MIT: New Optical Imaging System could be Deployed to find Tiny Tumors and Detect Cancer Earlier – “A Game Changing Method”


 

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Near-infrared technology pinpoints fluorescent probes deep within living tissue; may be used to detect cancer earlier. MIT researchers have devised a way to simultaneously image in multiple wavelengths of near-infrared light, allowing them to determine the depth of particles emitting different wavelengths. Image courtesy of the researchers

Many types of cancer could be more easily treated if they were detected at an earlier stage. MIT researchers have now developed an imaging system, named “DOLPHIN,” which could enable them to find tiny tumors, as small as a couple of hundred cells, deep within the body. 

In a new study, the researchers used their imaging system, which relies on near-infrared light, to track a 0.1-millimeter fluorescent probe through the digestive tract of a living mouse. They also showed that they can detect a signal to a tissue depth of 8 centimeters, far deeper than any existing biomedical optical imaging technique.

The researchers hope to adapt their imaging technology for early diagnosis of ovarian and other cancers that are currently difficult to detect until late stages.

“We want to be able to find cancer much earlier,” says Angela Belcher, the James Mason Crafts Professor of Biological Engineering and Materials Science at MIT and a member of the Koch Institute for Integrative Cancer Research, and the newly-appointed head of MIT’s Department of Biological Engineering. “Our goal is to find tiny tumors, and do so in a noninvasive way.”

Belcher is the senior author of the study, which appears in the March 7 issue of Scientific Reports. Xiangnan Dang, a former MIT postdoc, and Neelkanth Bardhan, a Mazumdar-Shaw International Oncology Fellow, are the lead authors of the study. Other authors include research scientists Jifa Qi and Ngozi Eze, former postdoc Li Gu, postdoc Ching-Wei Lin, graduate student Swati Kataria, and Paula Hammond, the David H. Koch Professor of Engineering, head of MIT’s Department of Chemical Engineering, and a member of the Koch Institute.

Deeper imaging

Existing methods for imaging tumors all have limitations that prevent them from being useful for early cancer diagnosis. Most have a tradeoff between resolution and depth of imaging, and none of the optical imaging techniques can image deeper than about 3 centimeters into tissue. Commonly used scans such as X-ray computed tomography (CT) and magnetic resonance imaging (MRI) can image through the whole body; however, they can’t reliably identify tumors until they reach about 1 centimeter in size.

Belcher’s lab set out to develop new optical methods for cancer imaging several years ago, when they joined the Koch Institute. They wanted to develop technology that could image very small groups of cells deep within tissue and do so without any kind of radioactive labeling.

Near-infrared light, which has wavelengths from 900 to 1700 nanometers, is well-suited to tissue imaging because light with longer wavelengths doesn’t scatter as much as when it strikes objects, which allows the light to penetrate deeper into the tissue. To take advantage of this, the researchers used an approach known as hyperspectral imaging, which enables simultaneous imaging in multiple wavelengths of light.

The researchers tested their system with a variety of near-infrared fluorescent light-emitting probes, mainly sodium yttrium fluoride nanoparticles that have rare earth elements such as erbium, holmium, or praseodymium added through a process called doping. Depending on the choice of the doping element, each of these particles emits near-infrared fluorescent light of different wavelengths.

Using algorithms that they developed, the researchers can analyze the data from the hyperspectral scan to identify the sources of fluorescent light of different wavelengths, which allows them to determine the location of a particular probe. By further analyzing light from narrower wavelength bands within the entire near-IR spectrum, the researchers can also determine the depth at which a probe is located. The researchers call their system “DOLPHIN”, which stands for “Detection of Optically Luminescent Probes using Hyperspectral and diffuse Imaging in Near-infrared.”

To demonstrate the potential usefulness of this system, the researchers tracked a 0.1-millimeter-sized cluster of fluorescent nanoparticles that was swallowed and then traveled through the digestive tract of a living mouse. These probes could be modified so that they target and fluorescently label specific cancer cells.

“In terms of practical applications, this technique would allow us to non-invasively track a 0.1-millimeter-sized fluorescently-labeled tumor, which is a cluster of about a few hundred cells. To our knowledge, no one has been able to do this previously using optical imaging techniques,” Bardhan says.

