materials and technologies.
The Marble Center has wasted no time getting up to speed in its first year, and has provided support for innovative research projects including theranostic nanoparticles that can both detect and treat cancers, real-time imaging of interactions between cancer and immune cells to better understand response to cancer immunotherapies, and delivery technologies for several powerful RNA-based therapeutics able to engage specific cancer targets with precision.
As part of its efforts to help foster a multifaceted science and engineering research force, the center has provided fellowship support for trainees — as well as valuable opportunities for mentorship, scientific exchange, and professional development.
Promoting broader engagement, the Marble Center serves as a bridge to a wide network of nanomedicine resources, connecting its members to MIT.nano, other nanotechnology researchers, and clinical collaborators across Boston and beyond. The center has also convened a scientific advisory board, whose members hail from leading academic and clinical centers around the country, and will help shape the center’s future programs and continued expansion.
As the Marble Center begins another year of collaborations and innovation, there is a new milestone in sight for 2018. Nanomedicine has been selected as the central theme for the Koch Institute’s 17th Annual Cancer Research Symposium. Scheduled for June 15, 2018, the event will bring together national leaders in the field, providing an ideal forum for Marble Center members to share the discoveries and advancements made during its sophomore year.
“Having next year’s KI Annual Symposium dedicated to nanomedicine will be a wonderful way to further expose the cancer research community to the power of doing science at the nanoscale,” Bhatia says. “The interdisciplinary approach has the power to accelerate new ideas at this exciting interface of nanotechnology and medicine.”
To learn more about the people and projects of the Koch Institute Marble Center for Cancer Nanomedicine, visit nanomedicine.mit.edu.
Researchers are hoping to use nanotechnology to develop more targeted treatments for drug-resistant bacteria. In this illustration, an antimicrobial peptide is packaged in a silicon nanoparticle to target bacteria in the lung. Image: Jose-Luis Olivares/MIT
Targeted treatment could be used for pneumonia and other bacterial infections.
Antibiotic resistance is a growing problem, especially among a type of bacteria that are classified as “Gram-negative.” These bacteria have two cell membranes, making it more difficult for drugs to penetrate and kill the cells.
Researchers from MIT and other institutions are hoping to use nanotechnology to develop more targeted treatments for these drug-resistant bugs. In a new study, they report that an antimicrobial peptide packaged in a silicon nanoparticle dramatically reduced the number of bacteria in the lungs of mice infected with Pseudomonas aeruginosa, a disease causing Gram-negative bacterium that can lead to pneumonia.
This approach, which could also be adapted to target other difficult-to-treat bacterial infections such as tuberculosis, is modeled on a strategy that the researchers have previously used to deliver targeted cancer drugs.
“There are a lot of similarities in the delivery challenges. In infection, as in cancer, the name of the game is selectively killing something, using a drug that has potential side effects,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science.
Bhatia is the senior author of the study, which appears in the journal Advanced Materials. The lead author is Ester Kwon, a research scientist at the Koch Institute. Other authors are Matthew Skalak, an MIT graduate and former Koch Institute research technician; Alessandro Bertucci, a Marie Curie Postdoctoral Fellow at the University of California at San Diego; Gary Braun, a postdoc at the Sanford Burnham Prebys Medical Discovery Institute; Francesco Ricci, an associate professor at the University of Rome Tor Vergata; Erkki Ruoslahti, a professor at the Sanford Burnham Prebys Medical Discovery Institute; and Michael Sailor, a professor at UCSD.
As bacteria grow increasingly resistant to traditional antibiotics, one alternative that some researchers are exploring is antimicrobial peptides — naturally occurring defensive proteins that can kill many types of bacteria by disrupting cellular targets such as membranes and proteins or cellular processes such as protein synthesis.
A few years ago, Bhatia and her colleagues began investigating the possibility of delivering antimicrobial peptides in a targeted fashion using nanoparticles. They also decided to try combining an antimicrobial peptide with another peptide that would help the drug cross bacterial membranes. This concept was built on previous work suggesting that these “tandem peptides” could kill cancer cells effectively.
For the antimicrobial peptide, the researchers chose a synthetic bacterial toxin called KLAKAK. They attached this toxin to a variety of “trafficking peptides,” which interact with bacterial membranes. Of 25 tandem peptides tested, the best one turned out to be a combination of KLAKAK and a peptide called lactoferrin, which was 30 times more effective at killing Pseudomonas aeruginosa than the individual peptides were on their own. It also had minimal toxic effects on human cells.
To further minimize potential side effects, the researchers packaged the peptides into silicon nanoparticles, which prevent the peptides from being released too soon and damaging tissue while en route to their targets. For this study, the researchers delivered the particles directly into the trachea, but for human use, they plan to design a version that could be inhaled.
After the nanoparticles were delivered to mice with an aggressive bacterial infection, those mice had about one-millionth the number of bacteria in their lungs as untreated mice, and they survived longer. The researchers also found that the peptides could kill strains of drug-resistant Pseudomonas taken from patients and grown in the lab.
Infectious disease is a fairly new area of research for Bhatia’s lab, which has spent most of the past 17 years developing nanomaterials to treat cancer. A few years ago, she began working on a project funded by the Defense Advanced Research Projects Agency (DARPA) to develop targeted treatments for infections of the brain, which led to the new lung infection project.
“We’ve adapted a lot of the same concepts from our cancer work, including boosting local concentration of the cargo and then making the cargo selectively interact with the target, which is now bacteria instead of a tumor,” Bhatia says.
She is now working on incorporating another peptide that would help to target antimicrobial peptides to the correct location in the body. A related project involves using trafficking peptides to help existing antibiotics that kill Gram-positive bacteria to cross the double membrane of Gram-negative bacteria, enabling them to kill those bacteria as well.
The research was funded by the Koch Institute Support Grant from the National Cancer Institute, the National Institute of Environmental Health Sciences, and DARPA.