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
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.
RESEARCH TRIANGLE PARK, N.C. — Army research is the first to develop computational models using a microbiology procedure that may be used to improve novel cancer treatments and treat combat wounds.
Using the technique, known as electroporation, an electrical field is applied to cells in order to increase the permeability of the cell membrane, allowing chemicals, drugs, or DNA to be introduced into the cell.
For example, electro-chemotherapy is a cutting-edge cancer treatment that uses electroporation as a means to deliver chemotherapy into cancerous cells.
The research, funded by the U.S. Army and conducted by researchers at University of California, Santa Barbara and Université de Bordeaux, France, has developed a computational approach for parallel simulations that models the complex bioelectrical interaction at the tissue scale.
Previously, most research has been conducted on individual cells, and each cell behaves according to certain rules.
“When you consider a large number of them together, the aggregate exhibits novel coherent behaviors,” said Pouria Mistani, a researcher at UCSB. “It is this emergent phenomenon that is crucial for developing effective theories at the tissue-scale — novel behaviors that emerge from the coupling of many individual elements.”
This new research, published in the Journal of Computational Physics, is funded by the U.S. Combat Capabilities Development Command’s Army Research Lab, the Army’s corporate research laboratory known as ARL, through its Army Research Office.
“Mathematical research enables us to study the bioelectric effects of cells in order to develop new anti-cancer strategies,” said Dr. Joseph Myers, Army Research Office mathematical sciences division chief.
“This new research will enable more accurate and capable virtual experiments of the evolution and treatment of cells, cancerous or healthy, in response to a variety of candidate drugs.”
Researchers said a crucial element in making this possible is the development of advanced computational algorithms.
“There is quite a lot of mathematics that goes into the design of algorithms that can consider tens of thousands well-resolved cells,” said Frederic Gibou, a faculty member in the Department of Mechanical Engineering and Computer Science at UCSB.
Another potential application is accelerating combat wound healing using electric pulsation.
“It’s an exciting, but mainly unexplored area that stems from a deeper discussion at the frontier of developmental biology, namely how electricity influences morphogenesis,” — or the biological process that causes an organism to develop its shape — Gibou said. “In wound healing, the goal is to externally manipulate electric cues to guide cells to grow faster in the wounded region and accelerate the healing process.”
The common factor among these applications is their bioelectric physical nature. In recent years, it has been established that the bioelectric nature of living organisms plays a pivotal role in the development of their form and growth.
To understand bioelectric phenomena, Gibou’s group considered computer experiments on multicellular spheroids in 3-D. Spheroids are aggregates of a few tens of thousands of cells that are used in biology because of their structural and functional similarity with tumors.
“We started from the phenomenological cell-scale model that was developed in the research group of our colleague, Clair Poignard, at the Université de Bordeaux, France, with whom we have collaborated for several years,” Gibou said.
This model, which describes the evolution of transmembrane potential on an isolated cell, has been compared and validated with the response of a single cell in experiments.
“From there, we developed the first computational framework that is able to consider a cell aggregate of tens of thousands of cells and to simulate their interactions,” he said. “The end goal is to develop an effective tissue-scale theory for electroporation.”
One of the main reasons for the absence of an effective theory at the tissue scale is the lack of data, according to Gibou and Mistani. Specifically, the missing data in the case of electroporation is the time evolution of the transmembrane potential of each individual cell in a tissue environment. Experiments are not able to make those measurements, they said.
“Currently, experimental limitations prevent the development of an effective tissue-level electroporation theory,” Mistani said. “Our work has developed a computational approach that can simulate the response of individual cells in a spheroid to an electric field as well as their mutual interactions.”
Each cell behaves according to certain rules.
“But when you consider a large number of them together, the aggregate exhibits novel coherent behaviors,” Mistani said. “It is this emergent phenomenon that is crucial for developing effective theories at the tissue-scale — novel behaviors that emerge from the coupling of many individual elements.”
The effects of electroporation used in cancer treatment, for example, depend on many factors, such as the strength of the electric field, its pulse and frequency.
“This work could bring an effective theory that helps understand the tissue response to these parameters and thus optimize such treatments,” Mistani said. “Before our work, the largest existing simulations of cell aggregate electroporation only considered about one hundred cells in 3-D, or were limited to 2-D simulations. Those simulations either ignored the real 3-D nature of spheroids or considered too few cells for tissue-scale emergent behaviors to manifest.”
The researchers are currently mining this unique dataset to develop an effective tissue-scale theory of cell aggregate electroporation.
The CCDC Army Research Laboratory (ARL) is an element of the U.S. Army Combat Capabilities Development Command. As the Army’s corporate research laboratory, ARL discovers, innovates and transitions science and technology to ensure dominant strategic land power. Through collaboration across the command’s core technical competencies, CCDC leads in the discovery, development and delivery of the technology-based capabilities required to make Soldiers more effective to win our Nation’s wars and come home safely. CCDC is a major subordinate command of the U.S. Army Futures Command.
