Pancreatic cancer is one of the most lethal cancers, but difficult to diagnose: few sufferers have symptoms until the cancer has become large or already spread to other organs. Even then, symptoms can be vague and easily misconstrued as more common conditions.
This is why Dr. Yuling Wang is so excited by results of a trial completed in late 2019, which—using plasmonic nanoparticles developed by the Centre for Nanoscale BioPhotonics (CNBP)—successfully detected signs of the cancer in blood of patients undergoing treatment. The paper was recently published in the journal American Chemical Society—Sensors.
“The test gave a very high signal in the blood for late-stage or very serious tumors, where other techniques cannot detect anything,” said Dr. Wang, an associate investigator at the Centre’s Macquarie University node in Sydney, in work led by Prof Nicolle Packer. “We need to test many more patient samples to validate the approach, but the strength of the signal was very encouraging.”
They did this by developing a method, using surface-enhanced Raman spectroscopy nanotags, that simultaneously detects three known pancreatic cancer biomarkers in blood. Known as extracellular vesicles, or EVs, they contain DNA and proteins for cell-to-cell communication and are shed from pancreatic cancer cells into surrounding body fluids. The CNBP method zeros in on three: Glypican-1, epithelial cell adhesion molecules and CD44V6.
For the experiment, biopsies of healthy donors were provided alongside those of known sufferers of pancreatic cancer, in double-blind tests where the researchers did not know which was which. Nevertheless, the blood of sufferers was easily identified. The technique was so sensitive it could spot EVs as small as 113 nanometres in diameter—or less than 1% the width of a human hair—in every millilitre of blood.
The pancreas is part of the digestive system, secreting insulin into the bloodstream to regulate the body’s sugar level as well as important enzymes and hormones into the small intestine to help break down food. Pancreatic cancer is the fifth biggest cancer killer in Australia and has a 5-year survival rate of 8.7%. More than 3000 Australians are diagnosed annually, and surgery to remove the cancer is a long and complex process, requiring long hospital stays.
Because existing blood tests for the protein biomarkers of pancreatic cancer are unreliable, imaging with endoscopic ultrasound or MRI scans is necessary. Even then, anomalies can only be confirmed with a biopsy of the organ, which is invasive and ultimately relies on a trained pathologist to recognize signs of the cancer under a microscope. As a result, there’s some subjectivity involved and cancer can be present but still be missed.
“Our approach is non-invasive—we don’t need to take tissue from the patient, we just use a handheld device to test blood for targeted biomarkers, which gives a very quick result,” Dr. Wang said. It may also help provide earlier diagnosis of the cancer.
While the work is a proof-of-concept, it was also able to detect colorectal and bladder cancer biomarkers—although not as clearly as those for pancreatic cancer. Nevertheless, the results are so encouraging that a commercial partner has committed funding to CNBP so it can develop a handheld spectrometer for cancer biomarkers in blood.
How a new quantum sensor could improve cancer treatment
The development of medical imaging and monitoring methods has profoundly impacted the diagnosis and treatment of cancer. These non-invasive techniques allow health care practitioners to look for cancer in the body and determine if treatment is working.
But current techniques have limitations; namely, tumours need to be a specific size to be visible. Being able to detect cancer cells, even before there are enough to form a tumour, is a challenge that researchers around the world are looking to solve.
The solution may lie in nanotechnology
Researchers at the University of Waterloo’s Institute for Quantum Computing (IQC) have developed a quantum sensor that is promising to outperform existing technologies in monitoring the success of cancer treatments.
Artist’s rendering of the interaction of incident single photon pulses and a tapered semiconductor nanowire array photodetector.
“A sensor needs to be very efficient at detecting light,” explains principal investigator Michael Reimer, an IQC faculty member and professor in the Faculty of Engineering. “What’s unique about our sensor is that the light can be absorbed all the way, from UV to infrared. No commercially available device exists that can do that now.”
Current sensors reflect some of the light, and depending on the material, this reflection can add up to 30 percent of the light not being absorbed.
This next-generation quantum sensor designed in Reimer’s lab is very efficient and can detect light at the fundamental limit — a single photon — and refresh for the next one within nanoseconds. Researchers created an array of tapered nanowires that turn incoming photons into electric current that can be amplified and detected.
When applied to dose monitoring in cancer treatment, this enhanced ability to detect every photon means that a health practitioner could monitor the dose being given with incredible precision — ensuring enough is administered to kill the cancer cells, but not too much that it also kills healthy cells.
