Researchers at Oregon State University reach Milestone in use of Nanoparticles to kill Cancer with Heat


Abstract:
Researchers at Oregon State University have developed an improved technique for using magnetic nanoclusters to kill hard-to-reach tumors.

 

Magnetic nanoparticles – tiny pieces of matter as small as one-billionth of a meter – have shown anti-cancer promise for tumors easily accessible by syringe, allowing the particles to be injected directly into the cancerous growth.

Once injected into the tumor, the nanoparticles are exposed to an alternating magnetic field, or AMF. This field causes the nanoparticles to reach temperatures in excess of 100 degrees Fahrenheit, which causes the cancer cells to die.

But for some cancer types such as prostate cancer, or the ovarian cancer used in the Oregon State study, direct injection is difficult. In those types of cases, a “systemic” delivery method – intravenous injection, or injection into the abdominal cavity – would be easier and more effective.

The challenge for researchers has been finding the right kind of nanoparticles – ones that, when administered systemically in clinically appropriate doses, accumulate in the tumor well enough to allow the AMF to heat cancer cells to death.

Olena Taratula and Oleh Taratula of the OSU College of Pharmacy tackled the problem by developing nanoclusters, multiatom collections of nanoparticles, with enhanced heating efficiency. The nanoclusters are hexagon-shaped iron oxide nanoparticles doped with cobalt and manganese and loaded into biodegradable nanocarriers.

Findings were published in ACS Nano.

“There had been many attempts to develop nanoparticles that could be administered systemically in safe doses and still allow for hot enough temperatures inside the tumor,” said Olena Taratula, associate professor of pharmaceutical sciences. “Our new nanoplatform is a milestone for treating difficult-to-access tumors with magnetic hyperthermia. This is a proof of concept, and the nanoclusters could potentially be optimized for even greater heating efficiency.”

The nanoclusters’ ability to reach therapeutically relevant temperatures in tumors following a single, low-dose IV injection opens the door to exploiting the full potential of magnetic hyperthermia in treating cancer, either by itself or with other therapies, she added.

“It’s already been shown that magnetic hyperthermia at moderate temperatures increases the susceptibility of cancer cells to chemotherapy, radiation and immunotherapy,” Taratula said.

The mouse model in this research involved animals receiving IV nanocluster injections after ovarian tumors had been grafted underneath their skin.

“To advance this technology, future studies need to use orthotopic animal models – models where deep-seated tumors are studied in the location they would actually occur in the body,” she said. “In addition, to minimize the heating of healthy tissue, current AMF systems need to be optimized, or new ones developed.”

The National Institutes of Health, the OSU College of Pharmacy and Najran University of Saudi Arabia supported this research.

Also collaborating were OSU electrical engineering professor Pallavi Dhagat, postdoctoral scholars Xiaoning Li and Canan Schumann of the College of Pharmacy, pharmacy graduate students Hassan Albarqi, Fahad Sabei and Abraham Moses, engineering graduate student Mikkel Hansen, and pre-pharmacy undergrads Tetiana Korzun and Leon Wong.

Copyright © Oregon State University

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Looking at Nanotechnology in Biotechnology


For some time, the difference between a biotechnology company and a pharmaceutical company was straightforward.

A biotechnology focused on developing drugs with a biological basis. Pharmaceutical companies focused on drugs with a chemical basis.

It was sort of an artificial distinction, and is even more so now because pharmaceutical companies haven’t excluded biologics from their portfolios.

At one time there were even distinctions in the definitions related to small molecules versus large molecules, but those are largely in the dustbin of biopharma vocabulary. It’s one reason why “biopharma” itself is a useful word to bridge the two, and really, biotech and pharma are largely interchangeable.

Nanotechnology Versus Biotechnology

But what about nanotechnology? Is that biotechnology?

The answer to that seems to be … yes and no.

Nanotechnology typically refers to technology that is less than 100 nanometers in size. Although not horribly useful for differentiating things on the microscopic—or smaller—scale, there are 25,400,000 nanometers in an inch. So … small. Really small.

Wouldn’t that refer to many drugs? Yes, probably.

But nanotechnology typicallyrefers to tech made of manmade and inorganic materials in that size range. Again, the key word is “typically.”

There is overlap.  Liji Thomas, writing for Azo Nano, says, “Nanobiotechnology deals with technology which incorporates nanomolecules into biological systems, or which miniaturizes biotechnology solutions to nanometer size to achieve greater reach and efficacy….