A team of Tel Aviv University researchers revealed the heart, which was made using a patient’s own cells and biological materials.
— Read on m.jpost.com/HEALTH-SCIENCE/Israeli-scientists-print-first-3D-heart-586902/amp
A method for fooling breast cancer cells into fat cells has been discovered by researchers from the University of Basel.
The team were able to transform EMT-derived breast cancer cells into fat cells in a mouse model of the disease – preventing the formation of metastases. The proof-of-concept study was published in the journal Cancer Cell.
Malignant cells can rapidly respond and adapt to changing microenvironmental conditions, by reactivating a cellular process called epithelial-mesenchymal transition (EMT), enabling them to alter their molecular properties and transdifferentiate into a different type of cell (cellular plasticity).
Senior author of the study Gerhard Christofori, professor of biochemistry at the University of Basel, commented in a recent press release: “The breast cancer cells that underwent an EMT not only differentiated into fat cells, but also completely stopped proliferating.”
“As far as we can tell from long-term culture experiments, the cancer cells-turned-fat cells remain fat cells and do not revert back to breast cancer cells,” he explained.
Epithelial-mesenchymal transition and cancer
Cancer cells can exploit EMT – a process that is usually associated with the development of organs during embryogenesis – in order to migrate away from the primary tumor and form secondary metastases. Cellular plasticity is linked to cancer survival, invasion, tumor heterogeneity and resistance to both chemo and targeted therapies. In addition, EMT and the inverse process termed mesenchymal-epithelial transition (MET) both play a role in a cancer cell’s ability to metastasize.
Using mouse models of both murine and human breast cancer the team investigated whether they could therapeutically target cancer cells during the process of EMT – whilst the cells are in a highly plastic state. When the mice were administered Rosiglitazone in combination with MEK inhibitors it provoked the transformation of the cancer cells into post-mitotic and functional adipocytes (fat cells). In addition, primary tumor growth was suppressed and metastasis was prevented.
Cancer cells marked in green and a fat cell marked in red on the surface of a tumor (left). After treatment (right), three former cancer cells have been converted into fat cells. The combined marking in green and red causes them to appear dark yellow. Credit: University of Basel, Department of Biomedicine
Christofori highlights the two major findings in the study:
“Secondly, the conversion of malignant breast cancer cells into adipocytes not only changes their differentiation status but also represses their invasive properties and thus metastasis formation and their proliferation. Note that adipocytes do not proliferate anymore, they are called ‘post-mitotic’, hence the therapeutic effect.”
Since both drugs used in the preclinical study were FDA-approved the team are hopeful that it may be possible to translate this therapeutic approach to the clinic.
“Since in patients this approach could only be tested in combination with conventional chemotherapy, the next steps will be to assess in mouse models of breast cancer whether and how this trans-differentiation therapy approach synergizes with conventional chemotherapy. In addition, we will test whether the approach is also applicable to other cancer types. These studies will be continued in our laboratories in the near future.”
Journal Reference: Ronen et al. Gain Fat–Lose Metastasis: Converting Invasive Breast Cancer Cells into Adipocytes Inhibits Cancer Metastasis. Cancer Cell. (2019). Available at: https://www.cell.com/cancer-cell/fulltext/S1535-6108(18)30573-7
Gerhard Christofori was speaking to Laura Elizabeth Lansdowne, Science Writer for Technology Networks
A Time To Heal
Researchers from Imperial College London have created a new molecule that can “talk” to the cells in the area near injured tissues to encourage wound healing.
“This intelligent healing is useful during every phase of the healing process, has the potential to increase the body’s chance to recover, and has far-reaching uses on many different types of wounds,” lead researcher Ben Almquist said in a news release.
Setting A TrAP
The Imperial team describes the wound-healing molecules, which it calls traction force-activated payloads (TrAPs), in a study published Monday in the journal Advanced Materials.
The first step to creating TrAPs was folding segments of DNA into aptamers, which are three-dimensional shapes that latch tightly to proteins. The researchers then added a “handle” to one end of the aptamer.
As cells navigated the area near a wound during lab testing, they would pull on this handle, causing the aptamer to open and release proteins that encouraged wound healing. By changing the handle, the researchers found they could control which cells activated the TrAPs.
According to Almquist, “TrAPs provide a flexible method of actively communicating with wounds, as well as key instructions when and where they are needed.”
To The Clinic
It can take a long time for research to move from the laboratory to the clinical trial stage, but the TrAPs team might be able to speed along the path. That’s because aptamers are already used for drug delivery, meaning they’re already considered safe for human use.
TrAPs are also fairly straightforward to create, meaning it wouldn’t be difficult to scale the technology to industrial levels. According to the researchers’ paper, doctors could then deliver the TrAPs via anything from collagen sponges to polyacrylamide gels. So if future testing goes well, the molecules could soon change how we heal a variety of wounds.
