DNA ‘Origami’ takes Flight in Emerging Field of Nano Machines – “(a) … tool may eventually be used to fine tune immunotherapies for individual cancer patients”


dnaorigamita
DNA mechanotechnology expands the opportunities for research involving biomedicine and materials sciences, says Khalid Salaita, right, professor of chemistry at Emory University and co-author of the article, along with Aaron Blanchard, left, a graduate student in the Salaita Lab. Credit: Emory University

Just as the steam engine set the stage for the Industrial Revolution, and micro transistors sparked the digital age, nanoscale devices made from DNA are opening up a new era in bio-medical research and materials science.

The journal Science describes the emerging uses of DNA  in a “Perspective” article by Khalid Salaita, a professor of chemistry at Emory University, and Aaron Blanchard, a graduate student in the Wallace H. Coulter Department of Biomedical Engineering, a joint program of Georgia Institute of Technology and Emory.

The article heralds a new field, which Blanchard dubbed “DNA mechanotechnology,” to engineer DNA machines that generate, transmit and sense  at the nanoscale.

“For a long time,” Salaita says, “scientists have been good at making micro devices, hundreds of times smaller than the width of a human hair. It’s been more challenging to make functional nano devices, thousands of times smaller than that. But using DNA as the component parts is making it possible to build extremely elaborate nano devices because the DNA parts self-assemble.”

DNA, or deoxyribonucleic acid, stores and transmits genetic information as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C) and thymine (T). The DNA bases have a natural affinity to pair up with each other—A with T and C with G. Synthetic strands of DNA can be combined with natural DNA strands from bacteriophages. By moving around the sequence of letters on the strands, researchers can get the DNA strands to bind together in ways that create different shapes. The stiffness of DNA strands can also easily be adjusted, so they remain straight as a piece of dry spaghetti or bend and coil like boiled spaghetti.

The idea of using DNA as a construction material goes back to the 1980s, when biochemist Nadrian Seeman pioneered DNA nanotechnology. This field uses strands DNA to make functional devices at the nanoscale. The ability to make these precise, three-dimensional structures began as a novelty, nicknamed DNA origami, resulting in objects such as a microscopic map of the world and, more recently, the tiniest-ever game of tic-tac-toe, played on a DNA board.

Work on novelty objects continues to provide new insights into the mechanical properties of DNA. These insights are driving the ability to make DNA machines that generate, transmit and sense mechanical forces.

“If you put together these three main components of mechanical devices, you begin to get hammers and cogs and wheels and you can start building nano machines,” Salaita says. “DNA mechanotechnology expands the opportunities for research involving biomedicine and materials science. It’s like discovering a new continent and opening up fresh territory to explore.”

Potential uses for such devices include drug delivery devices in the form of nano capsules that open up when they reach a target site, nano computers and nano robots working on nanoscale assembly lines.

The use of DNA self-assembly by the genomics industry, for biomedical research and diagnostics, is further propelling DNA mechanotechnology, making DNA synthesis inexpensive and readily available. “Potentially anyone can dream up a nano-machine design and make it a reality,” Salaita says.

He gives the example of creating a pair of nano scissors. “You know that you need two rigid rods and that they need to be linked by a pivot mechanism,” he says. “By tinkering with some open-source software, you can create this design and then go onto a computer and place an order to custom synthesize your design. You’ll receive your order in a tube. You simply put the tube contents into a solution, let your device self-assemble, and then use a microscope to see if it works the way you thought that it would.”

Salaita’s lab is one of only about 100 around the world working at the forefront of DNA mechanotechnology. He and Blanchard developed the world’s strongest synthetic DNA-based motor, which was recently reported in Nano Letters.

A key focus of Salaita’s research is mapping and measuring how cells push and pull to learn more about the mechanical forces involved in the human immune system.

Salaita developed the first DNA force gauges for cells, providing the first detailed view of the mechanical forces that one molecule applies to another molecule across the entire surface of a living cell. Mapping such forces may help to diagnose and treat diseases related to cellular mechanics. Cancer cells, for instance, move differently from normal cells, and it is unclear whether that difference is a cause or an effect of the disease.