Earlier detection

The researchers also demonstrated that they could inject fluorescent particles into the body of a mouse or a rat and then image through the entire animal, which requires imaging to a depth of about 4 centimeters, to determine where the particles ended up. And in tests with human tissue-mimics and animal tissue, they were able to locate the probes to a depth of up to 8 centimeters, depending on the type of tissue.

Guosong Hong, an assistant professor of materials science and engineering at Stanford University, described the new method as “game-changing.”

“This is really amazing work,” says Hong, who was not involved in the research. “For the first time, fluorescent imaging has approached the penetration depth of CT and MRI, while preserving its naturally high resolution, making it suitable to scan the entire human body.”

Early Detect cancer-cells-600Read More About the Importance of Early Detection

This kind of system could be used with any fluorescent probe that emits light in the near-infrared spectrum, including some that are already FDA-approved, the researchers say. The researchers are also working on adapting the imaging system so that it could reveal intrinsic differences in tissue contrast, including signatures of tumor cells, without any kind of fluorescent label.

In ongoing work, they are using a related version of this imaging system to try to detect ovarian tumors at an early stage. Ovarian cancer is usually diagnosed very late because there is no easy way to detect it when the tumors are still small.

“Ovarian cancer is a terrible disease, and it gets diagnosed so late because the symptoms are so nondescript,” Belcher says. “We want a way to follow recurrence of the tumors, and eventually a way to find and follow early tumors when they first go down the path to cancer or metastasis. This is one of the first steps along the way in terms of developing this technology.”

The researchers have also begun working on adapting this type of imaging to detect other types of cancer such as pancreatic cancer, brain cancer, and melanoma.

The research was funded by the Koch Institute Frontier Research Program, the Marble Center for Cancer Nanomedicine, the Koch Institute Support (core) Grant from the National Cancer Institute, the NCI Center for Center for Cancer Nanotechnology Excellence, and the Bridge Project.

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


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

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

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

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

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

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

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

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

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

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

 

Platinum Nanoparticles Offer ‘Selective Treatment’ of Liver Cancer Cells


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Non-oxidised platinum nanoparticles have virtually no toxic effect on normal cells (bottom left). Once inside liver cancer cells (top right), the platinum is oxidised, releasing its toxic effect. Credit: ETH Zurich / Helma Wennemers

Researchers at ETH Zurich recently demonstrated that platinum nanoparticles can be used to kill liver cancer cells with greater selectivity than existing cancer drugs.

In recent years, the number of targeted  has continued to rise. However, conventional chemotherapeutic agents still play an important role in cancer treatment. These include -based  that attack and kill . But these agents also damage healthy tissue and cause severe side effects. Researchers at ETH Zurich have now identified an approach that allows for a more selective cancer treatment with drugs of this kind.

Platinum can be cytotoxic when oxidised to platinum(II) and occurs in this form in conventional platinum-based chemotherapeutics. Non-oxidised platinum(0), however, is far less toxic to cells. Based on this knowledge, a team led by Helma Wennemers, Professor at the Laboratory of Organic Chemistry, and Michal Shoshan, a postdoc in her group, looked for a way to introduce platinum(0) into the , and only then for it to be oxidised to platinum(II). To this end, they used non-oxidised platinum nanoparticles, which first had to be stabilized with a peptide. They screened a library containing thousands of peptides to identify a peptide suitable for producing platinum nanoparticles (2.5 nanometres in diameter) that are stable for years.

Oxidised inside the cell

Tests with cancer cell cultures revealed that the platinum(0) nanoparticles penetrate into cells. Once inside the specific environment of liver cancer cells, they become oxidised, triggering the cytotoxic effect of platinum(II).

Studies with ten different types of human cells also showed that the toxicity of the peptide-coated nanoparticles was highly selective to liver cancer cells. They have the same toxic effect as Sorafenib, the most common drug used to treat primary liver tumours today. However, the nanoparticles are more selective than Sorafenib and significantly more so than the well-known chemotherapeutic Cisplatin. It is therefore conceivable that the nanoparticles will have fewer side effects than conventional medication.