Moving quantum technology beyond the lab
Reimer published his findings in Nature Nanotechnology in March and is now working on a prototype to begin testing outside of his lab. Reimer’s goal is to commercialize the sensor in the next three to five years.
“I enjoy the fundamental research, but I’m also interested in bringing my research out of the lab and into the real world and making an impact to society,” says Reimer.
He is no stranger to bringing quantum technology to the marketplace. While completing his post doctorate at the Delft University of Technology in The Netherlands, Reimer was an integral part of the startup, Single Quantum, developing highly efficient single-photon detectors based on superconducting nanowires.
Reimer’s latest sensor has a wide range of applications beyond dose monitoring for cancer treatments. The technology also has the ability to significantly improve high-speed imaging from space and long-range, high-resolution 3D images.
“A broad range of industries and research fields will benefit from a quantum sensor with these capabilities,” said Reimer. “It impacts quantum communication to quantum lidar to biological applications. Anywhere you have photon-starved situations, you would want an efficient sensor.”
He is exploring all industries and opportunities to put this technology to use.
Breakthroughs come in unexpected places
After earning his undergraduate degree in physics at the University of Waterloo, Reimer moved to Germany to play professional hockey. While taking graduate courses at the Technical University of Munich, he met a professor of nanotechnology who sparked his interest in the field.
“I played hockey and science was my hobby,” says Reimer. “Science is still my hobby, and it’s amazing that it is now my job.” Reimer went on to complete his PhD at the University of Ottawa/National Research Council of Canada, and turned his attention to quantum light sources. Reimer is an internationally renowned expert in quantum light sources and sensors. The idea for the quantum sensor came from his initial research in quantum light sources.
“To get the light out from the quantum light source, we had to come up with a way that you don’t have reflections, so we made this tapered shape. We realized that if we can get the light out that way we could also do the reverse — that’s where the idea for the sensor came from.”
Reimer will be at the Waterloo Innovation Summit on October 1, to present his latest breakthrough and its potential impact on the health care sector. And while he works to bring the sensor to market, Reimer’s lab continues to push the boundaries of quantum photonics.
From discovering the path to perfect photon entanglement to developing novel solid-state quantum devices, Reimer’s research is advancing technologies that could disrupt a multitude of industries and research fields.
Just as the steam engine set the stage for the Industrial Revolution, and micro transistors sparked the digital age, nanoscale devices made from DNA are opening up a new era in bio-medical research and materials science.
The journal Science describes the emerging uses of DNA mechanical devices in a “Perspective” article by Khalid Salaita, a professor of chemistry at Emory University, and Aaron Blanchard, a graduate student in the Wallace H. Coulter Department of Biomedical Engineering, a joint program of Georgia Institute of Technology and Emory.
The article heralds a new field, which Blanchard dubbed “DNA mechanotechnology,” to engineer DNA machines that generate, transmit and sense mechanical forces at the nanoscale.
“For a long time,” Salaita says, “scientists have been good at making micro devices, hundreds of times smaller than the width of a human hair. It’s been more challenging to make functional nano devices, thousands of times smaller than that. But using DNA as the component parts is making it possible to build extremely elaborate nano devices because the DNA parts self-assemble.”
DNA, or deoxyribonucleic acid, stores and transmits genetic information as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C) and thymine (T). The DNA bases have a natural affinity to pair up with each other—A with T and C with G. Synthetic strands of DNA can be combined with natural DNA strands from bacteriophages. By moving around the sequence of letters on the strands, researchers can get the DNA strands to bind together in ways that create different shapes. The stiffness of DNA strands can also easily be adjusted, so they remain straight as a piece of dry spaghetti or bend and coil like boiled spaghetti.
The idea of using DNA as a construction material goes back to the 1980s, when biochemist Nadrian Seeman pioneered DNA nanotechnology. This field uses strands DNA to make functional devices at the nanoscale. The ability to make these precise, three-dimensional structures began as a novelty, nicknamed DNA origami, resulting in objects such as a microscopic map of the world and, more recently, the tiniest-ever game of tic-tac-toe, played on a DNA board.
Work on novelty objects continues to provide new insights into the mechanical properties of DNA. These insights are driving the ability to make DNA machines that generate, transmit and sense mechanical forces.
