Microrobot Fish Swims Through the Body to Vomit Drugs on cancer

Delivering chemotherapy drugs directly to cancers could help reduce side effects, and soon that job could be done by tiny 3D-printed robotic animals. These microrobots are steered by magnets, and only release their drug payload when they encounter the acidic environment around a tumor.

A new microrobot fish could one day swim through the body with a mouthful of drugs, and automatically spit them up when it encounters cancer cells

The new microrobots are made of hydrogel 3D printed into the shape of different animals, like a fish, a crab and a butterfly, with voids that can carry particles. The team adjusted the printing density in specific areas, like the edges of the crab’s claws or the fish’s mouth, so that they can open or close in response to changes in acidity. Finally, the microrobots were placed in a solution containing iron oxide nanoparticles to make them magnetic.

The end result was microrobots that could be loaded up with drug nanoparticles and steered towards a target location using magnets, where they would release their payload automatically due to changes in pH levels.

In lab tests, the researchers used magnets to guide a fish microrobot through simulated blood vessels, towards a cluster of cancer cells at one end. In that area, the team made the solution slightly more acidic and the fish opened its mouth and spat out the drugs on cue, killing the cancer cells. In other tests, crab microrobots could be made to clasp drug nanoparticles with their claws, scuttle to a target location, and release them.

Source: https://newatlas.com/

Synthetic Molecule Seeks out and Destroys Cancer Tumors

Activating the immune system at the site of a tumor can recruit and stimulate immune cells to destroy tumor cells. One strategy involves injecting immune-stimulating molecules directly into the tumor, but this method can be challenging for cancers that are not easily accessible.  Now, Stanford researchers have developed a new synthetic molecule that combines a tumor-targeting agent with another molecule that triggers immune activation. This tumor-targeted immunotherapy can be administered intravenously and makes its way to one or multiple tumor sites in the body, where it recruits immune cells to fight the cancer

Three doses of this new immunotherapy prolonged the survival of six of nine laboratory mice with an aggressive triple negative breast cancer. Of the six, three appeared cured of their cancer over the duration of the monthslong study. A single dose of this molecule induced complete tumor regression in five of 10 mice. The synthetic molecule showed similar results in a mouse model of pancreatic cancer.

We essentially cured some animals with just a few injections,” said Jennifer Cochran, PhD, the Shriram Chair of the Department of Bioengineering. “It was pretty astonishing. When we looked within the tumors, we saw they went from a highly immunosuppressive microenvironment to one full of activated B and T cells — similar to what happens when the immune-stimulating molecule is injected directly into the tumor. So, we’re achieving intra-tumoral injection results but with an IV delivery.”

A paper describing the study has been published online in Cell Chemical Biology. Cochran shares senior authorship with Carolyn Bertozzi, PhD, the Baker Family Director of Stanford ChEM-H, Anne T. and Robert M. Bass Professor in the School of Humanities and Sciences and professor of chemistry; and Ronald Levy, MD, the Robert K. and Helen K. Summy Professor in the School of Medicine. The lead authors are graduate student Caitlyn Miller and instructor of medicine Idit Sagiv-Barfi, PhD.

Source: https://med.stanford.edu/
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How to Make Tumor Eliminate Itself

A new technology developed by University of Zurich (UZH) researchers in Switzerland enables the body to produce therapeutic agents on demand at the exact location where they are needed. The innovation could reduce the side effects of cancer therapy and may hold the solution to better delivery of Covid-related therapies directly to the lungs.

Scientists have modified a common respiratory virus, called adenovirus, to act like a Trojan horse to deliver genes for cancer therapeutics directly into tumor cells. Unlike chemotherapy or radiotherapy, this approach does no harm to normal healthy cells. Once inside tumor cells, the delivered genes serve as a blueprint for therapeutic antibodies, cytokines and other signaling substances, which are produced by the cancer cells themselves and act to eliminate tumors from the inside out.