Joining forces with ETH Professor Detlef Günther and his research group, Wennemers and her team were able to determine the platinum content inside the cells and their nuclei using special mass spectrometry. They concluded that the platinum content in the nuclei of liver cancer cells was significantly higher than, for instance, in colorectal cancer . The authors believe that the platinum(II) ions – produced by oxidation of the  in the  – enter the nucleus, and there release their toxicity.

“We are still a very long and uncertain way away from a new drug, but the research introduced a new approach to improve the selectivity of drugs for certain types of  – by using a selective activation process specific to a given cell type,” Wennemers says. Future research will expand the chemical properties of the nanoparticles to allow for greater control over their biological effects.

 Explore further: Gold Nanoparticles Delivery Platinum Warheads to Tumors

More information: Michal S. Shoshan et al. Peptide-Coated Platinum Nanoparticles with Selective Toxicity against Liver Cancer Cells, Angewandte Chemie International Edition (2018). DOI: 10.1002/anie.201813149

Read more at: https://phys.org/news/2019-02-platinum-nanoparticles-treatment-liver-cancer.html#jCp

Nanomachines ‘Learn’ to Fight Cancer – ITMO University


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

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

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

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

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

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

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

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

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

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

 

Israeli Scientists Claim They’re On The Path To A Cure For Cancer – ACS Cautions


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It doesn’t seem possible. But they say it’s true. A small team of Israeli scientists is telling the world they will have the first “complete cure” for cancer within a year, The Jerusalem Post reported on Monday. And not only that, but they claim it will be brief, cheap and effective and will have no or minimal side-effects.

“We believe we will offer in a year’s time a complete cure for cancer,” said Dan Aridor, chairman of the board of Accelerated Evolution Biotechnologies Ltd. (AEBi), a company founded in 2000 in the ITEK incubator in the Kiryat Weizmann Science Park in Ness Ziona, Israel, just north of the Weizmann Institute of Science in Rehovot, Israel.

A development-stage biopharmaceutical company engaged in discovery and development of therapeutic peptides, AEBi developed the SoAP platform, a combinatorial biology screening platform technology, which provides functional leads—agonist, antagonist, inhibitor, etc.—to very difficult targets.

Still skepticism was high among those in the know. Weighing in on behalf of the American Cancer Society (ACS) on his blog, “A Cure For Cancer? Not So Fast,” Len Lichtenfeld, MD, ACS chief medical officer cautioned: “…it goes without saying, we all share the aspirational hope that they are correct. Unfortunately, we must be aware that this is far from proven as an effective treatment for people with cancer, let alone a cure.”

YOUNG ISRAELI CANCER RESEARCHRead More: Why Others Think This Claim Is Not Likely to Happen

Lichtenfeld went on to list several key points that he says must be kept in mind no matter what media reports say:

1. This is a news report based on limited information provided by researchers and a company working on this technology. It apparently has not been published in the scientific literature where it would be subject to review, support and/or criticism from knowledgeable peers.

2. My colleagues here at American Cancer Society tell me phage or peptide display techniques, while very powerful research tools for selecting high affinity binders, have had a difficult road as potential drugs. If this group is just beginning clinical trials, they may well have some difficult experiments ahead.

3. This is based on a mouse experiment which is described as “exploratory.” It appears at this point there is not a well-established program of experiments which could better define how this works—and may not work—as it moves from the laboratory bench to the clinic.

4. We all have hope that a cure for cancer can be found and found quickly. It is certainly possible this approach may be work. However, as experience has taught us so many times, the gap from a successful mouse experiment to effective, beneficial application of exciting laboratory concepts to helping cancer patients at the bedside is in fact a long and treacherous journey, filled with unforeseen and unanticipated obstacles.

5. It will likely take some time to prove the benefit of this new approach to the treatment of cancer. And unfortunately–based on other similar claims of breakthrough technologies for the treatment of cancer–the odds are that it won’t be successful.

“Our hopes are always on the side of new breakthroughs in the diagnosis and treatment of cancer. We are living in an era where many exciting advances are impacting the care of patients with cancer,” Lichtenfeld went on. “We hope that this approach also bears fruit and is successful. At the same time, we must always offer a note of caution that the process to get this treatment from mouse to man is not always a simple and uncomplicated journey.”