In 2016, Salaita used these DNA force gauges to provide the first direct evidence for the mechanical forces of T cells, the security guards of the immune system. His lab showed how T cells use a kind of mechanical “handshake” or tug to test whether a cell they encounter is a friend or foe. These mechanical tugs are central to a T cell’s decision for whether to mount an immune response.

“Your blood contains millions of different types of T cells, and each T cell is evolved to detect a certain pathogen or foreign agent,” Salaita explains. “T cells are constantly sampling cells throughout your body using these mechanical tugs. They bind and pull on proteins on a cell’s surface and, if the bond is strong, that’s a signal that the T cell has found a foreign agent.”

Salaita’s lab built on this discovery in a paper recently published in the Proceedings of the National Academy of Sciences (PNAS). Work led by Emory chemistry graduate student Rong Ma refined the sensitivity of the DNA force gauges. Not only can they detect these mechanical tugs at a force so slight that it is nearly one-billionth the weight of a paperclip, they can also capture evidence of tugs as brief as the blink of an eye.

The research provides an unprecedented look at the mechanical forces involved in the immune system. “We showed that, in addition to being evolved to detect certain foreign agents, T cells will also apply very brief mechanical tugs to foreign agents that are a near match,” Salaita says. “The frequency and duration of the tug depends on how closely the foreign agent is matched to the T cell receptor.”

The result provides a tool to predict how strong of an immune response a T cell will mount. “We hope this tool may eventually be used to fine tune immunotherapies for individual cancer patients,” Salaita says. “It could potentially help engineer T  to go after particular .”


Advertisements

Precious Metal Flecks Could be Catalyst for Better Cancer Therapies


Precious Metal Flecks Cancer shutterstock_716719006

 

Researchers have found a way to dispatch minute fragments of palladium—a key component in motor manufacture, electronics and the oil industry—inside cancerous cells.

Tiny extracts of a precious metal used widely in industry could play a vital role in new cancer therapies.

Scientists have long known that the metal, used in catalytic converters to detoxify exhaust, could be used to aid cancer treatment but, until now, have been unable to deliver it to affected areas.

A molecular shuttle system that targets specific cancer cells has been created by a team at the University of Edinburgh and the Universidad de Zaragoza in Spain.

The new method, which exploits palladium’s ability to accelerate—or catalyse—chemical reactions, mimics the process some viruses use to cross cell membranes and spread infection.

The team has used bubble-like pouches that resemble the biological carriers known as exosomes, which can transport essential proteins and genetic material between cells. These exosomes exit and enter cells, dump their content, and influence how the cells behave.

This targeted transport system, which is also exploited by some viruses to spread infection to other cells and tissues, inspired the team to investigate their use as shuttles of therapeutics.

The researchers have now shown that this complex communication network can be hijacked. The team created exosomes derived from lung cancer cells and cells associated with glioma—a tumour that occurs in the brain and spinal cord—and loaded them with palladium catalysts.

These artificial exosomes act as Trojan horses, taking the catalysts—which work in tandem with an existing cancer drug- straight to primary tumours and metastatic cells.

Having proved the concept in laboratory tests, the researchers have now been granted a patent that gives them exclusive rights to trial palladium-based therapies in medicine.

The study was funded by the Engineering and Physical Sciences Research Council and the European Research Council. It has been published in the journal, Nature Catalysis.

Professor Asier Unciti-Broceta, from the University of Edinburgh’s CRUK Edinburgh Centre, said: “We have tricked exosomes naturally released by cancer cells into taking up a metal that will activate chemotherapy drugs just inside the cancer cells, which could leave healthy cells untouched.”

Professor Jesús Santamaría, of the Universidad de Zaragoza, said: “This has the potential to be a very exciting technology. It could allow us to target the main tumour and metastatic cells, thus reducing the side effects of chemotherapy without compromising the treatment.”

Story Source:

Materials provided by University of Edinburgh. Note: Content may be edited for style and length.

Researchers Develop Nanoparticle-Based Vaccine for Skin Cancer


nanovaccine

Nano-particles developed by scientists at Tel Aviv University have proven effective to prevent and treat melanoma.

 

While scientists have made great strides over the years to treat cancer, a vaccine for the disease—which comes in many forms and with many complexities–has yet to be discovered.