READ MORE: New Material Could ‘Drive Wound Healing’ Using the Body’s Inbuilt Healing System [Imperial College London]
More on aptamers: New Nanobots Kill Cancerous Tumors by Cutting off Their Blood Supply
In 2016, Craig Venter and his team at Synthetic Genomics announced that they had created a lifeform called JCVI-syn3.0, whose genome consisted of only 473 genes.
This stripped-down organism was a significant breakthrough in the development of artificial life as it enabled us to understand more fully what individual genes do. (In the case of JCVI-syn3.0, most of them were used to create RNA and proteins, preserve genetic fidelity during reproduction and create the cell membrane.
The functions of about a third remain a mystery.)
Venter’s achievement followed an earlier breakthrough in 2014, when Floyd Romesberg at Romesberg Lab in California succeeded in creating xeno nucleic acid (XNA), a synthetic alternative to DNA, using amino acids not found among the naturally occurring four nucleotides: adenine, cytosine, guanine and thymine.
And, most recently we have seen huge advances in the use of CRISPR, a gene-editing tool that allows substitution or injection of DNA sequences at chosen locations in a genome.
Together, these developments mean that in 2019 we will have to take seriously the possibility of our developing multicellular artificial life, and we will need to start thinking about the ethical and philosophical challenges such a possibility brings up.
In the near future we can reasonably anticipate that a large number of unnatural single-cell life forms will be created using artificially edited genomes to correct for genetic defects or to add new features to an organism’s phenotype.
It is already possible to design bacterial forms, for example, that can metabolise pollutants or produce particular substances.
We can also anticipate that new life forms may be created that have never existed in nature through the use of conventional and perhaps artificially arranged codons (nucleotide sequences that manage protein synthesis).
These are likely to make use of the conventional machinery of mitotic cell reproduction and of conventional ribosomes, creating proteins through RNA or XNA interpretation.
And there will be increasing pressures to continue this research. We may need to accelerate the evolution of terrestrial life forms, for example, including homo sapiens, so that they carry traits and capabilities needed for life in space or even on our own changing planet.
All of this will bring up serious issues as to how we see ourselves – and behave – as a species.
While the creation of multicellular organisms that are capable of sexual reproduction is still a long way off, in 2019 we will need to begin a serious debate about whether artificially evolved humans are our future, and if we should put an end to these experiments before it is too late.
Vint Cerf of ‘Wired’
Scientists from Jülich together with colleagues from Aachen and Turin have produced a memristive element made from nanowires that functions in much the same way as a biological nerve cell.
The component is able to save and process information, as well as receive numerous signals in parallel. The resistive switching cell made from oxide crystal nanowires is thus an ideal candidate for use in building bioinspired “neuromorphic” processors, able to take over the diverse functions of biological synapses and neurons.
Systems with neuromorphic chips that imitate the way the human brain works offer significant advantages. These types of computers work in a decentralised way, having at their disposal a multitude of processors, which, like neurons in the brain, are connected to each other by networks. If a processor breaks down, another can take over its function.
What is more, just like in the brain, where practice leads to improved signal transfer, a bioinspired processor should have the capacity to learn.
“With today’s semiconductor technology, these functions are to some extent already achievable. These systems are, however, suitable for particular applications and require a lot of space and energy,” says Dr. Ilia Valov from Forschungszentrum Jülich. “Our nanowire devices made from zinc oxide crystals can inherently process and even store information, and are extremely small and energy efficient.”
For years, memristive cells have been ascribed the best chances of taking over the function of neurons and synapses in bioinspired computers. They alter their electrical resistance depending on the intensity and direction of the electric current flowing through them.
In contrast to conventional transistors, their last resistance value remains intact even when the electric current is switched off. Memristors are thus fundamentally capable of learning.
In order to create these properties, scientists at Forschungszentrum Jülich and RWTH Aachen University used a single zinc oxide nanowire, produced by their colleagues from the polytechnic university in Turin. Measuring approximately one 10,000th of a millimeter in size, this type of nanowire is over 1,000 times thinner than a human hair. The resulting memristive component not only takes up a tiny amount of space, but is also able to switch much faster than flash memory.
Nanowires offer promising novel physical properties compared to other solids and are used among other things in the development of new types of solar cells, sensors, batteries and computer chips. Their manufacture is comparatively simple. Nanowires result from the evaporation deposition of specified materials onto a suitable substrate, where they practically grow of their own accord.
In order to create a functioning cell, both ends of the nanowire must be attached to suitable metals, in this case platinum and silver. The metals function as electrodes, and in addition, release ions triggered by an appropriate electric current. The metal ions are able to spread over the surface of the wire and build a bridge to alter its conductivity.
Components made from single nanowiresare, however, still too isolated to be of practical use in chips. Consequently, the next step being planned by the Jülich and Turin researchers is to produce and study a memristive element, composed of a larger, relatively easy to generate group of several hundred nanowires offering more exciting functionalities.
Provided by Forschungszentrum Juelich
Explore further: Scientists create a prototype neural network based on memristors