MIT: How Tumors Behave on Acid: Acidic Environment Triggers Genes that Help Cancer Metastasize


MIT-Tumor-Acidity_0

In these tumor cells, acidic regions are labeled in red. Invasive regions of the cells, which express a protein called MMP14, are labeled in green. Image: Nazanin Rohani

Acidic environment triggers genes that help cancer cells metastasize.

Scientists have long known that tumors have many pockets of high acidity, usually found deep within the tumor where little oxygen is available. However, a new study from MIT researchers has found that tumor surfaces are also highly acidic, and that this acidity helps tumors to become more invasive and metastatic.

The study found that the acidic environment helps tumor cells to produce proteins that make them more aggressive. The researchers also showed that they could reverse this process in mice by making the tumor environment less acidic.

“Our findings reinforce the view that tumor acidification is an important driver of aggressive tumor phenotypes, and it indicates that methods that target this acidity could be of value therapeutically,” says Frank Gertler, an MIT professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study.

Former MIT postdoc Nazanin Rohani is the lead author of the study, which appears in the journal Cancer Research.

Mapping acidity

Scientists usually attribute a tumor’s high acidity to the lack of oxygen, or hypoxia, that often occurs in tumors because they don’t have an adequate blood supply. However, until now, it has been difficult to precisely map tumor acidity and determine whether it overlaps with hypoxic regions.

In this study, the MIT team used a probe called pH (Low) Insertion Peptide (pHLIP), originally developed by researchers at the University of Rhode Island, to map the acidic regions of breast tumors in mice. This peptide is floppy at normal pH but becomes more stable at low, acidic pH. When this happens, the peptide can insert itself into cell membranes. This allows the researchers to determine which cells have been exposed to acidic conditions, by identifying cells that have been tagged with the peptide.

To their surprise, the researchers found that not only were cells in the oxygen-deprived interior of the tumor acidic, there were also acidic regions at the boundary of the tumor and the structural tissue that surrounds it, known as the stroma.

“There was a great deal of tumor tissue that did not have any hallmarks of hypoxia that was quite clearly exposed to acidosis,” Gertler says. “We started looking at that, and we realized hypoxia probably wouldn’t explain the majority of regions of the tumor that were acidic.”

illustration-of-tumor-spreading          A new study explores how an acidic environment drives tumor spread.

Read More: How Does Tumor Acidity Help Cancer Spread

Further investigation revealed that many of the cells at the tumor surface had shifted to a type of cell metabolism known as aerobic glycolysis. This process generates lactic acid as a byproduct, which could account for the high acidity, Gertler says. The researchers also discovered that in these acidic regions, cells had turned on gene expression programs associated with invasion and metastasis. Nearly 3,000 genes showed pH-dependent changes in activity, and close to 300 displayed changes in how the genes are assembled, or spliced.

“Tumor acidosis gives rise to the expression of molecules involved in cell invasion and migration. This reprogramming, which is an intracellular response to a drop in extracellular pH, gives the cancer cells the ability to survive under low-pH conditions and proliferate,” Rohani says.

Those activated genes include Mena, which codes for a protein that normally plays a key role in embryonic development. Gertler’s lab had previously discovered that in some tumors, Mena is spliced differently, producing an alternative form of the protein known as MenaINV (invasive). This protein helps cells to migrate into blood vessels and spread though the body.

Another key protein that undergoes alternative splicing in acidic conditions is CD44, which also helps tumor cells to become more aggressive and break through the extracellular tissues that normally surround them. This study marks the first time that acidity has been shown to trigger alternative splicing for these two genes.

Reducing acidity

The researchers then decided to study how these genes would respond to decreasing the acidity of the tumor microenvironment. To do that, they added sodium bicarbonate to the mice’s drinking water. This treatment reduced tumor acidity and shifted gene expression closer to the normal state. In other studies, sodium bicarbonate has also been shown to reduce metastasis in mouse models.

Sodium bicarbonate would not be a feasible cancer treatment because it is not well-tolerated by humans, but other approaches that lower acidity could be worth exploring, Gertler says. The expression of new alternative splicing genes in response to the acidic microenvironment of the tumor helps cells survive, so this phenomenon could be exploited to reverse those programs and perturb tumor growth and potentially metastasis.

“Other methods that would more focally target acidification could be of great value,” he says.