“If you put together these three main components of mechanical devices, you begin to get hammers and cogs and wheels and you can start building nano machines,” Salaita says. “DNA mechanotechnology expands the opportunities for research involving biomedicine and materials science. It’s like discovering a new continent and opening up fresh territory to explore.”
Potential uses for such devices include drug delivery devices in the form of nano capsules that open up when they reach a target site, nano computers and nano robots working on nanoscale assembly lines.
The use of DNA self-assembly by the genomics industry, for biomedical research and diagnostics, is further propelling DNA mechanotechnology, making DNA synthesis inexpensive and readily available. “Potentially anyone can dream up a nano-machine design and make it a reality,” Salaita says.
He gives the example of creating a pair of nano scissors. “You know that you need two rigid rods and that they need to be linked by a pivot mechanism,” he says. “By tinkering with some open-source software, you can create this design and then go onto a computer and place an order to custom synthesize your design. You’ll receive your order in a tube. You simply put the tube contents into a solution, let your device self-assemble, and then use a microscope to see if it works the way you thought that it would.”
Salaita’s lab is one of only about 100 around the world working at the forefront of DNA mechanotechnology. He and Blanchard developed the world’s strongest synthetic DNA-based motor, which was recently reported in Nano Letters.
A key focus of Salaita’s research is mapping and measuring how cells push and pull to learn more about the mechanical forces involved in the human immune system.
Salaita developed the first DNA force gauges for cells, providing the first detailed view of the mechanical forces that one molecule applies to another molecule across the entire surface of a living cell. Mapping such forces may help to diagnose and treat diseases related to cellular mechanics. Cancer cells, for instance, move differently from normal cells, and it is unclear whether that difference is a cause or an effect of the disease.
In 2016, Salaita used these DNA force gauges to provide the first direct evidence for the mechanical forces of T cells, the security guards of the immune system. His lab showed how T cells use a kind of mechanical “handshake” or tug to test whether a cell they encounter is a friend or foe. These mechanical tugs are central to a T cell’s decision for whether to mount an immune response.
“Your blood contains millions of different types of T cells, and each T cell is evolved to detect a certain pathogen or foreign agent,” Salaita explains. “T cells are constantly sampling cells throughout your body using these mechanical tugs. They bind and pull on proteins on a cell’s surface and, if the bond is strong, that’s a signal that the T cell has found a foreign agent.”
Salaita’s lab built on this discovery in a paper recently published in the Proceedings of the National Academy of Sciences (PNAS). Work led by Emory chemistry graduate student Rong Ma refined the sensitivity of the DNA force gauges. Not only can they detect these mechanical tugs at a force so slight that it is nearly one-billionth the weight of a paperclip, they can also capture evidence of tugs as brief as the blink of an eye.
The research provides an unprecedented look at the mechanical forces involved in the immune system. “We showed that, in addition to being evolved to detect certain foreign agents, T cells will also apply very brief mechanical tugs to foreign agents that are a near match,” Salaita says. “The frequency and duration of the tug depends on how closely the foreign agent is matched to the T cell receptor.”
The result provides a tool to predict how strong of an immune response a T cell will mount. “We hope this tool may eventually be used to fine tune immunotherapies for individual cancer patients,” Salaita says. “It could potentially help engineer T cells to go after particular cancer cells.”
MIT engineers have designed a system that can repeatedly measure cancer cells as they flow through an array of mass sensors. Once the cells reach the end, they are collected for RNA-sequencing. Image courtesy of the researchers.
Courtesy of MIT News
Together, cell growth rate and gene expression shed light on why some tumor cells survive treatment.
By studying both the physical and genomic features of cancer cells, MIT researchers have come up with a new way to investigate why some cancer cells survive drug treatment while others succumb.
Their new approach, which combines measurements of cell mass and growth rate with analysis of a cell’s gene expression, could be used to reveal new drug targets that would make cancer treatment more effective. Exploiting these targets could help knock out the defenses that cells use to overcome the original drug treatment, the researchers say.
In a paper appearing in the Nov. 28 issue of the journal Genome Biology, the researchers identified a growth signaling pathway that is active in glioblastoma cells that are resistant to an experimental type of drug known as an MDM2 inhibitor.
“By measuring a cell’s mass and growth rate immediately prior to single-cell RNA-sequencing, we can now use a cell’s ‘fitness’ to classify it as responsive or nonresponsive to a drug, and to relate this to underlying molecular pathways,” says Alex K. Shalek, the Pfizer-Laubach Career Development Assistant Professor of Chemistry, a member of MIT’s Institute for Medical Engineering and Science (IMES), an extramural member of the Koch Institute for Integrative Cancer Research, and an associate member of the Ragon and Broad Institutes.
