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Scientists Discover How to Trick Cancer Cells to Consume Toxic Drugs

AHA Publisher — Fri, 07 May 2021 07:00:36 +0000

Massachusetts General Hospital via EurekAlert – BOSTON – New research led by a team at Massachusetts General Hospital (MGH) points to a promising strategy to boost tumors’ intake of cancer drugs, thereby increasing the effectiveness of chemotherapy treatments. The group’s findings are published in Nature Nanotechnology. Getting enough anticancer drugs into a tumor is often difficult, and a potential strategy to overcome this challenge involves binding the medications to albumin, the most abundant protein in blood. The strategy relies on tumors’ large appetite for protein nutrients that fuel malignant growth. When consuming available albumin, the tumors will inadvertently take in the attached drugs. A popular albumin-bound drug approved by the U.S. Food and Drug Administration is nanoparticle albumin-bound paclitaxel (nab-PTX), and it has been successfully used to treat late-stage lung and pancreatic cancers. “Not all patients respond to nab-PTX, though, and the effectiveness of its delivery to tumors has been mixed, owing to an incomplete understanding of how albumin impacts drug delivery and actions,” says senior author Miles Miller, PhD, a principal investigator in the MGH Center for Systems Biology and assistant professor of Radiology at Harvard Medical School. To provide insights, Miller and his colleagues assessed the delivery of nab-PTX to tumors at a single-cell resolution in mouse models of cancer. Using 3D microscopy and what’s called tissue clearing technology, the team found that cancer cells can take up a significant amount of nab-PTX, and that the consumption of these drugs is controlled by signaling pathways that are involved in the cells’ uptake of nutrients such as albumin. “This discovery suggested that if we could manipulate these pathways, we might be able to trick cancer cells into a nutrient-starved state, thereby enhancing their consumption of nab-PTX,” explains Ran Li, PhD, first author on the study and an instructor in the MGH Department of Radiology and the Center for Systems Biology. Indeed, treating tumors with an inhibitor of insulin-like growth factor 1 receptor, an important component of one of the signaling pathways, improved the accumulation of nab-PTX in tumors and boosted its effectiveness. “These results offer new possibilities to improve delivery of albumin-bound drugs in patients with diverse types of cancer,” says Miller. To read the original article click here.

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Hydrogels Offer New Hope for Cancer Treatment

