‘Swiss army knife’ Nanovaccine carries multiple weapons to battle tumors – cancer


Swiss Army Knife of Nano Ps 171129163851_1_540x360
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.

Story Source:

Materials provided by National Institute of Biomedical Imaging and BioengineeringNote: Content may be edited for style and length.


Journal Reference:

  1. 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 immunotherapyNature Communications, 2017; 8 (1) DOI: 10.1038/s41467-017-01386-7
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Researchers use nanoparticles to target and kill endometrial cancer


Cancer Killer 57-researchersuUI researchers loaded nanoparticles with two cancer drugs and injected them into lab mice with type II endometrial cancer. The super-lethal nanoparticles reduced tumor growth and extended survival rates. In this photo, tiny green …more

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  that attacks chemo-resistant  cells, loaded both into tiny nanoparticles, and created an extremely selective and lethal . 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 , 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  into mitosis and kill them—a phenomenon scientists refer to as “synthetic lethality.”

“Basically, we are taking advantage of the ‘ 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  deaths every year.

“For two decades, the standard therapy for type II  has been  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  that is both highly selective and highly effective is incredibly exciting.”

 Explore further: Genetic targets to chemo-resistant breast cancer identified

More information: Synthetically lethal nanoparticles for treatment of endometrial cancer, Nature Nanotechnology (2017). nature.com/articles/doi:10.1038/s41565-017-0009-7

 

Metal-free nanoparticle could expand MRI use, tumor detection



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.

Source: University of Nebraska-Lincoln

Converging on Cancer at the Nanoscale


MIT-KI-Marble-Center-Faculty-00_0The 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. cancer-shapeshiftin

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.

Transforming nanomedicine

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

Robert S. Langer, the David H. Koch Institute Professor.

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.

Looking ahead

Figure-1-11-Nanocarriers-for-cancer-theranostics-Nanoparticles-based-strategies-can-beThe 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.

MIT: Antibiotic Nanoparticles Fight Drug-Resistant Bacteria


MIT-Nano-Anti_0Researchers 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.

Synergistic peptides

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.

Adapting concepts

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.

Anne Trafton | MIT News Office

MIT: Antibiotic Nanoparticles fight drug-resistant bacteria


MIT-Nano-Anti_0

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

Antibiotic Nanoparticles fight drug-resistant bacteria

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.

Synergistic peptides

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.

Adapting concepts

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.

 

New “Quasiparticles ” Research Allows Data to be Recorded … with LIGHT!



Russian physicists with their colleagues from Europe through changing the light parameters, learned to generate quasiparticles – excitons, which were fully controllable and also helped to record information at room temperature. 

These particles act as a transitional form between photons and electrons so the researchers believe that with excitons, they will be able to create compact optoelectronic devices for rapid recording and processing an optical signal. The proposed method is based on use of a special class of materials called metal-organic frameworks. The study appeared in Advanced Materials. 

To simplify the description of complex effects in quantum mechanics, scientists have introduced a concept of quasiparticles. One of them which is called exciton is an “electron – hole” pair, which provides energy transfer between photons and electrons. 

According to the scientific community, this mediation of quasiparticles will help to combine optics with electronics to create a fundamentally new class of equipment – more compact and energy efficient. However, all exciton demo devices either operate only at low temperature, or are difficult to manufacture which inhibits their mass adoption.

 

In the new study, the scientists from ITMO University in Saint Petersburg, Leipzig University in Germany and Eindhoven University of Technology in the Netherlands could generate excitons at room temperature by changing the light parameters. 
The authors also managed to control the quasiparticles with ultra-high sensitivity of about hundreds of femtoseconds (10-13 s). Finally, they developed an easy method for data recording with excitons. This all became possible through the use of an individual class of materials called metal-organic frameworks.

 

Metal-organic frameworks (MOF) synthesized at ITMO University, have a layered structure. Between the layers, there is a physical attraction called van der Waals force. To prevent the plates from uncontrollably coming together, the interlayer space is filled with an organic liquid, which fixes the framework to be three-dimensional.

 

In such crystals, the researchers learned to bring two types of excitons individually: intralayer and interlayer. The first arise when a photon absorbed by the crystal turns into an electron-hole pair inside a layer, but the second appear when an electron and a hole belong to neighboring layers. In some time, both kinds of quasiparticles disintegrate, re-radiating the energy as a photon. But excitons can move around the crystal while they exist.