Shalek and Scott Manalis, the Andrew and Erna Viterbi Professor in the MIT departments of Biological Engineering and Mechanical Engineering and a member of the Koch Institute, are the senior authors of the study. The paper’s lead author is Robert Kimmerling, a recent MIT PhD recipient.
Cancer cell analysis
About a decade ago, Manalis’ lab invented a technology that allows researchers to measure the mass of single cells. In recent years, they have adapted the device, which measures cells’ masses as they flow through tiny channels, so that it can also measure cell growth rates by repeatedly weighing the cells over short periods of time.
Last year, working with researchers at Dana-Farber Cancer Institute (DFCI), Manalis and his colleagues used this approach to test drug responses of tumor cells from patients with multiple myeloma, a type of blood cancer. After treating the cells with three different drugs, the researchers measured the cells’ growth rates and found they were correlated with the cells’ susceptibility to the treatment.
“Single-cell biophysical properties such as mass and growth rate provide early indicators of drug response, thereby offering the potential to delineate sensitive cells from resistant cells while they are still viable,” Manalis says.
In their new study, the researchers wanted to add a genomic component, which they hoped could help reveal why only certain cells are susceptible to a particular drug. “We wanted to be able to take those measurements and add on some of the biological context for why a cell is growing a certain way or behaving a certain way,” Kimmerling says.
To accomplish this, Kimmerling and Manalis teamed up with Shalek, who has extensive experience in sequencing the messenger RNA (mRNA) of individual cells. This information can provide a snapshot of which genes are being expressed in a single cell at a particular moment.
The researchers modified the cell-weighing system so that cells would be spaced evenly as they flowed through, making it easier to collect them one at a time when they exit the system. The cells are weighed several times over the course of 20 minutes to determine growth rate, and as soon as they reach the end of the channel, they are immediately captured and ruptured to release their RNA for analysis. Shalek’s lab then sequenced the RNA of each of the cells. This approach enabled the mass and growth rate of each cell to be directly linked to its gene expression.
Once they had the system working, the researchers collaborated with Keith Ligon and his lab at DFCI to analyze cancer cells derived from a patient with glioblastoma, an aggressive type of brain cancer. The researchers treated the cells with an MDM2 inhibitor, a type of drug that helps to boost the function of p53, a protein that helps cells stop tumor formation. Such drugs are now in clinical trials to treat glioblastoma. In animal studies, this drug has been effective against tumors, but the tumors often grow back later.
In this study, the researchers hoped to find out why some glioblastoma cells survive MDM2 treatment. They treated the cells, measured their growth rates about 16 hours after the treatment, and then sequenced their RNA. “Before the cells have lost viability, we can measure their mass and their growth rate to reveal drug response heterogeneity to that treatment, and then link that with their gene expression,” Kimmerling says.
Importantly, the researchers found subpopulations of cells that were not responsive to the drug. RNA sequencing revealed that in cells that were responsive, genes required for programmed cell death were turned on. Meanwhile, in cells that did not seem to be vulnerable to the drug, genes involved in mTOR, a signaling pathway involved in growth and survival, were turned up.
“What we’re excited about here is we now have this list of biological targets to look into,” Kimmerling says. “We can start to generate testable hypotheses from these gene expression signatures that are more highly expressed in the cells that continue to grow after drug treatment.”
Possible drug targets
The researchers now plan to explore the possibility of targeting some of the genes that were turned up on the non-responding cells, in hopes of developing drugs that could be used together with the original MDM2 inhibitor. They also hope to adapt this approach for other types of cancers. Some, such as blood cancers, are easier to study than solid tumors, which are more difficult to separate into single cells.
“The hope is that we’ll be able to apply this technology to any sample that can be dissociated into a single-cell population,” Kimmerling says.
Another possible application of the cell-growth measurement technology is studying tumor cells from individual patients to try to predict how they will respond to a particular drug. Kimmerling, Manalis, and others have founded a company called Travera, which has licensed the technology and hopes to develop it for patient use. The company is currently not working on the RNA sequencing aspect of the technology, but that element could also be valuable to incorporate in the future, Kimmerling says.