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Howard Hughes Medical Institute, the National Institutes of Health, the KI Quinquennial Cancer Research Fellowship, and MIT’s Undergraduate Research Opportunities Program.

Other authors of the paper include Liangliang Hao, a former MIT postdoc; Maria Alexis and Konstantin Krismer, MIT graduate students; Brian Joughin, a lead research modeler at the Koch Institute; Mira Moufarrej, a recent graduate of MIT; Anthony Soltis, a recent MIT PhD recipient; Douglas Lauffenburger, head of MIT’s Department of Biological Engineering; Michael Yaffe, a David H. Koch Professor of Science; Christopher Burge, an MIT professor of biology; and Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science.

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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

 

Nanoscale blood test technique could lead to accelerated early diagnosis and personalized medicines


A technique to get more information from the blood of cancer patients than previously possible has been developed.

“We hope this technique could be a springboard for further research, from monitoring disease progression or recurrence, to identifying which treatment is best for each patient and potentially finding new biomarkers for early diagnosis.”- Professor Kostas Kostarelos

The discovery could potentially accelerate early diagnosis, speed up drug discovery and lead to advancements in personalised medicines.

The Cancer Research UK-funded study* is published in Advanced Materials today (Wednesday).

The scientists, from the University of Manchester, collected blood samples from women with advanced ovarian cancer who were treated with a type of chemotherapy called CAELYX®.

This chemotherapy drug is contained in a soft, lipid-based nanoparticle, called a liposome, which acts as a vessel to help minimise side effects**.

Women gave a sample of blood, following an injection of CAELYX® over a course of 90 minutes as part of their treatment. By extracting the injected liposomes, the scientists were able to detect a wide variety of biomolecules that stuck to the surface of the liposome – called the ‘biomolecule corona’.

Professor Kostas Kostarelos, lead author from the University of Manchester, said: “We’re astonished at how rich the information was on the surface of the liposomes taken from the blood. We hope this technique could be a springboard for further research, from monitoring disease progression or recurrence, to identifying which treatment is best for each patient and potentially finding new biomarkers for early diagnosis.”

This is a step forward in developing a better technique to gather information from patients’ blood – a ‘halo effect’ of biomolecules sticking to the liposomes has been seen before, but only after dipping the nanoparticles in blood samples in a tube outside the patient’s body.

Dr Marilena Hadjidemetriou, study author from the University of Manchester, said: “The blood is a potential goldmine of information, but there’s a challenge to amplify cancer signals that would otherwise be buried within the ‘noise’.

“More abundant proteins mask rarer and smaller molecules that could be significant in helping us to understand disease progression or finding potential new drug targets. This technique overcomes this challenge.”

Professor Caroline Dive, Cancer Research UK’s expert in liquid biopsies, said: “Finding a test to help diagnose, track and treat cancer is something many scientists are pursuing. Liquid biopsies are quicker, cheaper and less invasive than many other tests, and this technique is an important early step in developing such a test. Further work will reveal what the information captured using liposomes can tell us about the disease.”

The researchers now hope to use this technique in mice to help find the best patterns of biomarkers to identify cancers in the early stages of disease as part of their Cancer Research UK Pioneer Award, which funds innovative ideas from any discipline that could revolutionise our understanding of cancer.

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How nanotechnology research could cure cancer – genetic diseases


Genetic diseases may soon be a thing of the past thanks to nanotechnology, which employs tiny particles to manipulate cells and change our DNA.

Here is how cancer treatment often runs today: a patient develops an aggressive tumor. A surgeon operates to remove the tumor, but a few cancer cells remain, hiding in the body. Chemotherapy is administered, weakening both patient and cancer cells. But the cancer does not die; it comes back and eventually kills the patient.

Now imagine another scenario. After surgery, strands of DNA anchored in tiny gold particles are injected into the affected area. The DNA strands bind to the tumor cells, killing them directly, without the help of chemo. The healthy cells around the tumor cells, which don’t express the tumor gene, are untouched.

Just like that, all the tumor cell stragglers are rendered harmless, corrected on the genetic level. The patient is cured, and without having to endure months of chemotherapy and its brutal side effects: hair loss, nausea and extreme weakness.

The future of medicine won’t focus on treating the symptoms of a disease, according to reseachers: it will focus on curing it at the genetic level.

Nanotechnology, the science of working with particles that are one billionth of a meter, is enabling scientists to change gene expression on the cellular level, potentially curing a host of diseases.

