Cancer cell during cell division. Credit: National Institutes of Health
A new study at the University of Georgia has found a way to attack cancer cells that is potentially less harmful to the patient.
Sodium chloride nanoparticles—more commonly known as salt—are toxic to cancer cells and offer the potential for therapies that have fewer negative side effects than current treatments.
Led by Jin Xie, associate professor of chemistry, the study found that SCNPs can be used as a Trojan horse to deliver ions into cells and disrupt their internal environment, leading to cell death. SCNPs become salt when they degrade, so they’re not harmful to the body.
“This technology is well suited for localized destruction of cancer cells,” said Xie, a faculty member in the Franklin College of Arts and Sciences. “We expect it to find wide applications in treatment of bladder, prostate, liver, and head and neck cancer.”
Nanoparticles are the key to delivering SCNPs into cells, according to Xie and the team of researchers. Cell membranes maintain a gradient that keeps relatively low sodium concentrations inside cells and relatively high sodium concentrations outside cells.
The plasma membrane prevents sodium from entering a cell, but SCNPs are able to pass through because the cell doesn’t recognize them as sodium ions.
Once inside a cell, SCNPs dissolve into millions of sodium and chloride ions that are trapped inside by the gradient and overwhelm protective mechanisms, inducing rupture of the plasma membrane and cell death. When the plasma membrane ruptures, the molecules that leak out signal the immune system that there’s tissue damage, inducing an inflammatory response that helps the body fight pathogens.
“This mechanism is actually more toxic to cancer cells than normal cells, because cancer cells have relatively high sodium concentrations to start with,” Xie said.
Using a mouse model, Xie and the team tested SCNPs as a potential cancer therapeutic, injecting SCNPs into tumors. They found that SCNP treatment suppressed tumor growth by 66 percent compared to the control group, with no drop in body weight and no sign of toxicity to major organs.
They also performed a vaccination study, inoculating mice with cancer cells that had been killed via SCNPs or freeze thaw. These mice showed much greater resistance to a subsequent live cancer cell challenge, with all animals remaining tumor free for more than two weeks.
The researchers also explored anti-cancer immunity in a tumor model. After injecting primary tumors with SCNPs and leaving secondary tumors untreated, they found that the secondary tumors grew at a much lower speed than the control, showing a tumor inhibition rate of 53 percent.
Collectively, the results suggest that SCNPs killed cancer cells and converted the dying cancer cells to an in situ vaccine.
SCNPs are unique in the world of inorganic particles because they are made of a benign material, and their toxicity is based on the nanoparticle form, according to Xie.
“With a relatively short half-life in aqueous solutions, SCNPs are best suited for localized rather than systemic therapy. The treatment will cause immediate and immunogenic cancer cell death,” he said. “After the treatment, the nanoparticles are reduced to salts, which are merged with the body’s fluid system and cause no systematic or accumulative toxicity. No sign of systematic toxicity was observed with SCNPs injected at high doses.”
The study was published in Advanced Materials.
Along the genome, proteins form liquid-like droplets that appear to boost the expression of particular genes.
In recent years, MIT scientists have developed a new model for how key genes are controlled that suggests the cellular machinery that transcribes DNA into RNA forms specialized droplets called condensates. These droplets occur only at certain sites on the genome, helping to determine which genes are expressed in different types of cells.
In a new study that supports that model, researchers at MIT and the Whitehead Institute for Biomedical Research have discovered physical interactions between proteins and with DNA that help explain why these droplets, which stimulate the transcription of nearby genes, tend to cluster along specific stretches of DNA known as super enhancers. These enhancer regions do not encode proteins but instead regulate other genes.
“This study provides a fundamentally important new approach to deciphering how the ‘dark matter’ in our genome functions in gene control,” says Richard Young, an MIT professor of biology and member of the Whitehead Institute.
Young is one of the senior authors of the paper, along with Phillip Sharp, an MIT Institute Professor and member of MIT’s Koch Institute for Integrative Cancer Research; and Arup K. Chakraborty, the Robert T. Haslam Professor in Chemical Engineering, a professor of physics and chemistry, and a member of MIT’s Institute for Medical Engineering and Science and the Ragon Institute of MGH, MIT, and Harvard.
Graduate student Krishna Shrinivas and postdoc Benjamin Sabari are the lead authors of the paper, which appears in Molecular Cell on Aug. 8.
“A biochemical factory”
Every cell in an organism has an identical genome, but cells such as neurons or heart cells express different subsets of those genes, allowing them to carry out their specialized functions. Previous research has shown that many of these genes are located near super enhancers, which bind to proteins called transcription factors that stimulate the copying of nearby genes into RNA.