The research was funded by the Cancer Systems Biology Consortium U54 Research Center and the Cancer Center Support (core) Grant from the National Cancer Institute; the Searle Scholars Program; the Beckman Young Investigator Program; the National Institutes of Health, including an NIH New Innovator Award; the Pew-Stewart Scholars; and a Sloan Fellowship in Chemistry.
A £10 million interdisciplinary collaboration is to target the most challenging of cancers using nanomedicine.
“We are going to pierce through the body’s natural barriers and deliver anti-cancer drugs to the heart of the tumour.” – George Malliaras
While the survival rate for most cancers has doubled over the past 40 years, some cancers such as those of the pancreas, brain, lung and oesophagus still have low survival rates.
Such cancers are now the target of an Interdisciplinary Research Collaboration (IRC) led by the University of Cambridge and involving researchers from Imperial College London, University College London and the Universities of Glasgow and Birmingham.
“Some cancers are difficult to remove by surgery and highly invasive, and they are also hard to treat because drugs often cannot reach them at high enough concentration,” explains George Malliaras, Prince Philip Professor of Technology in Cambridge’s Department of Engineering, who leads the IRC. “Pancreatic tumour cells, for instance, are protected by dense stromal tissue, and tumours of the central nervous system by the blood-brain barrier.”
The aim of the project, which is funded for six years by the Engineering and Physical Sciences Research Council, is to develop an array of new delivery technologies that can deliver almost any drug to any tumour in a large enough concentration to kill the cancerous cells.
Chemists, engineers, material scientists and pharmacologists will focus on developing particles, injectable gels and implantable devices to deliver the drugs. Cancer scientists and clinicians from the Cancer Research UK Cambridge Centre and partner sites will devise and carry out clinical trials. Experts in innovative manufacturing technologies will ensure the devices are able to be manufactured and robust enough to withstand surgical manipulation.
One technology the team will examine is the ability of advanced materials to self-assemble and entrap drugs inside metal-organic frameworks. These structures can carry enormous amounts of drugs, and be tuned both to target the tumour and to release the drug at an optimal rate.
“We are going to pierce through the body’s natural barriers,” says Malliaras, “and deliver anti-cancer drugs to the heart of the tumour.”
Dr Su Metcalfe, a member of George Malliaras’s team and who is already using NanoBioMed to treat Multuple Sclerosis, added “the power of nanotechnology to synergise with potent anti-cancer drugs will be profound and the award will speed delivery to patients.”
Researchers at the Complutense University of Madrid (UCM) have developed a hybrid nanoplatform that locates tumours using three different types of contrast simultaneously to facilitate multimodal molecular medical imaging: magnetic resonance imaging (MRI), computed tomography (CT) and fluorescence optical imaging (OI).
The results of this study, led by the UCM Life Sciences Nanobiotechnology research team directed by Marco Filice and published in ACS Applied Materials & Interfaces, represent a major advance in medical diagnosis since just one session using a single contrast medium yields more precise, specific results with higher resolution, sensitivity and capacity to penetrate tissues.
“No single molecular imaging modality provides a perfect diagnosis. Our nanoplatform is designed to enable multimodal molecular imaging, thus overcoming the intrinsic limitations of each single image modality while maximising their advantages,” noted Marco Filice, a researcher in the Department of Chemistry and Pharmaceutical Sciences at the Complutense University of Madrid and the director of the study.
The platform, which has been tested on mice, targets solid cancers such as sarcomas. “However, due to its flexibility, the proposed nanoplatform can be modified, and with a suitable design of recognition element siting, it will be possible to expand detection to more types of cancer,” Filice said.
Named after the Roman god Janus, usually depicted as having two faces, these nanoparticles also “have two opposing faces, one of iron oxide embedded in a silica matrix that serves as a contrast medium for MRI and another of gold for CT,” explained Alfredo Sánchez, a researcher in the UCM Department of Analytical Chemistry and the first author of the study.
In addition, a molecular probe sited in a specific manner in the golden area permits fluorescence optical imaging while a peptide selective for hyperexpressed receptors in tumours (RGD sequence) and sited on the silica surface enveloping the iron oxide nanoparticles identifies the tumour and makes it possible to direct and transport the nanoplatform to its target.
Once the research team had synthesised the nanoparticles and determined their characteristics and toxicity, they then tested them in mouse models reared to present a fibrosarcoma in the right leg. The nanoparticle was injected in the tail. “Excellent imaging results were obtained for each modality tested,” reported Filice.