Bionanotechnology, on the other hand, deals with new nanostructures that are created for synthetic applications, the difference being that these are based upon biomolecules.”

Clear? Probably not. Here are some examples of biotechnology companies utilizing nanotechnology, along with whatever tools they need to develop their compounds.

PEEL Therapeutics. PEEL Therapeutics is a small biotech company, largely in stealth mode, founded by Joshua Schiffman, an associate professor of Pediatrics at the University of Utah and Avi Schroeder, an assistant professor of chemical engineering at the Technion-Israel Institute of Technology. 

Schiffman was doing work on a tumor suppressor gene, p53, which shows up at very high numbers in elephants. Elephants have significantly lower rates of cancer than humans, who normally have two normal copies of p53. Humans with a disease called Li-Fraumeni Syndrome, have only one, and they have a 100 percent change of getting cancer, or very close to it.

What PEEL is attempting to do is build a synthetic version of p53 and insert them into a novel drug delivery system using nanotechnology. “Peel,” by the way, is the phonetic spelling of the Hebrew word for elephants. eP53 has been successfully encapsulated in nanoparticles, and at least in petri dishes, has demonstrated proof of concept. Elephants are not being experimented upon.

Exicure. Based in Skokie, Illinois, Exicure (formerly known as AuraSense) is a clinical stage biotechnology company that’s working on a new class of immunomodulatory and gene regulating drugs that uses proprietary three-dimensional, spherical nucleic acid architecture.

The SNA technology came out of the laboratory of Chad Mirkin at the Northwestern University International Institute for Nanotechnology.

The company has received financing from the likes of Microsoft’s Bill Gates, Aonfounder Pat Ryan, David Walt, co-founder of Illumina, and Boon Hwee Koh, director of Agilent Technologies. 

The technology platform is complex, but it is essentially various single and double-stranded nucleic acids stuck on the outside of a nanosphere.

They are able to easily penetrate cells, which then trigger immune responses.

SpyBiotech. Headquartered in Oxford, UK, SpyBiotech focuses on the so-called “super glue” that combines two parts of the bacteria that causes strep throat. It was spun out of Oxford University, and was based on research performed by its Department of Biochemistry and the Jenner Institute. When the bacteria that cause step throat are separated, they are attracted to each other and attempt to reattach.

The company is working to use this principle to develop vaccines that, instead of using virus-causing bacteria, will bind onto viral infections.

One of the bacteria that can cause strep throat, impetigo and other infections, Streptococcus pyogenes, is often shortened to Spy, hence the name of the company. When Spy is split into a peptide (SpyTag) and its protein partner (SpyCatcher), they are attracted to each other. The researchers isolated the “glue” that creates the attraction, and believe it can be used to bond vaccines together.

The company has backing from GV,formerly Google Ventures, the venture fund backed by Alphabet/Google.

One of the company’s founders is Mark Howarth, professor of Protein Nanotechnology at the University of Oxford. The fact that he’s working on protein nanotechnology undercuts a traditional definition of nanotechnology as not using biological materials. On his website, Howarth notes that SpyTag and SpyCatcher “is the strongest protein interaction yet measured and is being applied around the world for diverse areas of basic research and biotechnology. We are extending this new class of protein interaction, to create novel possibilities for synthetic biology.”

Ultimately, when researchers are developing drugs, they are using whatever tools are necessary to find effective treatments for diseases. Biotechnology may more accurately be thought of as a set of tools and a philosophical approach to solving biological problems, compared to pharmaceuticals, and nanotechnology is yet another tool.

In the wider world of drug discovery and development, there is also increasing use of artificial intelligence, data science and computational algorithms as well. And who knows what will be used tomorrow.

Vanderbilt U – New nanoparticle targets tumor-infiltrating immune cells – Then ‘flips the switch’ to tell them to ‘Start Fighting’


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Immune cells (green and red) surround and prepare to destroy a cancer cell (blue, center) Credit: Alex Ritter, Jennifer Lippincott Schwartz and Gillian Griffiths, National Institutes of Health

 

A team of Vanderbilt University bioengineers today announced a major breakthrough in penetrating the cells inside tumors and flipping on a switch that tells them to start fighting.

Immunotherapy’s promise in the fight against cancer drew international attention after two scientists won a Nobel Prize this year for unleashing the ability of the immune system to eliminate tumor cells.

But their approach, which keeps cancer cells from shutting off the immune system’s powerful T-cells before they can fight tumors, is just one way to use the body’s natural defenses against deadly disease.