AHA Publisher — Fri, 16 Apr 2021 07:00:10 +0000

Tokyo University of Science via News-Medical – Hydrogels are often used as drug delivery systems, but to be effective carriers for anti-cancer drugs, they need to be responsive to varied stimuli in the tumor microenvironment. Now, scientists from Japan have developed novel hydrogels to effectively deliver drugs to tumor sites in response to temperature and pH changes in the tumor microenvironment. These multi-stimuli-responsive hydrogels can eliminate remnant cancer cells following tumor excision through controlled drug release, offering hope for effective cancer treatment. Cancer therapy in recent times relies on the use of several drugs derived from biological sources including different bacteria and viruses, among others. However, these bio-based drugs get easily degraded and therefore inactivated on administration into the body. Thus, effective delivery to and release of these drugs at target tumor sites are of paramount importance from the perspective of cancer therapy. Recently, scientists have discovered unique three-dimensional, water-containing polymers, called hydrogels, as effective drug delivery systems (DDSs). Drugs loaded into these hydrogels remain relatively stable owing to the network-like structure and organic tissue-like consistency of these DDSs. Besides, drug release from hydrogels can be controlled by designing them to swell and shrink in response to certain stimuli, or minute changes in conditions, like temperature or pH (which determines the acidity of an environment). For instance, when conditions are just the right level of acidic in the tumor microenvironment, these DDSs either shrink or swell and release the drug. However, there has been no method for the one-pot synthesis of hydrogels that respond to more than one such stimulus and degrade to release drugs at target tumor sites. Until now. Now, a team of scientists, led by Professor Akihiko Kikuchi from Tokyo University of Science, reports the production of unique degradable hydrogels that respond to changes under multiple conditions in “reducing” environments mimicking the microenvironment of tumors. In order to prepare degradable hydrogels that can release drugs in response to changes in the tumor microenvironment, we prepared hydrogels that respond to temperature, pH, and reducing environment, and analyzed their properties.” (Akihiko Kikuchi, Professor, Tokyo University of Science) In their study published in the Journal of Controlled Release, Prof. Kikuchi–along with his colleagues from Tokyo University of Science, Dr. Syuuhei Komatsu, Ms. Moeno Tago, and Ms. Yu Ando, and his collaborator on the study, Prof. Taka-Aki Asoh from Osaka University–details the steps of designing these novel hydrogels from the synthetic polymer poly(ethylene glycol) diglycidyl ether and the sulfur-containing organic compound cystamine. In response to low temperatures, these hydrogels swell up while they shrink at the physiological temperature. Additionally, the hydrogels respond to pH changes by virtue of possessing tertiary amino groups. It must be noted here that the pH of the tumor microenvironment fluctuates between 5.5 and 6.5 owing to glycolysis in the tumor cells. Under the reducing conditions of this environment, the hydrogels degrade because of the breakage of disulfide bonds and change into low molecular-weight water-soluble oligomers that are easily excreted from the body. To further test their drug release properties, the scientists loaded these hydrogels with specific proteins by exploiting their temperature-dependent swelling-deswelling behavior and tested the controlled release of drugs under acidic or reducing conditions. It was found that the amount of drug loaded onto these hydrogels could be controlled by changing the mesh size of the hydrogel polymer network by changing temperature, suggesting the possibility of customizing these DDSs for specific drug delivery. Besides, the hydrogel network structure and electrostatic interactions in the network ensured that the proteins were preserved intact until delivery, unaffected by the swelling and shrinking of the hydrogels with pH changes in the surrounding environment. The scientists found that the loaded protein drugs were completely released only under reducing conditions. Using these hydrogels and the tractability that they provide, doctors may soon be able to design “customized” hydrogels that are specific to patients, giving personalized medicine a big boost. In addition to that, this new DDS provides a way to kill cancer cells that are left behind after surgery. “The implantation of this material in the affected area after cancer resection may eliminate residual cancer cells, making it a more powerful therapeutic tool”. (Akihiko Kikuchi) As cancer tightens its vise grip around the world, treatment options need to be varied and upgraded for customized and effective therapy. This unique and simple design technique to produce multi-stimuli-responsive hydrogels for effective drug delivery to target tumor sites may just be one among several such promising techniques to mount an answer to the challenge cancer poses to humanity. To read the original article click here.

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Breakthrough Discovery Could Turn Cancer into a Treatable Disease

AHA Publisher — Tue, 22 Sep 2020 07:00:45 +0000

University of Salford via News-Medical Net – Professor Michael Lisanti and Professor Federica Sotgia have made a discovery that could turn cancer into a treatable disease and remove the fear from a cancer diagnosis. Despite years of research and billions of pounds of investment, there are no MHRA/FDA-approved drugs for the prevention of metastasis. As a consequence, cancer metastasis remains a mysterious, untreatable, lethal disease. What is cancer metastasis? Metastasis is what happens when cancer cells spread throughout the body, most often to other organs, like the brain, bone tissue, the lungs and the liver. Metastasis, more often than not, turns cancer into an untreatable, terminal disease. No effective therapies are available. After surgical removal of the primary tumor, most cancer patients are treated with chemo-therapy and radiation to eradicate the remaining tumor cells that have been left behind, by incomplete surgical removal of cancerous lesions. Unfortunately, many cancer patients ultimately undergo tumour recurrence, resulting in distant metastasis (cancer spread). As a result, more than 90% of these patients that undergo treatment failure, die from metastatic disease. Therefore, the discovery of inhibitors of metastasis could turn cancer into a chronic treatable disease and remove the fear from a cancer diagnosis. In order to fill this knowledge gap and meet clinical needs, researchers at the University of Salford have identified that the Achilles’ heel of metastasis is ATP-depletion, which can be achieved by simply removing the cancer cell’s ability to make new energy. Professor Michael Lisanti and Professor Federica Sotgia, who both work in Translational Medicine at The University of Salford, have designed and tested new inhibitors of cancer metastasis that are based on an existing FDA-approved antibiotic, namely Doxycycline, first approved in 1967. They have now chemically modified Doxycycline, making it 5 times more potent for the targeting of metastatic cancer cells. Fortunately, this modification also renders Doxycycline ineffective as an antibiotic, effectively removing the risk for the development of antibiotic resistant bacteria and infections. In addition, they show that this new drug, which is named Doxy-Myr, to reflect that addition of a fatty acid, is also non-toxic in pre-clinical studies. “While this new family of drugs must now undergo clinical trials the work directly shows proof of concept that it is feasible to successfully design drugs that can prevent metastasis, by targeting the process of cellular energy production. Hence, cutting off the fuel supply, prevents metastasis. This breakthrough could ultimately change clinical practice, by adding metastasis prevention, as a new, more effective, weapon in the war on cancer. ” (Professor Michael Lisanti, University of Salford) To read the original article click here.