Although there is still much to do before these experiments can be applied to humans, this research shows that personalised treatment is closer than ever to becoming a reality, thanks to nanotechnology and biotechnology.
More information: Alfredo Sánchez et al, Hybrid Decorated Core@Shell Janus Nanoparticles as a Flexible Platform for Targeted Multimodal Molecular Bioimaging of Cancer, ACS Applied Materials & Interfaces (2018). DOI: 10.1021/acsami.8b10452
Allison, who is the chair of Immunology and executive director of the Immunotherapy Platform, is the first MD Anderson scientist to receive the world’s most coveted award for discoveries in the fields of life sciences and medicine. Allison won for his work in launching an effective new way to attack cancer by treating the immune system rather than the tumor, according to a release.
“I’m honored and humbled to receive this prestigious recognition,” Allison says in a statement. “A driving motivation for scientists is simply to push the frontiers of knowledge. I didn’t set out to study cancer, but to understand the biology of T cells, these incredible cells to travel our bodies and work to protect us.”
Allison shares the award with Tasuku Honjo, M.D., Ph.D., of Kyoto University in Japan. When announcing the honor, the Nobel Assembly of Karolinska Institute in Stockholm noted in a statement that “stimulating the ability of our immune system to attack tumor cells, this year’s Nobel Prize laureates have established an entirely new principle for cancer therapy.”
The prize recognizes Allison’s basic science discoveries on the biology of T cells, the adaptive immune system’s soldiers, and his invention of immune checkpoint blockade to treat cancer. According to MD Anderson, Allison’s crucial insight was to block a protein on T cells that acts as a brake on their activation, freeing the T cells to attack cancer. He developed an antibody to block the checkpoint protein CTLA-4 and demonstrated the success of the approach in experimental models.
Allison’s work led to development of the first immune checkpoint inhibitor drug which would become the first to extend the survival of patients with late-stage melanoma. Follow-up studies show 20 percent of those treated live for at least three years with many living for 10 years and beyond, unprecedented results, according to the cancer center.
“Jim Allison’s accomplishments on behalf of patients cannot be overstated,” says MD Anderson president Peter WT Pisters, M.D., in a statement. “His research has led to life-saving treatments for people who otherwise would have little hope. The significance of immunotherapy as a form of cancer treatment will be felt for generations to come.”
“I never dreamed my research would take the direction it has,” Allison adds. “It’s a great, emotional privilege to meet cancer patients who’ve been successfully treated with immune checkpoint blockade. They are living proof of the power of basic science, of following our urge to learn and to understand how things work.”
A new cancer therapy using nanoparticles to deliver a combination therapy direct to cancer cells could be on the horizon, thanks to research from the University of East Anglia.
The new therapy, which has been shown to make breast cancer and prostate cancer tumours more sensitive to chemotherapy, is now close to entering clinical trials.
And scientists at UEA’s Norwich Medical School have confirmed that it can be mass-produced, making it a viable treatment if proved effective in human trials.
Using nanoparticles to get drugs directly into a tumour is a growing area of cancer research. The technology developed at UEA is the first of its kind to use nanoparticles to deliver two drugs in combination to target cancer cells.
The drugs, already approved for clinical use, are an anti-cancer drug called docetaxel, and fingolimod, a multiple sclerosis drug that makes tumours more sensitive to chemotherapy.
Fingolimod cannot currently be used in cancer treatment because it also supresses the immune system, leaving patients with dangerously low levels of white blood cells.
And while docetaxel is used to treat many cancers, particularly breast, prostate, stomach, head and neck and some lung cancers, its toxicity can also lead to serious side effects for patients whose tumours are chemo-resistant.
Because the nanoparticles developed by the UEA team can deliver the drugs directly to the tumour site, these risks are vastly reduced. In addition, the targeted approach means less of the drug is needed to kill off the cancer cells.
“So far nobody has been able to find an effective way of using fingolimod in cancer patients because it’s so toxic in the blood,” explains lead researcher, Dr. Dmitry Pshezhetskiy from the Norwich Medical School at UEA.
“We’ve found a way to use it that solves the toxicity problem, enabling these two drugs to be used in a highly targeted and powerful combination.”
The UEA researchers worked with Precision NanoSystems’ Formulation Solutions Team who used their NanoAssemblr technology to investigate if it was possible to synthesise the different components of the therapy at an industrial scale.
Following successful results on industrial scale production, and a published international patent application, the UEA team is now looking for industrial partners and licensees to move the research towards a phase one clinical trial.