 

The life time of intralayer excitons is relatively short, but their high density and agility allow one to use these quasiparticles to generate light in LEDs and lasers, for instance. Interlayer excitons are more stable, but slow-moving, so the researchers propose them to be used for the data recording. Both types of excitons fit processing of an optical signal, according to the physicists.

 

The innovative approach for information recording concerns the changing a distance between crystal layers to switch “on” and “off” the interlayer excitons. 
Valentin Milichko, the first author of the paper, associate professor of Department of Nanophotonics and Metamaterials at ITMO University, comments: “We locally heated the crystal with a laser. In the place of exposure, the layers stuck together and the luminescence of excitons disappeared while the rest of the crystal continued shining. This could mean that we recorded 1 bit of information, and the record, in the form of a dark spot, was kept for many days. 

To delete the data, it was enough to put the MOF into the same organic liquid that supports layers. In this case, the crystal itself is not affected, but the recorded information (the dark spot) disappears.”

 

The authors believe that in the future the new material will help to bring processing of an optical signal to the usual pattern of zeros and ones: “In fact, we can influence the exciton behavior in the crystal, changing the light intensity. At weak irradiation, excitons are accumulated (in ‘1’ state), but if the laser power increases, the concentration of quasiparticles grows so much that they can instantly disintegrate (in ‘0’ state),” says Valentin Milichko.

 

Typically, excitons occur in dielectric and semiconductor crystals, but the scientists could create these quasiparticles and get control over them in a completely different class of materials, which never was used for this. 
The MOF crystal combines organic components with inorganic that gives it additional properties not available for materials of a single nature. Thus, the organic term allows one to generate excitons at room temperature, but inorganic provides their efficient transfer around the crystal.

 

Valentin A. Milichko, Sergey V. Makarov, Alexey V. Yulin, Alexander V. Vinogradov, Andrei A. Krasilin, Elena Ushakova, Vladimir P. Dzyuba, Evamarie Hey-Hawkins, Evgeny A. Pidko, Pavel A. Belov (2017), Van der Waals metal-organic framework as an excitonic material for advanced photonics, Advanced Materials

*** From Nanotechnology World 

Florida State University Researchers take big step forward in nanotech-based drugs


Nanoparticle drug delivery F3.large

Florida State University Summary:New research takes a step forward in the understanding of nanoparticles and how they can best be used to deliver drugs.

Nanotechnology has become a growing part of medical research in recent years, with scientists feverishly working to see if tiny particles could revolutionize the world of drug delivery.

But many questions remain about how to effectively transport those particles and associated drugs to cells.

In an article published in Scientific Reports, FSU Associate Professor of Biological Science Steven Lenhert takes a step forward in the understanding of nanoparticles and how they can best be used to deliver drugs.

After conducting a series of experiments, Lenhert and his colleagues found that it may be possible to boost the efficacy of medicine entering target cells via a nanoparticle.

“We can enhance how cells take them up and make more drugs more potent,” Lenhert said.

Initially, Lenhert and his colleagues from the University of Toronto and the Karlsruhe Institute of Technology wanted to see what happened when they encapsulated silicon nanoparticles in liposomes — or small spherical sacs of molecules — and delivered them to HeLa cells, a standard cancer cell model.

The initial goal was to test the toxicity of silicon-based nanoparticles and get a better understanding of its biological activity.

Silicon is a non-toxic substance and has well-known optical properties that allow their nanostructures to appear fluorescent under an infrared camera, where tissue would be nearly transparent. Scientists believe it has enormous potential as a delivery agent for drugs as well as in medical imaging.

But there are still questions about how silicon behaves at such a small size.

“Nanoparticles change properties as they get smaller, so scientists want to understand the biological activity,” Lenhert said. “For example, how does shape and size affect toxicity?”

Scientists found that 10 out of 18 types of the particles, ranging from 1.5 nanometers to 6 nanometers, were significantly more toxic than crude mixtures of the material.

At first, scientists believed this could be a setback, but they then discovered the reason for the toxicity levels. The more toxic fragments also had enhanced cellular uptake. That information is more valuable long term, Lenhert said, because it means they could potentially alter nanoparticles to enhance the potency of a given therapeutic.

The work also paves the way for researchers to screen libraries of nanoparticles to see how cells react.

“This is an essential step toward the discovery of novel nanotechnology based therapeutics,” Lenhert said. “There’s big potential here for new therapeutics, but we need to be able to test everything first.”


Story Source:

Materials provided by Florida State University. Original written by Kathleen Haughney. Note: Content may be edited for style and length.