Researchers at Tel Aviv University have made a breakthrough in this endeavor with the development of a nano-vaccine for the most aggressive type of melanoma—skin cancer. The vaccine—based on a novel nanoparticle—already has shown effective in preventing the development of melanoma in mice as well as in treating the initial tumors that result from the disease, researchers said.

Researchers have developed a new nano-vaccine for melanoma, the most aggressive type of skin cancer. The vaccine is the first of its kind for cancer and paves the way for promising new prevention and treatment methods for the disease, researchers said. (Image source: Tel Aviv University)

Melanoma develops in the skin cells that produce melanin or skin pigment, but then can metastasize quickly into the brain and other organs. It currently is treated in a number of ways, including chemotherapy, radiation therapy, and immunotherapy.

All of these methods attack the disease after the fact; so far, no treatment has emerged to prevent or delay its growth in the first place, Professor Ronit Satchi-Fainaro, chair of the Department of Physiology and Pharmacology at Tel Aviv University, said in a press statement.

“The vaccine approach, which has proven so effective against various viral diseases, has not materialized yet against cancer,” said Satchi-Fainaro, who also is head of the Laboratory for Cancer Research and Nanomedicine at the university’s Sackler Faculty of Medicine. “In our study, we have shown for the first time that it is possible to produce an effective nano-vaccine against melanoma and to sensitize the immune system to immunotherapies.”

A New Approach

Nanoparticles about 170 nanometers in size are key to the approach researchers took to developing their novel vaccine. They packed two peptides—or short chains of amino acids—into each particle, which are made of a biodegradable polymer. Peptides are present in melanoma cells.

To test their vaccine, researchers injected the nano-particles into a mouse with melanoma to test its effectiveness. What they found is that the nanoparticles acted similarly to existing vaccines for viruses, which long have proved effective against viral-borne diseases, Satchi-Fainaro said.

“They stimulated the immune system of the mice, and the immune cells learned to identify and attack cells containing the two peptides–that is, the melanoma cells,” she said in the statement. “This meant that, from now on, the immune system of the immunized mice will attack melanoma cells if and when they appear in the body.”

Researchers published a study on their work in the journal Nature Nanotechnology.

Successful Prevention and Treatment

Satchi-Fainaro’s team focused on three different conditions to determine the nano-vaccine’s effectiveness. The first was to see if it would prevent the growth of the disease if melanoma cells were injected into mice, which it did, she said.

Researchers also used the nano-vaccine to treat a primary melanoma tumor in combination with immunotherapy treatments, they said. The treatment delayed the progression of the disease and significantly extended the lives of the mice in this study, researchers said.

Finally, the researchers gauged the nano-vaccine’s effectiveness in treating brain metastases, which are associated with melanoma, using tissue from patients with these metastases. The vaccine showed it could also be a successful treatment in this case, paving the way for “effective treatment of melanoma, even in the most advanced stages of the disease,” Satchi-Fainaro said in the statement.

The team plans to continue its work to develop nano-particles to vaccinate people not only against melanoma, but potentially against other forms of cancer as well, she added.

 

Tiny capsules offer alternative to viral delivery of gene therapy


tinycapsules
A graphic description of the nanocapsule delivery system. Credit: UW-Madison

New tools for editing genetic code offer hope for new treatments for inherited diseases, some cancers, and even stubborn viral infections. But the typical method for delivering gene therapies to specific tissues in the body can be complicated and may cause troubling side effects.

Researchers at the University of Wisconsin-Madison have addressed many of those problems by packing a gene-editing payload into a tiny customizable, synthetic . They described the  and its cargo today (Sept. 9, 2019) in the journal Nature Nanotechnology.

“In order to edit a gene in a cell, the editing tool needs to be delivered inside the cell safely and efficiently,” says Shaoqin “Sarah” Gong, a professor of biomedical engineering and investigator at the Wisconsin Institute for Discovery at UW-Madison. Her lab specializes in designing and building nanoscale delivery systems for targeted therapy.

“Editing the wrong tissue in the body after injecting gene therapies is of grave concern,” says Krishanu Saha, also a UW-Madison biomedical engineering professor and steering committee co-chair for a nationwide consortium on genome editing with $190 million in support from the National Institutes of Health. “If  are inadvertently edited, then the patient would pass on the gene edits to their children and every subsequent generation.”