 

A team of Vanderbilt University bioengineers today announced a major breakthrough in another: penetrating tumor-infiltrating immune cells and flipping on a switch that tells them to start fighting. The team designed a nanoscale particle to do that and found early success using it on human melanoma tissue.

“Tumors are pretty conniving and have evolved many ways to evade detection from our immune system,” said John T. Wilson, assistant professor of chemical and biomolecular engineering and biomedical engineering. “Our goal is to rearm the immune system with the tools it needs to destroy cancer cells.

“Checkpoint blockade has been a major breakthrough, but despite the huge impact it continues to have, we also know that there are a lot of patients who don’t respond to these therapies. We’ve developed a nanoparticle to find tumors and deliver a specific type of molecule that’s produced naturally by our bodies to fight off cancer.” 2018-immunotherapy-generic-banner-3

That molecule is called cGAMP, and it’s the primary way to switch on what’s known as the stimulator of interferon genes (STING) pathway: a natural mechanism the body uses to mount an immune response that can fight viruses or bacteria or clear out malignant cells. Wilson said his team’s nanoparticle delivers cGAMP in a way that jump-starts the immune response inside the tumor, resulting in the generation of T-cells that can destroy the tumor from the inside and also improve responses to checkpoint blockade.

While the Vanderbilt team’s research focused on melanoma, their work also indicates that this could impact treatment of many cancers, Wilson said, including breast, kidney, head and neck, neuroblastoma, colorectal and lung cancer.

His findings appear today in a paper titled “Endosomolytic Polymersomes Increase the Activity of Cyclic Dinucleotide STING Agonists to Enhance Cancer Immunotherapy” in the journal Nature Nanotechnology.

Daniel Shae, a Ph.D. student on Wilson’s team and first author of the manuscript, said the process began with developing the right nanoparticle, built using “smart” polymers that respond to changes in pH that he engineered to enhance the potency of cGAMP. After 20 or so iterations, the team found one that could deliver cGAMP and activate STING efficiently in mouse immune cells, then mouse tumors and eventually human tissue samples.

“That’s really exciting because it demonstrates that, one day, this technology may have success in patients,” Shae said.

Story Source:

Materials provided by Vanderbilt University. Original written by Heidi Nieland Hall. Note: Content may be edited for style and length.


Journal Reference:

  1. Daniel Shae, Kyle W. Becker, Plamen Christov, Dong Soo Yun, Abigail K. R. Lytton-Jean, Sema Sevimli, Manuel Ascano, Mark Kelley, Douglas B. Johnson, Justin M. Balko, John T. Wilson. Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer immunotherapyNature Nanotechnology, 2019; DOI: 10.1038/s41565-018-0342-5

Touratech Guardo Adventure Gloves with Nanotechnology


When the engineers at Touratech designed the new Guardo Adventure Glove, they took into account all of the conditions riders face during a motorcycle trip.

From terrain to climate, everything was considered when Guardo was created. The result is a highly functional, breathable, protective and comfortable glove that’s perfect for any ride, no matter what is encountered.

Sharktec® Nanotechnology is widely used in tactical applications and was a clear choice for the palm and fingers of the Guardo Adventure Glove. 

Sharktec® is cut and fire resistant, vibration damping, and provides incredible grip even when wet or oily. It feels rubbery and flexible, but is one of the toughest glove materials on the planet.

Touratech Guardo 02

After a day in the saddle (at the KTM Ultimate Race Qualifier) wearing the Guardo Adventure Gloves I can confidently say these are the best adventure-specific gloves I have ever used. – Iain Glynn, Chief Riding Officer, Touratech-USA

Along with the Sharktec® palm and fingers, Touratech utilized only the optimum materials for adventure riding gloves with a supple goatskin shell, neoprene and spandex on the backs of the fingers supplemented by hand heel and hand edge reinforcement with Superfabric©. The fingertips are touchscreen friendly and the soft finger knuckle protectors are next-level quality.

Touratech’s Guardo Adventuregloves are ideally suited for anything an adventure can throw at the rider.

Touratech-USA.com

Touratech Guardo 08

Environmentally friendly photoluminescent nanoparticles for more vivid display colors


IMAGE: THESE ARE STRUCTURES OF SILVER INDIUM SULFIDE/GALLIUM SULFIDE CORE/SHELL QUANTUM DOTS AND PICTURES OF THE CORE/SHELL QUANTUM DOTS UNDER ROOM LIGHT. view more 

CREDIT: OSAKA UNIVERSITY

Osaka, Japan – Most current displays do not always accurately represent the world’s colors as we perceive them by eye, instead only representing roughly 70% of them. To make better displays with true colors commonly available, researchers have focused their efforts on light-emitting nanoparticles.