From Forbes – Robin Seaton Jefferson – 

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


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

 

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

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

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

 

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

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

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

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

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

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

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

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

Story Source:

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


Journal Reference:

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

New Cancer Research – Converting Cancer Cells to Fat Cells to Stop Cancer’s Spread


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: 

“Firstly, we demonstrate that breast cancer cells that undergo an EMT and thus become malignant, metastatic and therapy-resistant, exhibit a high degree of stemness, also referred to as plasticity. It is thus possible to convert these malignant cells into other cell types, as shown here by a conversion to adipocytes.”

“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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

Story Source:

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


Journal Reference:

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

Sprayable gel could help the body fight off cancer … after surgery


sprayablegelA scanning electron microscope image of a gel developed by UCLA researchers that could help prevent cancer from recurring after surgery. Credit: University of California, Los Angeles

Many people who are diagnosed with cancer will undergo some type of surgery to treat their disease—almost 95 percent of people with early-diagnosed breast cancer will require surgery and it’s often the first line of treatment for people with brain tumors, for example. But despite improvements in surgical techniques over the past decade, the cancer often comes back after the procedure.

AAfter surgery sprayable gel kp69pm-800x533

Now, a UCLA-led  has developed a spray gel embedded with immune-boosting drugs that could help. In a peer-reviewed study, the substance was successful half of the time in awakening lab animals’ immune systems to stop the cancer from recurring and inhibit it from spreading to other parts of the body.

A paper describing the work is published online in the journal Nature Nanotechnology.

The researchers, led by Zhen Gu, a professor of bioengineering at the UCLA Samueli School of Engineering and member of the UCLA Jonsson Comprehensive Cancer Center, tested the biodegradable spray gel in mice that had advanced melanoma tumors surgically removed. They found that the gel reduced the growth of the tumor cells that remained after surgery, which helped prevent recurrences of the cancer: After receiving the treatment, 50 percent of the mice survived for at least 60 days without their tumors regrowing.

The spray not only inhibited the recurrence of tumors from the area on the body where it was removed, but it also controlled the development of tumors in other parts of the body, said Gu, who is also a member of the California NanoSystems Institute at UCLA.

Cancer-treatment-655x353The substance will have to go through further testing and approvals before it could be used in humans. But Gu said that the scientists envision the gel being applied to the tumor resection site by surgeons immediately after the tumor is removed during surgery.

“This sprayable gel shows promise against one of the greatest obstacles in curing cancer,” Gu said. “One of the trademarks of cancers is that it spreads. In fact, around 90 percent of people with cancerous tumors end up dying because of  recurrence or metastasis. Being able to develop something that helps lower this risk for this to occur and has low toxicity is especially gratifying.”

The researchers loaded nanoparticles with an antibody specifically targeted to block CD47, a protein that cancer cells release as a “don’t-eat-me” signal. By blocking CD47, the antibody enables the immune system to find and ultimately destroy the cancer cells.

The nanoparticles are made of calcium carbonate, a substance that is the main component of egg shells and is often found in rocks. Researchers chose  because it can be gradually dissolved in surgical wound sites, which are slightly acidic, and because it boosts the activity of a type of macrophage that helps rid the body of foreign objects, said Qian Chen, the study’s lead author and a  in Gu’s lab.

“We also learned that the gel could activate T cells in the immune system to get them to work together as another line of attack against lingering  cells,” Chen said.

Once the solution is sprayed on the surgical site, it quickly forms a gel embedded with the nanoparticles. The gel helps stop at the surgical site and promotes would healing; the nanoparticles gradually dissolve and release the anti-CD47 antibodies into the body.

The  will continue testing the approach in animals to learn the optimal dose, best mix of nanoparticles and ideal treatment frequency, before testing the gel on human patients.

 Explore further: Gradual release of immunotherapy at site of tumor surgery prevents tumors from returning

More information: Qian Chen et al. In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment, Nature Nanotechnology (2018). DOI: 10.1038/s41565-018-0319-4

 

MIT – Measuring cancer cell “fitness” reveals drug susceptibility and the potential to treat non-responsive cancer cells


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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.