Most genome editing is done with , according to Gong. Viruses have billions of years of experience invading cells and co-opting the cell’s own machinery to make new copies of the virus. In gene therapy, viruses can be altered to carry genome-editing machinery rather than their own viral  into cells. The editing machinery can then alter the cell’s DNA to, say, correct a problem in the genetic code that causes or contributes to disease.

“Viral vectors are attractive because they can be very efficient, but they are also associated with a number of safety concerns including undesirable immune responses,” says Gong.

New cell targets can also require laborious alterations of viral vectors, and manufacturing tailored viral vectors can be complicated.

“It is very difficult—if not impossible—to customize many viral vectors for delivery to a specific cell or tissue in the body,” Saha says.

Gong’s lab coated a  payload—namely, a version of the gene-editing tool CRISPR-Cas9 with guide RNA designed in Saha’s lab—with a thin polymer shell, resulting in a capsule about 25 nanometers in diameter. The surface of the nanocapsule can be decorated with functional groups such as peptides which give the nanoparticles the ability to target certain .

The nanocapsule stays intact outside cells—in the bloodstream, for example—only to fall apart inside the target cell when triggered by a molecule called glutathione. The freed payload then moves to the nucleus to edit the cell’s DNA. The nanocapsules are expected to reduce unplanned genetic edits due to their short lifespan inside a cell’s cytoplasm.

This project is a collaboration combining UW-Madison expertise in chemistry, engineering, biology and medicine. Pediatrics and ophthalmology professor Bikash R. Pattnaik and comparative biosciences professor Masatoshi Suzuki and their teams worked to demonstrate gene editing in mouse eyes and skeletal muscles, respectively, using the nanocapsules.

Because the nanocapsules can be freeze-dried, they can be conveniently purified, stored, and transported as a powder, while providing flexibility for dosage control. The researchers, with the Wisconsin Alumni Research Foundation, have a patent pending on the nanoparticles.

“The , superior stability, versatility in surface modification, and high editing efficiency of the nanocapsules make them a promising platform for many types of gene therapies,” says Gong.

The team aims to further optimize the nanocapsules in ongoing research for efficient editing in the brain and the eye.


Explore further

Researchers redefine the footprint of viral vector gene therapy

Light and nanotechnology prevent bacterial infections on medical implants – Reducing Costs and Recurring Surgeries


Image of the surgical implants, covered with gold nanoparticles (pile of meshes on the left) compared to the original surgical meshes previous to the treatment (pile of meshes on the right). Credit: ICFO

Invented approximately 50 years ago, surgical medical meshes have become key elements in the recovery procedures of damaged-tissue surgeries, the most common being hernia repair.

When implanted within the tissue of the patient, the flexible and conformable design of these meshes hold muscles securely and allows quicker recovery than conventional surgical procedures of sewing and stitching.

However, the insertion of a medical implant in a patient’s body carries the risk of bacterial contamination during surgery and subsequent formation of an infectious biofilm over the surface of the surgical .

Such biofilms tend to act like a plastic coating, preventing any sort of antibiotic agent from reaching and attacking the formed on the film in order to stop the infection. Thus, antibiotic therapies, which are time-limited, could fail against super-resistant bacteria and the patient could end up in recurring or never-ending surgeries that could even lead to death.

In fact, according to the European Antimicrobial Resistance Surveillance Network (EARS-Net), in 2015, more than 30,000 deaths in Europe were linked to infections with antibiotic-resistant bacteria.

Physicians have used several approaches to prevent implant contamination during surgery. Post-surgery aseptic protocols have been established and implemented to fight these antibiotic-resistant bacteria, but none have entirely fulfilled the role of solving this issue.

SEM micrographs of the S. aureus biofilm formed on the surgical mesh surface. Credit: ICFO

In a recent study published in Nano Letters and highlighted in Nature Photonics, ICFO researchers Dr. Ignacio de Miguel, Arantxa Albornoz, led by ICREA Prof. at ICFO Romain Quidant, in collaboration with researchers Irene Prieto, Dr. Vanesa Sanz, Dr. Christine Weis and Dr. Pau Turon from the B. Braun and pharmaceutical device company, have devised a novel technique that uses nanotechnology and photonics to dramatically improve the performance of medical meshes for surgical implants.