Such nanoparticles can also be used in medical research to light up and keep track of drugs when developing and testing new medicines in the body. However, the metal these light-emitting nanoparticles are based on, namely cadmium, is highly toxic, which limits its applications in medical research and in consumer products–many countries may soon introduce bans on toxic nanoparticles.

It is therefore vital to create non-toxic versions of these nanoparticles that have similar properties: they must produce very clean colors and must do so in a very energy-efficient way. So far researchers have succeeded in creating non-toxic nanoparticles that emit light in an efficient manner by creating semiconductors with three types of elements in them, for example, silver, indium, and sulfur (in the form of silver indium disulfide (AgInS2)). However, the colors they emit are not pure enough–and many researchers declared that it would be impossible for such nanoparticles to ever emit pure colors.

Now, researchers from Osaka University have proven that it is possible by fabricating semiconductor nanoparticles containing silver indium disulfide and adding a shell around them consisting of a semiconductor material made of two different elements, gallium and sulfur. The team was able to reproducibly create these shell-covered nanoparticles that are both energy efficient and emit vivid, clean colors. The team have recently published their research in the Nature journal NPG Asia Materials.

“We synthesized non-toxic nanoparticles in the normal way: mix all ingredients together and heat them up. The results were not fantastic, but by tweaking the synthesis conditions and modifying the nanoparticle cores and the shells we enclosed them in, we were able to achieve fantastic efficiencies and very pure colors,” study coauthor Susumu Kuwabata says.

Enclosing nanoparticles in semiconductor shells in nothing new, but the shells that are currently used have rigidly arranged atoms inside them, whereas the new particles are made of a more chaotic material without such a rigid structure.

“The silver indium disulfide particles emitted purer colors after the coating with gallium sulfide. On top of that, the shell parts in microscopic images were totally amorphous. We think the less rigid nature of the shell material played an important part in that–it was more adaptable and therefore able to take on more energetically favorable conformations,” first author Taro Uematsu says.

The team’s results demonstrate that it is possible to create cadmium-free, non-toxic nanoparticles with very good color-emitting properties by using amorphous shells around the nanoparticle cores.

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The article, “Narrow band-edge photoluminescence from AgInS2 semiconductor nanoparticles by the formation of amorphous III-VI semiconductor shells” was published in NPG Asia Materials, https://doi.org/10.1038/s41427-018-0067-9.

Identifying the ‘Culprit’ (molecule) for the Cause of Alzheimer’s: A ‘Big Bang’ Research Breakthrough at UT Southwestern O’Donnell Brain Institute + Video


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It’s being called the “big bang” breakthrough in Alzheimer’s research. Doctors at UT Southwestern’s O’Donnell Brain Institute have detected what they believe are changes in a single molecule that could act as the starting point for the deadly, memory-stealing disease.

Scientists are fairly certain that a molecule called “tau” is the culprit.

Alzheimer’s is characterized by clumps of tangled protein in the brain. According to the Alzheimer’s Association, one in three seniors will die of the disease — and that’s more than breast and prostate cancer combined.

Ultimately, researchers hope that warning signals for the disease can be effectively detected and therefore prevented with something as simple as a vaccine or pill.

“I anticipate a day when we will think about these diseases like Alzheimer’s and Parkinson’s as problems that only people who don’t get medical care develop,” said Dr. Diamond.

Researchers know that there is much work ahead. It could be several years before the discovery is ready for human clinical trials. Until then, supporters say it’s critical for lawmakers to fund research at all levels.UTSW II luo-chen

Patients can also get involved in local studies so doctors can learn as much as they can from seniors as they age. And while the advances won’t happen overnight, doctors say the overriding message for the community in the discovery is that there is hope.

“There’s tremendous hope!” said Dr. Diamond. “We are actually super excited in our field. When I look at the future, I see many, many opportunities for good shots on goal.”

And if he’s right, the discovery could be a life-changing win for the world.

Watch the Video

 

Exploring Nanotechnology to Enhance Treatment, Diagnosis & Drug Discovery


What can you do with a liberal arts degree? Native New Yorker Daniel Heller, PhD, majored in history, added in some basic science courses, and started his working life as a middle school science teacher. After taking some additional chemistry coursework during non-teaching hours, Heller parlayed it all into a doctorate in chemistry from the University of Illinois.

