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.

Source

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.

Novel Nanomedicine Inhibits Progression of Pancreatic Cancer in Mice – Tel Aviv University


Nanomedicine I download

Survival rates in pancreatic cancer linked 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.

Nanomedicine III imagesThe 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.”

Nanomedicine I downloadCalling 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.Nanomedicine II pancreatic-cancer-1140x641

“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.

Fighting Cancer and Drug Resistance – A ‘Nanosystem’ Does Both


Cancer is often referred to as “smart,” and this term often refers to the ability of these cells to proliferate without purpose or restraint.

The ability of cancer cells to develop multidrug resistance (MDR), a major problem that patients can face, making treatment against this disease even more elusive.

In an effort to combat both cancer cell proliferation and MDR, a recent study conducted by researchers from the National Health Research Institutes of Taiwan and the National Science Council of Taiwan have developed a nanosystem capable of addressing both challenges in the field of cancer therapy.

Drug Resistance and Cancer

Patients with several forms of blood cancer and solid tumors in the breast, ovaries, lungs and lower gastrointestinal tract can become untreatable as a result of multidrug resistance (MDR).

In MDR, the cancer cells of these patients become resistant to commonly used therapeutic drugs as a result of an overexpression of ATP-binding cassette (ABC) transporters that effectively push out drug molecules following administration.

P-glycoprotein and what is termed as the multidrug resistance-associated protein (MRP) are two of the most studied pumps present in cancer cells that are capable of rejecting chemotherapeutic drugs.

By avoiding the toxic effects of these drugs, cancer cells are able to continue to proliferate and metastasize to other organs of the body.

Unfortunately, some of the most commonly used cancer therapeutic drugs such as colchicine, vinblastine, doxorubicin, etoposide, paclitaxel, certain vinca alkaloids and other small molecules have shown resistance in various cancer cells.

Current research efforts in the field of anticancer drug discovery have looked towards the administration of combinatorial technology to be administered with cancer to effectively prevent cancer cells from physically removing therapeutic drugs when administered together.

While blocking the action of pumps like MRP and P-glycoprotein has shown some efficacy, transcription factors, such as c-Jun, which plays a role in cell, proliferation and MDR, can still potentiate metastasis.

Therefore, there remains a need to develop cancer therapies that work against drug resistance and simultaneously prevent further metastasis.

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The Efficacy of Administering Doxorubicin Mesoporous Silica Nanoparticles (MSNs)

Mesoporous silica nanoparticles (MSNs) are well-documented drug delivery vehicles that allow for a high drug loading capacity with minimal side effects upon administration.

The tunable size properties, thermal stability, photostability and ease of functionalization to different applications make MSNs one of the most promising options for therapeutic delivery systems.

In the recent study published in Nano Futures, the group of scientists led by Leu-Wei Lo covalently conjugated MSNs with doxorubicin and tested the ability of these nanosystems to be taken up by cancer cells in vitro.

The PC-3 cell line of metastatic human prostate carcinoma cells were treated with 100 μg/ml of either Dox-MSNs that were conjugated with DNAzyme, (Dox-MSN-Dz), Dox-MSNs or control MSNs for 24 hours to study the ability of these cells to survive following treatment.

The researchers found the Dox-MSN-Dz reduced cell survival rates by over 80%, whereas the Dox-MSNs alone still reduced cell survival rates by 60%.

The results of this study confirm the therapeutic potential of the developed multifunctional nanosystem, which incorporates doxorubicin, a widely used chemotherapeutic drug, MSNs and DNAzyme.

Not only did this nanosystem improve the cytotoxicity of doxorubicin to a resistance cancer cell line, but it also successfully reduced migration of cancer cells by inhibiting c-Jun.

While further in vivo studies need to be conducted to fully evaluate the ability of Dox-MSN-Dz to prevent metastasis and invade highly resistance cancer cells, the results of this study are promising.

Future research initiatives that incorporate different chemotherapeutic drugs into a similar nanosystem design could also show similar bifunctional properties as presented here.

Image Credit:

fusebulb/Shutterstock.com

References:

1 “A co-delivery nanosystem of chemotherapeutics and DNAzyme overcomes cancer drug resistance and metastasis” S. Sun, C. Liu, et al. Nano Futures. (2017). DOI: 10.1088/2399-1984/aa996f.