Also included within the nanoparticle package are molecules that will show up on an MRI scan, enabling clinicians to monitor the spread of the particles through the body.
The team has already carried out trials in mice that show the therapy is effective in reducing breast and prostate tumours. These results were published in 2017.
“Significantly, all the components used in the therapy are already cleared for clinical use in Europe and the United States,” says Dr. Pshezhetskiy. “This paves the way for the next stage of the research, where we’ll be preparing the therapy for patient trials.”
“New FTY720-docetaxel nanoparticle therapy overcomes FTY720-induced lymphopenia and inhibits metastatic breast tumour growth,” by Heba Alshaker, Qi Wang, Shyam Srivats, Yimin Chao, Colin Cooper and Dmitri Pchejetski was published in Breast Cancer Research and Treatment on 10 July 2017.
“Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer,” by Qi Wang, Heba Alshaker, Torsten Böhler, Shyam Srivats, Yimin Chao, Colin Cooper and Dmitri Pchejetski was published in Scientific Reports on 19 July 2017.
More information: Heba Alshaker et al. New FTY720-docetaxel nanoparticle therapy overcomes FTY720-induced lymphopenia and inhibits metastatic breast tumour growth, Breast Cancer Research and Treatment (2017). DOI: 10.1007/s10549-017-4380-8
Qi Wang et al. Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer, Scientific Reports (2017). DOI: 10.1038/s41598-017-06142-x
Extracellular vesicle-like metal-organic framework nanoparticles are developed for the intracellular delivery of biofunctional proteins. The biomimetic nanoplatform can protect the protein cargo and overcome various biological barriers to achieve systemic delivery and autonomous release. Credit: Zheng Lab/Penn State
A biomimetic nanosystem can deliver therapeutic proteins to selectively target cancerous tumors, according to a team of Penn State researchers.
A biomimetic nanosystem can deliver therapeutic proteins to selectively target cancerous tumors, according to a team of Penn State researchers. Using a protein toxin called gelonin from a plant found in the Himalayan mountains, the researchers caged the proteins in self-assembled metal-organic framework (MOF) nanoparticles to protect them from the body’s immune system. To enhance the longevity of the drug in the bloodstream and to selectively target the tumor, the team cloaked the MOF in a coating made from cells from the tumor itself.
Blood is a hostile environment for drug delivery. The body’s immune system attacks alien molecules or else flushes them out of the body through the spleen or liver. But cells, including cancer cells, release small particles called extracellular vesicles that communicate with other cells in the body and send a “don’t eat me” signal to the immune system.
“We designed a strategy to take advantage of the extracellular vesicles derived from tumor cells,” said Siyang Zheng, associate professor of biomedical and electrical engineering at Penn State. “We remove 99 percent of the contents of these extracellular vesicles and then use the membrane to wrap our metal-organic framework nanoparticles. If we can get our extracellular vesicles from the patient, through biopsy or surgery, then the nanoparticles will seek out the tumor through a process called homotypic targeting.”
Gong Cheng, lead author on a new paper describing the team’s work and a former post-doctoral scholar in Zheng’s group now at Harvard, said, “MOF is a class of crystalline materials assembled by metal nodes and organic linkers. In our design, self-assembly of MOF nanoparticles and encapsulation of proteins are achieved simultaneously through a one-pot approach in aqueous environment. The enriched metal affinity sites on MOF surfaces act like the buttonhook, so the extracellular vesicle membrane can be easily buckled on the MOF nanoparticles. Our biomimetic strategy makes the synthetic nanoparticles look like extracellular vesicles, but they have the desired cargo inside.”
The nanoparticle system circulates in the bloodstream until it finds the tumor and locks on to the cell membrane. The cancer cell ingests the nanoparticle in a process called endocytosis. Once inside the cell, the higher acidity of the cancer cell’s intracellular transport vesicles causes the metal-organic framework nanoparticles to break apart and release the toxic protein into cytosol and kill the cell.
“Our metal-organic framework has very high loading capacity, so we don’t need to use a lot of the particles and that keeps the general toxicity low,” Zheng said.
The researchers studied the effectiveness of the nanosystem and its toxicity in a small animal model and reported their findings in a cover article in the Journal of the American Chemical Society.
The researchers believe their nanosystem provides a tool for the targeted delivery of other proteins that require cloaking from the immune system. Penn State has applied for patent protection for the technology.