“Nanotechnology medical developments over the coming years will have a wide variety of uses and could potentially save a great number of lives,” says Eleonore Pauwels, senior associate and scholar at the Wilson Center, an interdisciplinary policy research center.

The science of using nanoparticles got its start with a lecture by theoretical physicist Richard Feynman in 1959, but because of the technical challenges, it is only in the past 10 years or so that the technology has really taken off for practical medical applications.

Figuring out how to consistently create the right nanoparticle, get it into the right tissue, ensure it is not degraded and does what it was programmed to do, took some time.

The science of nanotechnology depends on the fact that when things get super small, they function differently. Protein, for example, is a naturally occurring nanoparticle. A single protein molecule is a very different entity than a human being, which is made up of many protein molecules.

Gold, which is used often in medicine, is red when broken down into tiny particles. That microscopic bright red color has been used for centuries to give red stained glass its color.

“Because of their small size, engineered nanomaterials have unique properties that do not exist at the larger scale: increased surface area, charge, reactivity and other physicochemical properties, all of which may affect how nanomaterials interact with biological entities, like cells,” says Sara Brenner, assistant professor of nanobioscience at SUNY Polytechnic Institute.

Scientists are learning to take advantage of those properties to create new treatments. One of the most powerful examples uses DNA, says Chad Mirkin, a professor at Northwestern University and director of the International Institute for Nanotechnology.

DNA is rod shaped and normally would not be able to enter cells, which have developed protection against entry from foreign DNA segments.

But by using nanotechnology, many little snippets of DNA can be attached to a tiny, round synthetic core. The receptors on cells that would block rod shaped DNA do not recognize the tiny spheres of DNA and allow it to enter.

Using that property, a whole new class of treatments for genetic diseases is being developed.

By being able to insert DNA into existing cells, scientists can “attack disease at its genetic root and turn off receptors that regulate how a cell functions, stopping a disease pathway in its tracks,” explains Mirkin.

Right now, most of the research into developing therapies using spheres of DNA is focused on disease of the liver, says Mirkin, as anything a person takes in is going to be processed in the liver. Another area of research into nanotech treatments is the skin, as the treatment can be applied topically, making it easy to target one area.

“Potential applications are virtually endless,” explains Brenner. “But some areas of investigation right now for gene therapy are cancer, diabetes, AIDS, cystic fibrosis and heart disease.”

As research into using nanoparticles advances, scientists hope to be able to not just turn off specific signals in cells, but also eventually insert genes to correct for defects and cure more complex diseases.

Called gene therapy, it would involve inserting larger fragments of DNA into cells that have faulty DNA. For example, cystic fibrosis is caused by a defective gene called CFTR. If scientists can figure out a way to get a non-defective copy of the gene into the cells and correct it, they could cure the disease.

“Approximately 4,000 diseases have been found to have a genetic component and are therefore potential targets for gene therapy,” according to Brenner.

While nanotechnology has the potential to revolutionize medicine and how we view treatment of diseases, there are still kinks to work out.

Some of the challenges with nanotechnology include how to get nanoparticles into the right cells and tissues, and how to get them into the cells safely without the nanoparticles degrading.

Nanotechnology is still in its infancy, however. It’s only recently that we were able to produce microscopes that allowed us to see and manipulate nanoparticles. 

Research requires bringing together a number of disciplines like chemistry, biomedical engineering, biology and physics. But pharmaceutical companies have already begun work on creating treatments using nanotech, and many are in various stages of development now. “It’s not a pipe dream,” says Mirkin. Being able to cure genetic diseases of all kinds is on the horizon.

MD Anderson Cancer Center: U of Texas (Houston) scientist wins Nobel Prize for breakthrough cancer treatment


Allison’s groundbreaking work with T cells helped him net the award. Photo courtesy of MD Anderson Cancer Center

The already much-heralded University of Texas MD Anderson Cancer Center has just scored global bragging rights. Jim Allison, Ph.D., a scientist at MD Anderson Cancer Center, has been awarded the 2018 Nobel Prize in Physiology or Medicine, it was announced on October 1, 2018.

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.”

Nanoparticle therapy could deliver double blow to cancer


Cancer double blow 56cd5fec14a8a

 

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 , which has been shown to make breast  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  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 .

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 .

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  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 ,” 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.