In collaboration since 2012, the team of researchers at ICFO and B. Braun Surgical, S.A., developed a medical mesh with a particular feature: The surface of the mesh was chemically modified to anchor millions of gold nanoparticles.

Why? Because gold nanoparticles have been proven to convert light into heat highly efficiently at localized regions.

The technique of using gold nanoparticles in light-heat conversion processes had already been tested in cancer treatments in previous studies.

Knowing that more than 20 million hernia repair operations take place every year around the world, the researchers believed this method could reduce the medical costs in recurrent operations while eliminating the expensive and ineffective antibiotic treatments that are currently being employed to tackle this problem.

Schematic view of plasmon-enabled biofilm prevention on surgical meshes. Credit: ICFO

Thus, in their in-vitro experiment and through a thorough process, the team coated the surgical mesh with millions of , uniformly spreading them over the entire structure. They tested the meshes to ensure the long-term stability of the particles, the non-degradation of the material, and the non-detachment or release of nanoparticles into the surrounding environment (flask). They were able to observe a homogenous distribution of the nanoparticles over the structure using a scanning electron microscope.

Once the modified mesh was ready, the team exposed it to S. aureus bacteria for 24 hours until they observed the formation of a biofilm on the surface. Subsequently, they began exposing the mesh to short, intense pulses of near  (800 nm) over 30 seconds to ensure  was reached, before repeating this treatment 20 times with four seconds of rest intervals between each pulse.

They discovered the following: First, they saw that illuminating the mesh at the specific frequency would induce localized surface plasmon resonances in the nanoparticles—a mode that results in the efficient conversion of light into heat, burning the bacteria at the surface.

Second, by using a fluorescence confocal microscope, they observed how much of the bacteria had died or was still alive. They observed that the remaining living biofilm bacteria became planktonic cells, recovering their sensitivity or weakness toward antibiotic therapy and to immune system response. They observed that upon increasing the amount of light delivered to the surface of the mesh, the dead bacteria would lose their adherence and peel off the surface. 

Third, they confirmed that operating at near infrared light ranges was completely compatible with in-vivo settings, meaning that such a technique would most probably not damage the surrounding healthy tissue. Finally, they repeated the treatment and confirmed that the recurrent heating of the mesh had not affected its conversion efficiency capabilities.

ICREA Prof at ICFO Romain Quidant says, “The results of this study have paved the way towards using plasmon nanotechnologies to prevent the formation of bacterial biofilm at the surface of surgical implants. There are still several issues that need to be addressed but it is important to emphasize that such a technique will indeed signify a radical change in operation procedures and further patient post recovery.”

Director of Research and Development of B. Braun Surgical, S.A. Dr. Pau Turon, says, “Our commitment to help healthcare professionals to avoid hospital related infections pushes us to develop new strategies to fight bacteria and biofilms. Additionally, the research team is exploring to extend such technology to other sectors where biofilms must be avoided.”

More information: Ignacio de Miguel et al, Plasmon-Based Biofilm Inhibition on Surgical Implants, Nano Letters(2019).  DOI: 10.1021/acs.nanolett.9b00187

Journal information: Nano Letters , Nature Photonics

Provided by ICFO

Scientists Use Near-Infrared Light and Injected DNA Nanodevice to Guide Stem Cells to a Wound – Accelerating the Healing Process


D4hhmicU4AAC5hv

Researchers can guide stem cells (like those in the illustration above) to an injury by using near-infrared light and an injected DNA nanodevice. (Image credit: Juan Gaertner/Shutterstock.com)

Imagine physicians having a remote control that they could employ to drive a patient’s own cells to a wound to accelerate the healing process.

Such a device is still away from reality, however, scientists have described in the ACS journal Nano Letters of having taken a key initial step: They employed near-infrared light and an injected DNA nanodevice to direct stem cells to a wound, which helped in the regrowth of muscle tissue in mice.