Journal Reference:

  1. Aubrey E. Kusi-Appiah, Melanie L. Mastronardi, Chenxi Qian, Kenneth K. Chen, Lida Ghazanfari, Plengchart Prommapan, Christian Kübel, Geoffrey A. Ozin, Steven Lenhert. Enhanced cellular uptake of size-separated lipophilic silicon nanoparticles. Scientific Reports, 2017; 7: 43731 DOI: 10.1038/srep43731

 

A ‘nano-golf course’ to assemble precisely nanoparticules


nano-golf-course-ananogolfcouTo show how well their method works, the researchers produced geometrically complex structures by writing out the alphabet with nanoparticles — the smallest segment display in the world. Credit: Nature Nanotechnology (2016). DOI: 10.1038/nnano.2016.179

Whether it has to do with making pens or building space shuttles, the manufacturing process consists of creating components and then carefully assembling them. But when it comes to infinitely small structures, manipulating and assembling high-performance nanoparticles on a substrate is no mean feat.

Researchers in EPFL’s Laboratory of Microsystems, which is headed by Jürgen Brugger, have come up with a way to position hundreds of thousands of very precisely on a one centimeter square surface. The nanoparticles were placed within one nanometer – versus 10 to 20 nanometers using conventional methods – and oriented within one degree.

Their work, which was published in Nature Nanotechnology, sets the stage for the development of nanometric devices such as optical detection equipment and biological sensors. “If we manage to place one nanometer apart, we could, for example, confine light to an extraordinary degree and detect or interact with individual molecules,” said Valentin Flauraud, the lead author.

“Playing golf” with nanoparticles

For their study, the researchers used gold nanoparticles that were grown chemically in a liquid. “These nanoparticles exhibit better properties than those produced through evaporation or etching, but it is more difficult to manipulate them, because they are suspended in a liquid,” said Flauraud.

A 'nano-golf course' to assemble precisely nanoparticules
     
A drop full of nanoparticles is dragged across a substrate with nanometric barriers and holes. When the nanoparticles encounter these obstacles, they detach from the liquid and are captured by the holes. Credit: Valentin Flauraud

Their technique consists of taking a drop of liquid full of nanoparticles and heating it so that the nanoparticles cluster in a given spot. This drop is then dragged across a substrate with nanometric barriers and holes.

When the nanoparticles encounter these obstacles, they detach from the liquid and are captured by the holes. “It’s a little like playing miniature golf,” said the researcher. Each trap is designed to orient a nanoparticle in a specific way. “The challenge was to figure out how the liquid, the particles and the substrate interact at the nanometric scale so we could trap the nanoparticles effectively,” said Massimo Mastrangeli, the second author and now a researcher at the Max Planck Institute for Intelligent Systems in Stuttgart.

Writing out the alphabet with nanoparticles

To show how well their method works, the researchers took on several challenges. First, they tested the optical properties of their system with a powerful in EPFL’s Interdisciplinary Center for Electron Microscopy (CIME).

They then showed that their technique could be used to produce geometrically complex structures by writing out the alphabet with nanoparticles – the smallest segment display in the world. “All of this work was conducted at EPFL and is the result of strong synergies between the various technical platforms and the labs,” said Professor Brugger. “It’s an excellent example of how top-down and bottom-up methods can be combined, opening the door to numerous unexplored fields of nanotechnology.”

Explore further: 3-D nanoprinting to turbocharge microscopes

More information: Valentin Flauraud et al, Nanoscale topographical control of capillary assembly of nanoparticles, Nature Nanotechnology (2016). DOI: 10.1038/nnano.2016.179

Sheets like graphene: Tailored chemistry links nanoparticles in stable monolayers


Just like carbon atoms in sheets of graphene, nanoparticles can form stable layers with minimal thicknesses of the diameter of a single nanoparticle. A novel method of linking nanoparticles into such extremally thin films has been developed at the Institute of Physical Chemistry of the Polish Academy of Sciences in Warsaw.

The chemical tailor cuts his coat according to… his nanoparticles. The tailoring successes to date of researchers synthesizing layers of nanoparticles would not be adequate to stage even the most modest of chemical fashion shows. Nanoparticles could be organized into single-particle layer thicknesses – that is, monolayers – but these were not stable structures. It was not possible to link nanoparticles together in a stable manner in monolayers. Until now.

“In recent years, our group at the Institute of Physical Chemistry of the Polish Academy of Sciences in Warsaw has been working on developing a universal platform for the synthesis of stable monolayers of nanoparticles. Today we have proof that our ‘tailored’ method of chemically bonding nanoparticles in monolayers actually works,” says Dr. Marcin Fialkowski, professor at IPC PAS, and demonstrates a tiny, shiny layer, deposited on a plate, with the smallest possible thickness – equal to the diameter of a single nanoparticle of gold.