 Explore further: Lipid molecules can be used for cancer growth

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

Read more at: https://phys.org/news/2018-08-nanoparticle-therapy-cancer.html#jCp

Penn State: Camouflaged nanoparticles deliver killer ‘knock-out’ protein to cancer


Killer Protein for Cancer Treatment 180615094843_1_540x360

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.

Story Source:

Materials provided by Penn State. Original written by Walt Mills. Note: Content may be edited for style and length.

 

New Targeting strategy developed by Penn State may open door to better cancer drug delivery


Drug delivery targetingstrIn the transition from benign to malignant, cancer cells transition from stiff to soft. Mechanotargeting harnesses mechanics to improve targeting efficiency of nanparticle-based therapeutic agents. Credit: Zhang lab/vecteezy.com

Bioengineers may be able to use the unique mechanical properties of diseased cells, such as metastatic cancer cells, to help improve delivery of drug treatments to the targeted cells, according to a team of researchers at Penn State.

Many labs around the world are developing nanoparticle-based,  to selectively target tumors. They rely on a key-and-lock system in which protein keys on the surface of the nanoparticle click into the locks of a highly expressed protein on the surface of the cancer cell. The cell membrane then wraps around the nanoparticle and ingests it. If enough of the nanoparticles and their drug cargo is ingested, the cancer cell will die.

The adhesive force of the lock and key is what drives the nanoparticle into the cell, said Sulin Zhang, professor of engineering science and mechanics.

“It is almost universal that whenever there is a driving force for a process, there always is a resistive force,” Zhang said. “Here, the driving force is biochemical—the protein-protein interaction.”

The resistive force is the mechanical energy cost required for the membrane to wrap around the nanoparticle. Until now, bioengineers only considered the driving force and designed nanoparticles to optimize the chemical interactions, a targeting strategy called “chemotargeting.” Zhang believes they should also take into account the mechanics of the  to design nanoparticles to achieve enhanced targeting, which forms a new targeting strategy called “mechanotargeting.”

“These two targeting strategies are complementary; you can combine chemotargeting and mechanotargeting to achieve the full potential of nanoparticle-based diagnostic and therapeutic agents,” Zhang said. “The fact is that targeting efficiency requires a delicate balance between driving and resistive forces. For instance, if there are too many keys on the nanoparticle surface, even though these keys only weakly interact with the nonmatching locks on normal cells, these weak, off-target interactions may still provide enough adhesion energy for the nanoparticles to penetrate the  and kill the healthy cells.”

On the other hand, if the adhesion energy is not high enough, the nanoparticle won’t get into the cell.

In “Mechanotargeting: Mechanics-dependent Cellular Uptake of Nanoparticles,” published online ahead of print in the journal Advanced Materials, Zhang and the team report the results of experiments on cancer cells grown on hydrogels of variable stiffness. On soft hydrogels the cells remained cohesive and benign and experienced a nearly constant stress that limited the uptake of the nanoparticles. But on stiff hydrogels the cells became metastatic and adopted a three-dimensional shape, offering more surface area for nanoparticles to adhere, and became less stressed. Under this condition, the cells took up five times the number of nanoparticles as the benign cells.

“The nanoparticles are fluorescent, so we count the number of  that get into the cell by the fluorescence intensity. We found that in the malignant cells the intensity is five times higher,” Zhang said. “That proves that mechanotargeting works.”

 Explore further: Nanoparticle aggregates for destruction of cancer cells

More information: Qiong Wei et al, Mechanotargeting: Mechanics-Dependent Cellular Uptake of Nanoparticles, Advanced Materials (2018). DOI: 10.1002/adma.201707464

 

Nanorobots successfully target and kill cancerous tumors


Science fiction no more

In an article out today in Nature Biotechnology, scientists were able to show tiny autonomous bots have the potential to function as intelligent delivery vehicles to cure cancer in mice.

These DNA nanorobots do so by seeking out and injecting cancerous tumors with drugs that can cut off their blood supply, shriveling them up and killing them.

“Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth,” the paper explains.

DNA nanorobots are a somewhat new concept for drug delivery. They work by getting programmed DNA to fold into itself like origami and then deploying it like a tiny machine, ready for action.

DNA nanorobots, Nature Biotechnology 2018

The scientists behind this study tested the delivery bots by injecting them into mice with human breast cancer tumors. Within 48 hours, the bots had successfully grabbed onto vascular cells at the tumor sites, causing blood clots in the tumor’s vessels and cutting off their blood supply, leading to their death.