Complex signaling pathways synchronize cellular activities like proliferation, movement, and even death. For instance, when signaling molecules attach to proteins known as receptor tyrosine kinases on a cell’s surface, they stimulate the receptors to pair up and phosphorylate each other. This process can trigger other proteins that eventually result in a cell moving or growing.

Hong-Hui Wang, Zhou Nie, and partners doubted if they could set up a nanodevice to cells that would rewire this system, activating the receptors by near-infrared light rather than signaling molecules. The scientists opted for near-infrared as it can penetrate living tissues, in contrast to visible or ultraviolet light. The group aimed a receptor tyrosine kinase known as MET, which is important for wound healing.

The scientists developed a DNA molecule that can attach to two MET receptors at the same time, binding them together and stimulating them. In order to make the system responsive to light, the researchers linked multiple copies of the DNA sequence to gold nanorods. On irradiating near-infrared light, the nanorods get heated up and release the DNA so that it could trigger the receptors.

The scientists introduced the DNA-bound gold nanorods into mice at the injured area and illuminated a near-infrared light on the mice for a few minutes. After three days, more muscle stem cells had moved to the wound in treated mice when compared to those in untreated mice. The treated mice also exhibited improved signs of muscle regeneration in comparison to control mice.

The researchers acknowledge funding from the National Natural Science Foundation of China, National Science and Technology Major Project, the Young Top-Notch Talent for Ten Thousand Talent Program, the Keypoint Research and Invention Program of Hunan Province, and the National Institutes of Health.

 

 

Researchers at CUNY create guidelines for morphable nanomaterials to diagnose, target and effectively treat Life-Threatening Illness such as Cancer, Cardiovascular and Autoimmune diseases


Sensing Nanomaterials newpaperprov

Peptides spontaneously form spherical or worm-like nanostructures that can be morphed or broken down by enzymes overexpressed in cancer cells. By controlling the shape and charge of the nanostructures, scientists can predict the rate of …more

Scientists have long sought to develop drug therapies that can more precisely diagnose, target and effectively treat life-threatening illness such as cancer, cardiovascular and autoimmune diseases.

One promising approach is the design of morphable nanomaterials that can circulate through the body and provide diagnostic information or release precisely targeted drugs in response to disease-marker enzymes. Thanks to a newly published paper from researchers at the Advanced Science Research Center (ASRC) at The Graduate Center of The City University of New York, Brooklyn College, and Hunter College, scientists now have design guidance that could rapidly advance development of such nanomaterials.

In the paper, which appears online in the journal ACS Nano, researchers detail broadly applicable findings from their work to characterize a  that can predictably, specifically and safely respond when it senses overexpression of the enzyme matrix metalloproteinase-9 (MMP-9). MMP-9 helps the body breakdown unneeded extracellular materials, but when levels are too high, it plays a role in the development of cancer and several other diseases.

“Right now, there are no clear rules on how to optimize the nanomaterials to be responsive to MMP-9 in predictable ways,” said Jiye Son, the study’s lead author and a Graduate Center Ph.D. student working in one of the ASRC Nanoscience Initiative labs. “Our work outlines an approach using short peptides to create enzyme-responsive nanostructures that can be customized to take on specific therapeutic actions, like only targeting  and turning on drug release in close proximity of these cells.”

Researchers designed a modular peptide that spontaneously assembles into nanostructures, and predictably and reliably morphs or breaks down into  when they come in contact with the MMP-9 enzyme. The designed components include a charged segment of the nanostructure to facilitate its sensing and engagement with the enzyme; a cleavable segment of the structure so that it can lock onto the enzyme and determine how to respond; and a hydrophobic segment of the structure to facilitate self-assembly of the therapeutic response.

“This work is a critical step toward creating new smart-drug delivery vehicles and diagnostic methods with precisely tunable properties that could change the face of disease treatment and management,” said ASRC Nanoscience Initiative Director Rein Ulijn, whose lab is leading the work. “While we specifically focused on creating nanomaterials that could sense and respond to MMP-9, the components of our design guidance can facilitate development of nanomaterials that sense and respond to other cellular stimuli.”

Among other advances, the research team’s work builds on their previous findings, which showed that amino acid peptides can encapsulate and transform into fibrous drug depots upon interaction with MMP-9. The group is collaborating with scientists at Memorial Sloan Kettering and Brooklyn College to use their findings to create a novel cancer therapy.