Today he is a biomedical engineer at Memorial Sloan Kettering Cancer Center (MSKCC), New York City, where his Cancer Nanomedicine Laboratory team invents new technologies that can assist health care in helping human kind.

Heller chuckled when mentioning his circuitous life path and some of the stops along the way: performing as a wizard at a Renaissance Fair (“…liquid nitrogen turns into a pretty impressive potion…”), trying to master the Argentine tango, appreciating his brother’s equally non-traditional path as a drummer in heavy metal bands, and happily settling into married life with his wife who is a primary care physician.

In recent years, he has also managed to garner solid industry credentials in the form of awards, including the NSF CAREER Award (2018), Pershing Square Sohn Prize for Young Innovators in Cancer Research (2017), and NIH Director’s New Innovator Award (2012), among others.

“I like inventing,” Heller stated simply. “In my lab, we often think of ourselves as biomedical engineers whose primary goal is invent new technologies to improve cancer research, diagnosis, and therapy.

Only when I arrived at MSKCC did I realize how far that is from the way biologists think. I was trained that our goal is to invent, and to learn new science along the way, while a biologist’s goal is to understand nature and develop tools mainly as a means to an end. I didn’t have a huge biomedical background coming in, but by talking to the people around me at Sloan Kettering and Weill Cornell Medicine [where he is an Assistant Professor], I have learned a great deal.”

As detailed on his laboratory website (www.mskcc.org/research-areas/labs/daniel-heller), Heller and team are “… developing nanomedicines to target precision agents to disease sites, including to metastatic cancers. We are also addressing the problem of the early detection of cancer and other diseases by building implantable nanosensors.

To enable the discovery of new medicines, we also are inventing new nanosensors and imaging tools to accelerate drug development and biomedical research.”

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Nanoparticles in Treatment

Heller told Oncology Times that it all begins with interaction and collaboration. “We are lucky because we get to dig deep with the clinicians, clinician/scientists, and biologists to understand exactly what might be wrong with a particular mode of therapy,” said Heller of his development process. “An oncologist might talk to us about a drug or class of therapies that have particular problems and specific side effects, such as dose-limiting toxicity that prevents people from getting enough of a therapy to adequately inhibit the target in the tumor.”

He added that problems often stem from the fact that a drug negatively affects tissue that is not part of the tumor. “Can we avoid that one vulnerable tissue that will really mess up the use of this drug for treating the tumor? Can we prevent the drug from getting into that tissue?” asked Heller rhetorically. Clearly, he believes it is possible with the help of nanoparticles.

He noted that people erroneously think of nanoparticles as being “the smallest of the small.” But small molecule drugs, and even protein drugs, are much smaller than nanoparticles. Most drugs can diffuse all over the body. “But if we put the drug into a larger nanoparticle, we can keep it from spraying out over all the tissues,” detailed Heller.

His team also must consider how to deliver the nanoparticle containing the drug to a precise location in the tumor site, and whether there is a target that can lead it to that tumor site. “Most of the targets we are looking for are not on the tumor cells themselves, but on the blood vessels that are feeding the tumor,” said Heller. “Our targets are not drug targets, but rather gateways to the tumor, molecules on blood vessels in tumors sites, or sites of inflammation. Then we make sure that the nanoparticle has a molecule on the outside of it that can stick to those targets.”

The research takes the engineering team into the realms of vascular biology, vascular transport, and an understanding of how materials can get across the blood, across the blood/brain barrier, across the tumor barrier. “We are also exploring signaling pathways,” said Heller. “When trying to deliver a kinase inhibitor, for example, we must consider the target we are hitting, where else that target is in the body, and if there any other off-target proteins elsewhere in the body that the drug will hit. We also have to think about resistance mechanisms and compensatory pathways. So as a team we have been learning a lot of physiology.”

Heller says his 5-year-old laboratory contains requisite benches, a tissue culture room, and a studio equipped with lasers and optics for work on sensors. In the basement reside the all-important mice, critical to preclinical development and testing. Looking at target proteins in the body of a mouse, the team is able to determine if a drug encased in a nanoparticle hits the target, if it works better in a nanoparticle, and if it has the same side effects.

The eventual goal is to translate this understanding and these emerging technologies to clinical use and human patients. But it is a long row to hoe. “Once a technology is developed, it must go through the full ‘investigational new drug’ FDA process,” Heller lamented. “Even if a known compound is inside the particle, the whole particle is treated as a new drug.