Remarkably, the bots did not cause clotting in other parts of the body, just the cancerous cells they’d been programmed to target, according to the paper.

The scientists were also able to demonstrate the bots did not cause clotting in the healthy tissues of Bama miniature pigs, calming fears over what might happen in larger animals.

The goal, say the scientists behind the paper, is to eventually prove these bots can do the same thing in humans. Of course, more work will need to be done before human trials begin.

Regardless, this is a huge breakthrough in cancer research. The current methods of either using chemotherapy to destroy every cell just to get at the cancer cell are barbaric in comparison. Using targeted drugs is also not as exact as simply cutting off blood supply and killing the cancer on the spot. Should this new technique gain approval for use on humans in the near future it could have impressive affects on those afflicted with the disease.

New nanoparticle may aid cancer detection


Cellular Messenger Cornell 9-scientistsdiAn intricate pattern – a molecular model of the influenza virus. The influenza virion (as the infectious particle is called) is roughly spherical. It is an enveloped virus – that is, the outer layer is a lipid membrane which is taken from the host cell in which the virus multiplies. 

A new nanoparticle, at the cellular level, may reveal how cancer cells move to different locations in the human body. This process involves co-opting the human body’s inter-cellular delivery service.

The insight into the cellular messenger system comes from Weill Cornell Medicine scientists. The discovery is of importance since it could help medical scientists to understand how cancer cells can spread to various other locations.

 

With the research, the medics have used a novel technique called asymmetric flow field-flow fractionation. Through this the researchers were able to shift and sort a particular type of nano-sized particles termed exosomes. These particles are secreted by cancer cells and they are formed of DNA, RNA, fats and proteins.

 

Exosomes are cell-derived vesicles that are present in many cell fluids, including blood, and urine; they provide a means of intercellular communication and of transmission of macromolecules between cells. In medicine exosomes can potentially be used for prognosis, for therapy, and as biomarkers for health and disease.

 

By using the asymmetric flow field-flow fractionation, the scientists were able to separate out two distinct exosome subtypes. This has led to the discovery of the new type of nanoparticle. Asymmetrical flow field flow fractionation is a common and state-of-the art method for fractionation and separation of macromolecules and particles in a suspension.

 

Metastatic breast cancer in pleural fluid.

Metastatic breast cancer in pleural fluid. euthman/flickr

 

Discussing the research with Controlled Environments magazine, lead researcher Dr. David Lyden explains further: We found that exomeres are the most predominant particle secreted by cancer cells. They are smaller and structurally and functionally distinct from exosomes. Exomeres largely fuse with cells in the bone marrow and liver, where they can alter immune function and metabolism of drugs.”

 

The researcher adds: “The latter finding may explain why many cancer patients are unable to tolerate even small doses of chemotherapy due to toxicity.”

 

Importantly exosomes and exomeres have different biophysical characteristics, like stiffness and electric charge. With this, the findings show, the more rigid the particle, the easier it is likely taken up by cells, rendering exomeres more effective messengers of transferring tumor information to recipient cells.

 

The research further shows how exosomes and exomeres differ in relation to their influence in triggering cancer. Exomeres can carry metabolic enzymes to the liver. Here exomeres are able to cause the liver to “reprogram” its metabolic function and trigger tumor progression.

 

The researchers plan to patent the new technology and develop a diagnostic tool to assist with cancer detection. This will help medics to understand how cancers grow and spread to other organs.

 

The research has been published in the journal Nature Cell Biology. The research paper is titled “Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation.”

 

In related news, Digital Journal has previously reported that researchers have used nanotechnology to improve drug delivery. This is in the form of tailorable nanoscale emulsions which effectively interact with their intended targets (see: “Delivering drugs via nanoscale emulsion.”)

 

Essential Science

 

Demonstrating the need for good cleaning and disinfection using ultraviolet light to show how easy i...

Demonstrating the need for good cleaning and disinfection using ultraviolet light to show how easy it is to miss parts of a surface when cleaning. Tim Sandle

 

This article is part of Digital Journal’s regular Essential Science columns. Each week Tim Sandle explores a topical and important scientific issue. Last week the association between household cleaning chemicals and respiratory problems was examined in light of a new study from the University of Bergen in Norway, which raises concerns about the longer-term health impact.

 

The week before the topic of nanotechnology and the development of a new generation of antimalarial drugs was discussed.