About three years ago, Sharp, Young, and Chakraborty joined forces to try to model the interactions that occur at enhancers.
In a 2017 Cell paper, based on computational studies, they hypothesized that in these regions, transcription factors form droplets called phase-separated condensates. Similar to droplets of oil suspended in salad dressing, these condensates are collections of molecules that form distinct cellular compartments but have no membrane separating them from the rest of the cell.
In a 2018 Science paper, the researchers showed that these dynamic droplets do form at super enhancer locations. Made of clusters of transcription factors and other molecules, these droplets attract enzymes such as RNA polymerases that are needed to copy DNA into messenger RNA, keeping gene transcription active at specific sites.
“We had demonstrated that the transcription machinery forms liquid-like droplets at certain regulatory regions on our genome, however we didn’t fully understand how or why these dewdrops of biological molecules only seemed to condense around specific points on our genome,” Shrinivas says.
As one possible explanation for that site specificity, the research team hypothesized that weak interactions between intrinsically disordered regions of transcription factors and other transcriptional molecules, along with specific interactions between transcription factors and particular DNA elements, might determine whether a condensate forms at a particular stretch of DNA. Biologists have traditionally focused on “lock-and-key” style interactions between rigidly structured protein segments to explain most cellular processes, but more recent evidence suggests that weak interactions between floppy protein regions also play an important role in cell activities.
In this study, computational modeling and experimentation revealed that the cumulative force of these weak interactions conspire together with transcription factor-DNA interactions to determine whether a condensate of transcription factors will form at a particular site on the genome. Different cell types produce different transcription factors, which bind to different enhancers. When many transcription factors cluster around the same enhancers, weak interactions between the proteins are more likely to occur. Once a critical threshold concentration is reached, condensates form.
“Creating these local high concentrations within the crowded environment of the cell enables the right material to be in the right place at the right time to carry out the multiple steps required to activate a gene,” Sabari says. “Our current study begins to tease apart how certain regions of the genome are capable of pulling off this trick.”
These droplets form on a timescale of seconds to minutes, and they blink in and out of existence depending on a cell’s needs.
“It’s an on-demand biochemical factory that cells can form and dissolve, as and when they need it,” Chakraborty says. “When certain signals happen at the right locus on a gene, the condensates form, which concentrates all of the transcription molecules. Transcription happens, and when the cells are done with that task, they get rid of them.”
“A functional condensate has to be more than the sum of its parts, and how the protein and DNA components work together is something we don’t fully understand,” says Rohit Pappu, director of the Center for Science and Engineering of Living Systems at Washington University, who was not involved in the research. “This work gets us on the road to thinking about the interplay among protein-protein, protein-DNA, and possibly DNA-DNA interactions as determinants of the outputs of condensates.”
A new view
Weak cooperative interactions between proteins may also play an important role in evolution, the researchers proposed in a 2018 Proceedings of the National Academy of Sciences paper.
The sequences of intrinsically disordered regions of transcription factors need to change only a little to evolve new types of specific functionality. In contrast, evolving new specific functions via “lock-and-key” interactions requires much more significant changes.
“If you think about how biological systems have evolved, they have been able to respond to different conditions without creating new genes.
We don’t have any more genes that a fruit fly, yet we’re much more complex in many of our functions,” Sharp says. “The incremental expanding and contracting of these intrinsically disordered domains could explain a large part of how that evolution happens.”
Similar condensates appear to play a variety of other roles in biological systems, offering a new way to look at how the interior of a cell is organized.
Instead of floating through the cytoplasm and randomly bumping into other molecules, proteins involved in processes such as relaying molecular signals may transiently form droplets that help them interact with the right partners.
“This is a very exciting turn in the field of cell biology,” Sharp says. “It is a whole new way of looking at biological systems that is richer and more meaningful.”
Some of the MIT researchers, led by Young, have helped form a company called Dewpoint Therapeutics to develop potential treatments for a wide variety of diseases by exploiting cellular condensates.
There is emerging evidence that cancer cells use condensates to control sets of genes that promote cancer, and condensates have also been linked to neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and Huntington’s disease.
The research was funded by the National Science Foundation, the National Institutes of Health, and the Koch Institute Support (core) Grant from the National Cancer Institute.
Melanoma in skin biopsy with H&E stain — this case may represent superficial spreading melanoma. Credit: Wikipedia/CC BY-SA 3.0
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