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Scientists Propose Nanoparticles That Can Treat Cancer with Magnetic Fluid Hyperthermia

AHA Publisher — Sat, 14 Mar 2020 07:00:08 +0000

ITMO University via EurekAlert – A group of Russian scientists have synthesized manganese-zinc ferrite nanoparticles that can potentially be used in cancer treatment. A group of Russian scientists have synthesized manganese-zinc ferrite nanoparticles that can potentially be used in cancer treatment. Due to their unique magnetic properties, the particles can serve as deactivators of affected cells while having almost no negative impact on healthy tissues. The results have been published in the Journal of Sol-Gel Science and Technology. One of the most important global goals in today’s medicine is finding ways to combat cancer. Currently, there are several kinds of treatments with differing effectiveness and various side effects. In most cases, the treatment causes harmful impact not only to cancer cells but also the adjacent healthy tissues or the body at large. Magnetic fluid hyperthermia is a promising method that can help alleviate the side effects of cancer treatment. This method involves introducing a magnetic nanoparticles-containing sol into a tumor followed by its exposure to a variable magnetic field. This causes the heating of the nanoparticles and leads to the deactivation of cancer cells. However, the majority of the materials used for this purpose are toxic to the body. What is more, the particles continue to heat up to relatively high temperatures, which entails serious damage to healthy tissues. These problems could be solved by the application of special nanoparticles which can change their magnetic properties depending on the temperature. In physics, there is such a notion as the Curie temperature (also known as the Curie point), which is the temperature at which a sharp decrease in magnetization is observed. “When the Curie temperature is reached, a ferromagnetic changes into a paramagnetic, consequently the particles cease to be as susceptible to the magnetic field and their further heating stops,” explains Vasilii Balanov, a Master’s student at ITMO University and one of the research’s authors. “When the temperature drops back again, the particles resume their heating. Essentially, we observe a self-management of temperature in a narrow range. If we select a composition that experiences such a transition at the temperature we need, then it could prove effective for magnetic fluid hyperthermia.” Choosing the material, the scientists opted for ferrites – compounds of iron oxide (III)Fe2O3 with oxides of other metals. Generally, thanks to their properties, these materials are widely applied in computer technologies, but, as it turned out, they can also be used for medical purposes. “We took the particles with the general formula Zn(x)Mn(1-x)Fe2O4, in which zinc and manganese are selected in a certain proportion,” expounds Vasilii Balanov. “They don’t have a toxic effect on the body, and with the right ratio of manganese and zinc we were able to achieve a Curie temperature in the range of 40-60 degrees Celsius. This temperature allows us to deactivate cancer cells, concurrently, the short-term thermal contact is relatively harmless to healthy tissues.” As of now, the scientists have already synthesized the nanoparticles and studied their magnetic properties. The experiments confirmed that the material doesn’t heat up above 60 degrees Celsius when exposed to a variable magnetic field. Coming next will be the experiments on living cells and, if these are successful, on animals. To read the original article click here.