 Explore further: Scientists create nanomaterials that reconfigure in response to biochemical signals

More information: Jiye Son et al, Customizing Morphology, Size, and Response Kinetics of Matrix Metalloproteinase-Responsive Nanostructures by Systematic Peptide Design, ACS Nano (2019). DOI: 10.1021/acsnano.8b07401

 

Nanomachines ‘Learn’ to Fight Cancer – ITMO University


Nano Machines Cancer rna
A hairpin loop from a pre-mRNA. Highlighted are the nucleobases (green) and the ribose-phosphate backbone (blue). Note that this is a single strand of RNA that folds back upon itself. Credit: Vossman/ Wikipedia

Scientists from ITMO in collaboration with international colleagues have proposed new DNA-based nanomachines that can be used for gene therapy for cancer. This new invention can greatly contribute to more effective and selective treatment of oncological diseases. The results were published in Angewandte Chemie.

Gene therapy is considered one of the promising ways of treating oncological diseases, even though the current approaches are far from perfect. Oftentimes, the agents fail to discern malignant  from healthy ones, and are bad at interacting with folded RNA targets.

In order to solve this issue, scientists, including a Russian team from ITMO University headed by professor Dmitry Kolpashchikov, proposed special nanomachines. They sought to develop particular molecules, deoxyribozymes, which can interact with targeted RNA, bind them, unfold and cleave. According to the idea, these nanomachines have to recognize DNA oncomarkers and form complexes that can break down messenger RNA of vital  with high selectivity, which will then result in apoptotic death of malignant cells.

The researchers tested the efficiency of the new machines in a model experiment and learned that they can cleave folded RNA molecules better than the original deoxyribozymes. They showed that the design of the nanomachine makes it possible to break down targeted RNA in the presence of a DNA oncomarker only, and the use of RNA-unfolding arms provides for better efficiency. The scientists also learned that the nanomachine can inhibit the growth of , though cellular experiments didn’t show high specificity. The researchers associate this result with a possibly poor choice of the RNA target and a low stability of DNA structures in the cell.

The new approach differs fundamentally from the ones used before. The existing  agents are aimed at suppressing the expression of oncological markers. In the research in question, the scientists focused on the messenger RNA of vital genes, and the oncological marker was used as an activator. This makes it possible to apply the DNA nanomachine in treating any kind of cancer by using new DNA oncomarkers for activating the breakdown of targeted molecules.

The  opens new ways of treating oncological diseases. Still, there are many experiments to be conducted before it can be applied in therapy.

“For now, we are trying to introduce new functional elements in the framework that will contribute to a more effective recognition of oncological markers, and are also optimizing the DNA nanomachine for various RNA targets. In order to improve the efficiency and selectiveness of our constructions in cellular conditions, we are selecting new RNA targets and studying the stability of DNA machines in cells, which we plan to improve with the help of already existing chemical modifications,” comments Daria Nedorezova, Master’s student at ITMO University.

 Explore further: A new nanomachine shows potential for light-selective gene therapy

More information: Dmitry M Kolpashchikov et al, Towards DNA Nanomachines for Cancer Treatment: Achieving Selective and Efficient Cleavage of Folded RNA, Angewandte Chemie (2019). DOI: 10.1002/ange.201900829

 

Ultra ultrasound to revolutionize Technology – From Medical Devices to Unmanned Vehicles


ultraultraso    Credit: University of Queensland

A new and extremely sensitive method of measuring ultrasound could revolutionise everything from medical devices to unmanned vehicles.

Researchers at The University of Queensland have combined modern nanofabrication and nanophotonics techniques to build the ultraprecise  sensors on a silicon chip.

Professor Warwick Bowen, from UQ’s Precision Sensing Initiative and the Australian Centre for Engineered Quantum Systems, said the development could usher in a host of exciting new technologies.

“This is a major step forward, since accurate ultrasound measurement is critical for a range of applications,” he said.

“Ultrasound is used for medical ultrasound, often to examine , as well as for  biomedical imaging to detect tumours and other anomalies.