That means we can’t just give it to clinicians to trial in patients; first the FDA must allow us to start a clinical trial.” Though regulatory delays are a frustration, the researcher said enthusiasm remains high because the potential of the new technologies is so powerful.

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Nanoparticles in Detection

The Cancer Nanomedicine Laboratory also maintains an interest in developing innovative approaches to cancer detection that is “… easier and more predictive. We found that we can detect some cancers earlier by measuring certain biomarkers in a person without having to take blood or biofluids to do it,” said Heller.

Instead, a tiny sensor made of carbon nanotubes is inserted inside a person. The nanotubes give off infrared light that can pass through tissues. “We can implant nanomaterial in a body, shoot light into it from outside the body, and then get a reading externally,” detailed Heller. “These nanomaterials are very sensitive to certain stimuli. We can put an antibody onto the surface of the nanotube and when it binds to an antigen we can see a signal change—a shift in the wavelength of the nanotube fluorescence—through the tissue.” (The team successfully detected ovarian cancer signaling changes in a mouse model. This work was detailed in a paper, Non-Invasive Ovarian Cancer Biomarker Detection via an Optical Nanosensor Implant, coauthored by Heller in Science Advances [2018;4(4):eaaq1090]).

Implications for future use of this technology in humans are significant. Heller said the first possible application could be in people with risk factors for certain diseases. “We could implant a biomarker or panel of biomarkers in people to detect early stage cancer, to measure cancer recurrence, or to monitor treatment and have earlier warning when therapy stops working.”

Asked how early the signaling changes would become apparent, Heller said it depends on the level of a given marker in the tissue. “With ovarian cancer, we would look at the technology as an intrauterine device, placed near the source of the cancer. If we were to wait for biomarkers to reach a high enough level to be detected in the blood, we likely would be dealing with late-stage cancer. If we can measure that biomarker right next to the ovaries or fallopian tube, we would see signal changes at an even earlier point in the life cycle of the cancer.”

Looking downstream of this work, Heller said the team is already questioning if it might be possible to insert a small sensor under the skin, in the blood, or even in a tattoo to measure all kinds of biomarkers, then report a whole panel in real time, at early stages, back to a wearable Fitbit-like device. “The long-term hope is to find super easy ways to measure lots of biomarkers in real time,” said Heller.

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Nanoparticles in Discovery

A third aspect of the work underway in Heller’s lab focuses on making research tools, specifically using carbon nanotubes as sensors in drug discovery assays. Heller believes the sensors will be able to measure things that have not been measurable before, or measured in ways that could not be accomplished before, such as in living cells and living tissue. “By measuring an analyte inside living cells or living tissue in mice, we gain the ability to do studies that cannot be done otherwise. This will allow us to address new hypotheses, and it will be helpful for drug development and for basic researchers at institutions such as MSKCC.”

Heller stressed that it is exactly institutions like MSKCC that can lead the way in helping biomedical engineers interact more fully with biomedical researchers. “Even though both of these concepts have the word ‘biomedical’ in them, ‘biomedical engineering’ departments come from engineering schools, while ‘biomedical research’ comes from places that often do not have engineering schools.

So there is a disconnect,” said Heller. “I realize how valuable it is to me as an engineering researcher to be in a biomedical institution and come in contact with the people who study biomedical questions and understand the medical problems. Biomedical institutions would benefit greatly from organized efforts to bring in engineering researchers whose goal it is to understand and make new technologies to address their problems.”

Heller laughed at the suggestion that some of the things he makes sound like cinematic props from the vintage sci-fi flick, The Incredible Voyage. “Sometimes people think we are the science fiction lab of Memorial Sloan Kettering,” he admitted with humor. And when asked if the younger history student/middle school teacher/or physical scientist in him ever thinks, “I can’t believe I am doing this kind of stuff,” he answered without hesitation, “Yeah, all the time. I think I have gotten to where I am by not defining myself. It’s important to be flexible. Where does it stop? It doesn’t. If you keep changing you can aspire to do anything you want.”

Valerie Neff Newitt is a contributing writer.

The remarkable nanostructure of human bone – Revealed


Interweaving mineral and protein form continuous networks to provide the strength essential for functional bones.

Credit: Dr Roland Kröger

Summary:

Using advanced 3D nanoscale imaging of the mineral in human bone, research teams have shown that the mineral crystals of bone have a hierarchical structure integrated into the larger-scale make-up of the skeleton.

Scientists have produced a 3D nanoscale reconstruction of the mineral structure of bone.

Bone performs equally well whether in an accelerating cheetah or in a heavy elephant, thanks to its toughness and strength.