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Could Cancer Immunotherapy Success Depend on Gut Bacteria?

AHA Publisher — Mon, 09 Mar 2020 07:00:38 +0000

UT Southwestern Medical Center via EurekAlert- Could the response to cancer immunotherapy depend on bacteria that originate in the gut and travel to the tumor? DALLAS – March 6, 2020 – A study by researchers at UT Southwestern Medical Center and the University of Chicago suggests exactly that, revealing that gut bacteria can penetrate tumor cells and boost the effectiveness of an experimental immunotherapy that targets the CD47 protein. Using mouse models of malignancy, the scientists found that the intestinal microbe Bifidobacterium accumulates within tumors, transforming anti-CD47 unresponsive tumors into responsive ones. The team’s study, published today in the Journal of Experimental Medicine, discovered that the response to treatment depends on the type of bacteria living in the animals’ guts. They then identified the mechanism, finding that the combination of antibodies against CD47 and gut bacteria works via the body’s STING pathway of innate immunity – the body’s first line of defense against infection. Their experiments used mice from different resource facilities, antibiotic-fed mice, and mice raised in a germ-free environment. In one experiment, they studied mice raised in two different facilities and that had distinct mixtures of bacteria in their intestines. One group was responsive to anti-CD47 and another was not. The second group became responsive, however, after being housed with the responders, indicating that oral transfer or contact transmission of gut bacteria occurred between groups, the researchers say. The protein CD47 is expressed in high levels on the surface of many cancer cells, where it acts as a “don’t eat me” signal to the immune system’s macrophages, commonly known as white blood cells. As a result, anti-CD47, also known as CD47 blockade therapy, is currently under investigation in multiple clinical trials. However, the mouse studies that predated those trials had mixed results, with only some mice responding to the anti-CD47 therapy, explains corresponding author Yang-Xin Fu, M.D., Ph.D., professor of pathology, immunology, and radiation at UT Southwestern. “We felt we needed to improve anti-CD47 therapy and understand the mechanisms,” he says, leading them to wonder about the gut microbiome, the bacteria that grow in the intestines and aid with digestion. That bacterial ecosystem, sometimes called the microbiota, is also known to affect the gut’s ability to resist pathogens and the host’s response to cancer immunotherapy. “But how the microbiota does that has been unclear,” Fu says. “This study finds that some of the bacteria from the gut travel to the tumor and get into the cells, or microenvironment, where the bacteria facilitate CD47 blockade’s ability to attack the tumor. We found it does that via the immune signaling pathway called stimulator of interferon genes (STING).” The findings suggest that a probiotic might someday be used to improve anti-CD47 therapy, says Fu, a Cancer Prevention and Research Institute (CPRIT) Scholar and holder of the Mary Nell and Ralph B. Rogers Professorship in Immunology at UT Southwestern. The researchers also found that tumor-bearing mice that normally respond to anti-CD47 treatment failed to respond if their gut bacteria were killed off by antibiotics. In contrast, anti-CD47 treatment became effective in mice that are usually nonresponsive when these animals were supplemented with Bifidobacteria, a type of bacteria that is often found in the gastrointestinal tract of healthy mice and humans. They further discovered that the bacteria migrate into tumors, activating the STING immune signaling pathway. This sets off production of immune signaling molecules such as type 1 interferons and activating immune cells that appear to attack and destroy the tumor once the anti-CD47 agent nullifies the CD47’s “don’t eat me” tag, the researchers report. The researchers found that mice genetically unable to activate type 1 interferon failed to respond to the bacteria-immunotherapy approach. Similarly, mice unable to access the STING pathway showed no benefit from the combined bacteria-immunotherapy approach, confirming that STING signaling is essential. “It is very possible that more than one type of gut microbiota could enhance tumor immunity in a similar way and we would like to investigate that,” he adds. This article has been modified. To read the original article click here.

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