“It’s also commonly used for spatial applications, like in the sonar imaging of underwater objects or in the navigation of unmanned aerial vehicles.

“Improving these applications requires smaller, higher precision sensors and, with this new technique, that’s exactly what we’ve been able to develop.”

The technology is so sensitive that it can hear, for the first time, the miniscule random forces from surrounding air molecules.

“We’ve developed a near perfect ultrasound detector, hitting the limits of what the technology is capable of achieving,” Professor Bowen said.

“We’re now able to measure ultrasound waves that apply tiny forces – comparable to the gravitational force on a virus – and we can do this with sensors smaller than a millimetre across.”

Research leader Dr. Sahar Basiri-Esfahani, now at Swansea University, said the accuracy of the  could change how scientists understand biology.

“We’ll soon have the ability to listen to the sound emitted by living bacteria and cells,” she said.

“This could fundamentally improve our understanding of how these small biological systems function.

“A deeper understanding of these biological systems may lead to new treatments, so we’re looking forward to seeing what future applications emerge.”

The research is published in Nature Communications.

 Explore further: Miniaturised pipe organ could aid medical imaging

More information: Sahar Basiri-Esfahani et al. Precision ultrasound sensing on a chip, Nature Communications (2019). DOI: 10.1038/s41467-018-08038-4

 

Washington State U – Bio-inspired nanoscale Research – Nano-Flowers may lead lead to more effective drug delivery and diagnostics for cancer and other illnesses


bio inspired drug delivery 190110141800_1_540x360
Schematic representation of the movement of the flower-like particle as it makes its way through a cellular trap to deliver therapeutic genes.
Credit: WSU

Washington State University researchers have developed a novel way to deliver drugs and therapies into cells at the nanoscale without causing toxic effects that have stymied other such efforts.

The work could someday lead to more effective therapies and diagnostics for cancer and other illnesses.

Led by Yuehe Lin, professor in WSU’s School of Mechanical and Materials Engineering, and Chunlong Chen, senior scientist at the Department of Energy’s Pacific Northwest National Laboratory (PNNL), the research team developed biologically inspired materials at the nanoscale that were able to effectively deliver model therapeutic genes into tumor cells. They published their results in the journal, Small.

Researchers have been working to develop nanomaterials that can effectively carry therapeutic genes directly into the cells for the treatment of diseases such as cancer. The key issues for gene delivery using nanomaterials are their low delivery efficiency of medicine and potential toxicity.

“To develop nanotechnology for medical purposes, the first thing to consider is toxicity — That is the first concern for doctors,” said Lin.

The flower-like particle the WSU and PNNL team developed is about 150 nanometers in size, or about one thousand times smaller than the width of a piece of paper. It is made of sheets of peptoids, which are similar to natural peptides that make up proteins. The peptoids make for a good drug delivery particle because they’re fairly easy to synthesize and, because they’re similar to natural biological materials, work well in biological systems.

The researchers added fluorescent probes in their peptoid nanoflowers, so they could trace them as they made their way through cells, and they added the element fluorine, which helped the nanoflowers more easily escape from tricky cellular traps that often impede drug delivery.

The flower-like particles loaded with therapeutic genes were able to make their way smoothly out of the predicted cellular trap, enter the heart of the cell, and release their drug there.

“The nanoflowers successfully and rapidly escaped (the cell trap) and exhibited minimal cytotoxicity,” said Lin.

After their initial testing with model drug molecules, the researchers hope to conduct further studies using real medicines.

“This paves a new way for us to develop nanocargoes that can efficiently deliver drug molecules into the cell and offers new opportunities for targeted gene therapies,” he said.

The WSU and PNNL team have filed a patent application for the new technology, and they are seeking industrial partners for further development.

Story Source:

Materials provided by Washington State UniversityNote: Content may be edited for style and length.


Journal Reference:

  1. Yang Song, Mingming Wang, Suiqiong Li, Haibao Jin, Xiaoli Cai, Dan Du, He Li, Chun-Long Chen, Yuehe Lin. Efficient Cytosolic Delivery Using Crystalline Nanoflowers Assembled from Fluorinated PeptoidsSmall, 2018; 14 (52): 1803544 DOI: 10.1002/smll.201803544