The properties of bone can be attributed to its hierarchical organisation, where small elements form larger structures.

However, the nanoscale organisation and relationship between bone’s principle components — mineral and protein — have not been fully understood.

Using advanced 3D nanoscale imaging of the mineral in human bone, research teams from the University of York and Imperial College London have shown that the mineral crystals of bone have a hierarchical structure integrated into the larger-scale make-up of the skeleton.

Researchers combined a number of advanced electron microscopy-based techniques, and found that the principal building blocks of mineral at the nanometre scale are curved needle-shaped nanocrystals that form larger twisted platelets that resemble propeller blades.

The blades continuously merge and split throughout the protein phase of bone. The interweaving mineral and protein form continuous networks to provide the strength essential for functional bones.

Lead author, Associate Professor Roland Kröger, from the University of York’s Department of Physics, said: “Bone is an intriguing composite of essentially two materials, the flexible protein collagen and the hard mineral called apatite.”

“There is a lot of discussion about the way these two stiff and flexible phases uniquely combine to provide toughness and strength to bone.

“The combination of the two materials in a hierarchical manner provides bone with mechanical properties that are superior to those of its individual components alone and we find that there are 12 levels of hierarchy in bone.”

Dr Natalie Reznikov, formerly of Imperial College, London and an author on the paper, said: “If we compare this arrangement, for example, to an individual living in a room of a house, this extends to a house in a street, then the street in a neighbourhood, a neighbourhood in a city, a country and on it goes. If you continue to 12 levels you are reaching the size of a galaxy! ”

Professor Molly Stevens, from Imperial College, London, added: “This work builds on the shoulders of many beautiful previous studies investigating the fundamental properties and structure of bone and helps to unlock an important missing piece of the puzzle.”

Besides the large number of nested structures in bone, a common feature of all of them is a slight curvature, providing twisted geometry. To name a few, the mineral crystals are curved, the protein strands (collagen) are braided, the mineralized collagen fibrils twist, and the entire bones themselves have a twist, such as those seen in the curving shape of a rib for example.

Fractals are common in Nature: you can see self-similar patterns in lightning bolts, coast lines, tree branches, clouds and snowflakes. This means that the structure of bone follows a fundamental order principle in Nature.

The authors believe that the fractal-like structure of bone is one of the key reasons for its remarkable attributes.

The findings are published in the journal Science.

University of Delaware: Programming DNA to deliver cancer drugs


DNA has an important job — it tells your cells which proteins to make. Now, a research team at the University of Delaware has developed technology to program strands of DNA into switches that turn proteins on and off. Credit: University of Delaware

DNA has an important job—it tells your cells which proteins to make. Now, a research team at the University of Delaware has developed technology to program strands of DNA into switches that turn proteins on and off.

UD’s Wilfred Chen Group describes their results in a paper published Monday, March 12 in the journal Nature Chemistry. This technology could lead to the development of new cancer therapies and other drugs.

Computing with DNA

This project taps into an emerging field known as DNA computing. Data we commonly send and receive in everyday life, such as text messages and photos, utilize binary code, which has two components—ones and zeroes. DNA is essentially a code with four components, the nucleotides guanine, adenine, cytosine, and thymine. In cells, the arrangement of these four nucleotides determines the output—the proteins made by the DNA. Here, scientists have repurposed the DNA code to design logic-gated DNA circuits.

“Once we had designed the system, we had to first go into the lab and attach these DNA strands to various proteins we wanted to be able to control,” said study author Rebecca P. Chen, a doctoral student in chemical and biomolecular engineering (no relation to Wilfred Chen).

The custom sequence designed DNA strands were ordered from a manufacturer while the proteins were made and purified in the lab. Next, the protein was attached to the DNA to make protein-DNA conjugates.

The group then tested the DNA circuits on E. coli bacteria and human cells. The target proteins organized, assembled, and disassembled in accordance with their design.

“Previous work has shown how powerful DNA nanotechnology might possibly be, and we know how powerful proteins are within cells,” said Rebecca P. Chen. “We managed to link those two together.”

Applications to drug delivery

The team also demonstrated that their DNA-logic devices could activate a non-toxic cancer prodrug, 5-fluorocytosine, into its toxic chemotherapeutic form, 5-fluorouracil. Cancer prodrugs are inactive until they are metabolized into their therapeutic form.

In this case, the scientists designed DNA circuits that controlled the activity of a protein that was responsible for conversion of the prodrug into its active form. The DNA circuit and protein activity was turned “on” by specific RNA/DNA sequence inputs, while in the absence of said inputs the system stayed “off.”