Monolayers of chemically stitched together nanoparticles of gold produced at the IPC PAS have surface areas of the order of square millimetres, and for obvious reasons they are very delicate. Mechanically they resemble acrylic plates: when subjected to forces they initially deform elastically, after which they suddenly crack.

“Our monolayers are not large, because we only wanted to demonstrate the correctness of the concept of their synthesis. Nothing stands in the way of producing monolayers in the way that we propose with areas having many square centimetres,” says Prof. Fialkowski.

Nanoparticle layers have been produced for years at the interface i.e. the thin area (interface) between two immiscible liquids. When introduced into a heavier liquid, upon mechanical agitation, appropriately prepared nanoparticles flow out of it and distribute themselves randomly on the border with the lighter liquid. Order can be brought into the chaos reigning here by compressing the nanoparticles with pistons from the side and thereby compacting them. Monolayers produced in this manner were hitherto not durable and when trying to remove them from the interface they simply fell apart. In turn, structures bound chemically, capable of surviving separation from the interface, upon closer investigation always turned out to be either multi-layers or amorphous composites of nanoparticles.

“Our monolayers are stable because we have linked the nanoparticles with special ‘staples’, or linker-molecules. Each linker joins together two adjacent nanoparticles by strong covalent bonds, that is, chemically”, explains Dr. Tomasz Andryszewski (IPC PAS), lead author of the publication in the journal Chemistry of Materials.

The gold nanoparticles used in experiments at the IPC PAS have diameters of about five nanometres (billionths of a metre); the length of the linkers used is only one and a half. For such a short linker to bind together adjacent nanoparticles, these have to be appropriately shifted towards each other.

“The main difficulty in our work lay in the fact that we had to reconcile two requirements that were in principle opposite. Due to the length of the linker we knew that the nanoparticles should be brought together to be a small distance apart, meaning that they would have to be subjected to relatively large forces. Therefore we didn’t want the nanoparticles to pop out of the interface. At the same time, we had to somehow prevent the nanoparticles from sticking together into random structures”, describes Dr. Andryszewski.

To meet these conditions, the nanoparticles were coated with small, specially designed molecules (ligands), which on one side contained amine groups (with nitrogen and hydrogen), and on the other – thiol groups (with sulphur and hydrogen). The thiol parts combined with the gold, whilst the amino parts located themselves on the outside of the nanoparticles and gave them a positive electric charge.

“The gold nanoparticles modified by us act as buoys with a large displacement: they locate themselves at the boundary between the liquids so durably that even strong agitation is not able to push them out. At the same time they repel each other electrostatically. As a result, each nanoparticle is guaranteed a ‘private space’ around itself, necessary for the preservation of order,” explains PhD student Michalina Iwan (IPC PAS).

When the appropriately prepared nanoparticles had already been squeezed into monolayers at the interface, a linking substance was injected into the system. The crosslinking reaction reminiscent of automatic stapling took place at room temperature and at normal pressure, without the need for any initiators or catalysts. After the chemical anastomosis the monolayer could be removed from the interface between the liquids, dried out, and even subjected to the action of strong solvents.

The physical properties of monolayers derived using tailored chemistry can be modified by selecting appropriate linkers. Longer, polymer linkers would allow the formation of monolayers with a higher elasticity. Using current-conducting linkers it would in turn be possible to produce e.g. monolayers with specifically determined optoelectronic properties. The use of still other linkers could result in monolayers exhibiting a piezoresistive effect, i.e. changing their electrical conductivity under the influence of mechanical deformations. The presented method of synthesis is also important for basic research: in the future, it will enable the direct investigation of, among others, the mechanical properties of single nanoparticles.

The synthetic platform for the production of nanoparticle monolayers was developed and tested at the IPC PAS, and came about under the Foundation for Polish Science TEAM grant.

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The Institute of Physical Chemistry of the Polish Academy of Sciences was established in 1955 as one of the first chemical institutes of the PAS. The Institute’s scientific profile is strongly related to the newest global trends in the development of physical chemistry and chemical physics. Scientific research is conducted in nine scientific departments. CHEMIPAN R&D Laboratories, operating as part of the Institute, implement, produce and commercialise specialist chemicals to be used, in particular, in agriculture and pharmaceutical industry. The Institute publishes approximately 200 original research papers annually.