Materials provided by Penn State. Original written by Walt Mills. Note: Content may be edited for style and length.
Survival rates in pancreatic cancerlinked to inverse correlation between specific oncogene and tumor suppressant, Tel Aviv University researchers say
A new Tel Aviv University study pinpoints the inverse correlation between a known oncogene — a gene that promotes the development of cancer — and the expression of an oncosuppressor microRNA as the reason for extended pancreatic cancer survival. The study may serve as a basis for the development of an effective cocktail of drugs for this deadly disease and other cancers.
The study, which was published in Nature Communications, was led by Prof. Ronit Satchi-Fainaro, Chair of the Department of Physiology and Pharmacology at TAU’s Sackler Faculty of Medicine, and conducted by Hadas Gibori and Dr. Shay Eliyahu, both of Prof. Satchi-Fainaro’s multidisciplinary laboratory, in collaboration with Prof. Eytan Ruppin of TAU’s Computer Science Department and the University of Maryland and Prof. Iris Barshack and Dr. Talia Golan of Chaim Sheba Medical Center, Tel Hashomer.
Pancreatic cancer is among the most aggressive cancers known today. The overwhelming majority of pancreatic cancer patients die within just a year of diagnosis. “Despite all the treatments afforded by modern medicine, some 75% of all pancreatic cancer patients die within 12 months of diagnosis, including many who die within just a few months,” Prof. Satchi-Fainaro says.
“But around seven percent of those diagnosed will survive more than five years. We sought to examine what distinguishes the survivors from the rest of the patients,” Prof. Satchi-Fainaro continues. “We thought that if we could understand how some people live several years with this most aggressive disease, we might be able to develop a new therapeutic strategy.”
Calling a nano-taxi
The research team examined pancreatic cancer cells and discovered an inverse correlation between the signatures of miR-34a, a tumor suppressant, and PLK1, a known oncogene. The levels of miR-34a were low in pancreatic cancer mouse models, while the levels of the oncogene were high. This correlation made sense for such an aggressive cancer. But the team needed to see if the same was true in humans.
The scientists performed RNA profiling and analysis of samples taken from pancreatic cancer patients. The molecular profiling revealed the same genomic pattern found earlier in mouse models of pancreatic cancer.
The scientists then devised a novel nanoparticle that selectively delivers genetic material to a tumor and prevents side effects in surrounding healthy tissues.
“We designed a nanocarrier to deliver two passengers: (1) miR-34a, which degrades hundreds of oncogenes; and (2) a PLK1 small interfering RNA (siRNA), that silences a single gene,” Prof. Satchi-Fainaro says. “These were delivered directly to the tumor site to change the molecular signature of the cancer cells, rendering the tumor dormant or eradicating it altogether.
“The nanoparticle is like a taxi carrying two important passengers,” Prof. Satchi-Fainaro continues. “Many oncology protocols are cocktails, but the drugs usually do not reach the tumor at the same time. But our ‘taxi’ kept the ‘passengers’ — and the rest of the body — safe the whole way, targeting only the tumor tissue. Once it ‘parked,’ an enzyme present in pancreatic cancer caused the carrier to biodegrade, allowing the therapeutic cargo to be released at the correct address — the tumor cells.”
Improving the odds
To validate their findings, the scientists injected the novel nanoparticles into pancreatic tumor-bearing mice and observed that by balancing these two targets — bringing them to a normal level by increasing their expression or blocking the gene responsible for their expression — they significantly prolonged the survival of the mice.
“This treatment takes into account the entire genomic pattern, and shows that affecting a single gene is not enough for the treatment of pancreatic cancer or any cancer type in general,” according to Prof. Satchi-Fainaro.
Research for the study was funded by the European Research Council (ERC), Tel Aviv University’s Cancer Biology Research Center (CBRC) and the Israel Science Foundation (ISF).
American Friends of Tel Aviv University (AFTAU) supports Israel’s most influential, comprehensive and sought-after center of higher learning, Tel Aviv University (TAU). TAU is recognized and celebrated internationally for creating an innovative, entrepreneurial culture on campus that generates inventions, startups and economic development in Israel. For three years in a row, TAU ranked 9th in the world, and first in Israel, for alumni going on to become successful entrepreneurs backed by significant venture capital, a ranking that surpassed several Ivy League universities. To date, 2,400 patents have been filed out of the University, making TAU 29th in the world for patents among academic institutions.