To do this, the scientists based their sequence inputs on microRNA, small RNA molecules that regulate cellular gene expression. MicroRNA in cancer cells contains anomalies that would not be found in healthy cells. For example, certain microRNA are present in cancer cells but absent in healthy cells. The group calculated how nucleotides should be arranged to activate the cancer prodrug in the presence of cancer microRNA, but stay inactive and non-toxic in a non-cancerous environment where the microRNA are missing.

When the cancer microRNAs were present and able to turn the DNA circuit on, cells were unable to grow. When the circuit was turned off, cells grew normally.

Wilfred Chen (left) and Rebecca P. Chen are developing new biomolecular tools to address key global health problems. Credit: University of Delaware/ Evan Krape

This technology could have wide applications not only to other diseases besides cancer, but also beyond the biomedical field. For example, the research team demonstrated that their technology could be applied to the production of biofuels, by utilizing their technology to guide an enzymatic cascade, a series of chemical reactions, to break down a plant fiber.

Using the newly developed technology, researchers could target any DNA sequence of their choosing and attach and control any protein they want. Someday, researchers could “plug and play” programmed DNA into a variety of cells to address a variety of diseases, said study author Wilfred Chen, Gore Professor of Chemical Engineering.

“This is based on a very simple concept, a logical combination, but we are the first to make it work,” he said. “It can address a wide scope of problems, and that makes it very intriguing.”

More information: Rebecca P. Chen et al, Dynamic protein assembly by programmable DNA strand displacement, Nature Chemistry (2018). DOI: 10.1038/s41557-018-0016-9

Provided by: University of Delaware

Is It Possible? Will You Soon be Able to Replace Your Glasses And Contacts With Nanoparticle Eyedrops?


A revolutionary, cutting-edge technology, developed by researchers at Bar-Ilan University’s Institute of Nanotechnology and Advanced Materials (BINA), has the potential to provide a new alternative to eyeglasses, contact lenses, and laser correction for refractive errors.

The technology, known as Nano-Drops, was developed by Dr. David Smadja (Ophthalmologist from Shaare Zedek Medical Center), Prof. Zeev Zalevsky, from Bar-Ilan’s Kofkin Faculty of Engineering, and Prof. Jean-Paul Moshe Lellouche, Head of the Department of Chemistry at Bar-Ilan. A related patent on this new invention was recently filed by Birad – Research & Development Company Ltd., the commercializing company of Bar-Ilan University.

Nano-Drops achieve their optical effect and correction by locally modifying the corneal refractive index. The magnitude and nature of the optical correction is adjusted by an optical pattern that is stamped onto the superficial layer of the corneal epithelium with a laser source. The shape of the optical pattern can be adjusted for correction of myopia (nearsightedness), hyperopia (farsightedness) or presbyopia (loss of accommodation ability). The laser stamping onto the cornea takes a few milliseconds and enables the nanoparticles to enhance and ‘activate’ this optical pattern by locally changing the refractive index and ultimately modifying the trajectory of light passing through the cornea.

The laser stamping source does not relate to the commonly known ‘laser treatment for visual correction’ that ablates corneal tissue. It is rather a small laser device that can connect to a smartphone and stamp the optical pattern onto the corneal epithelium by placing numerous adjacent pulses in a very speedy and painless fashion.  Tiny corneal spots created by the laser allow synthetic and biocompatible nanoparticles to enter and locally modify the optical power of the eye at the desired correction.

In the future this technology may enable patients to have their vision corrected in the comfort of their own home. To accomplish this, they would open an application on their smartphone to measure their vision, connect the laser source device for stamping the optical pattern at the desired correction, and then apply the Nano-Drops to activate the pattern and provide the desired correction.

Upcoming in-vivo experiments in rabbits will allow the researchers to determine how long the effect of the Nano-Drops will last after the initial application. Meanwhile, this promising technology has been shown, through ex-vivo experiments, to efficiently correct nearly 3 diopters of both myopia and presbyopia in pig eyes.

Bar-Ilan University, founded in 1955, was one of the first comprehensive research universities to be established in Israel.  From 70 students to 17,000, its milestone achievements in the sciences and humanities have made an indelible imprint on the landscape of the nation.  The university has 8 faculties, four of which focus on STEM research. They include Medicine, Exact Sciences (Physics, Chemistry, Computer Science, Biophysics and Mathematics), Life Sciences and Engineering.

Bar-Ilan University