Imaris Snapshot

View of the tumor from the inside. A piece of the tumor was made completely transparent and scanned in 3D with a special microscope. The components labeled with fluorescent colors were rendered in a rotatable 3D representation on the computer (red: blood vessels, turquoise: tumor cells, yellow: therapeutic antibody)

We trick the tumor into eliminating itself through the production of anti-cancer agents by its own cells,” says postdoctoral fellow Sheena Smith, who led the development of the delivery approach. Research group leader Andreas Plückthun explains: “The therapeutic agents, such as therapeutic antibodies or signaling substances, mostly stay at the place in the body where they’re needed instead of spreading throughout the bloodstream where they can damage healthy organs and tissues.”

The UZH researchers call their technology SHREAD: for SHielded, REtargetted ADenovirus. It builds on key technologies previously engineered by the Plückthun team, including to direct adenoviruses to specified parts of the body to hide them from the immune  system. With the SHREAD system, the scientists made the tumor itself produce a clinically approved breast cancer antibody, called trastuzumab (Herceptin®), in the mammary of a mouse. They found that, after a few days, SHREAD produced more of the antibody in the tumor than when the drug was injected directly. Moreover, the concentration in the bloodstream and in other tissues where side effects could occur were significantly lower with SHREAD. The scientists used a very sophisticated, high-resolution 3D imaging method and tissues rendered totally transparent to show how the therapeutic antibody, produced in the body, creates pores in blood vessels of the tumor and destroys tumor cells, and thus treats it from the inside.

Source: https://www.media.uzh.ch/

Nano BiosuperCapacitor Provides Energy for Biomedical Applications

The miniaturization of microelectronic sensor technology, microelectronic robots or intravascular implants is progressing rapidly. However, it also poses major challenges for research. One of the biggest is the development of tiny but efficient energy storage devices that enable the operation of autonomously working microsystems – in more and more smaller areas of the human body for example. In addition, these energy storage devices must be bio-compatible if they are to be used in the body at all. Now there is a prototype that combines these essential properties. The breakthrough was achieved by an international research team led by Prof. Dr. Oliver G. Schmidt, Professorship of Materials Systems for Nanoelectronics at Chemnitz University of Technology (Germany), initiator of the Center for Materials, Architectures and Integration of Nanomembranes (MAIN) at Chemnitz University of Technology and director at the Leibniz Institute for Solid State and Materials Research (IFW) Dresden. The Leibniz Institute of Polymer Research Dresden (IPF) was also involved in the study as a cooperation partner.

In the current issue of Nature Communications, the researchers report on the smallest microsupercapacitors to date, which already functions in (artificial) blood vessels and can be used as an energy source for a tiny sensor system to measure pH.

This storage system opens up possibilities for intravascular implants and microrobotic systems for next-generation biomedicine that could operate in hard-to-reach small spaces deep inside the human body. For example, real-time detection of blood pH can help predict early tumor growing. “It is extremely encouraging to see how new, extremely flexible, and adaptive microelectronics is making it into the miniaturized world of biological systems“, says research group leader Prof. Dr. Oliver G. Schmidt, who is extremely pleased with this research success.

The architecture of our nano-bio supercapacitors offers the first potential solution to one of the biggest challenges – tiny integrated energy storage devices that enable the self-sufficient operation of multifunctional microsystems,” says Dr. Vineeth Kumar, researcher in Prof. Schmidt’s team and a research associate at the MAIN research center.

Ever smaller energy storage devices in the submillimeter range – so-called “nano-supercapacitors” (nBSC) – for even smaller microelectronic components are not only a major technical challenge, however. This is because, as a rule, these supercapacitors do not use biocompatible materials but, for example, corrosive electrolytes and quickly discharge themselves in the event of defects and contamination. Both aspects make them unsuitable for biomedical applications in the body. So-called “biosupercapacitors (BSCs)” offer a solution. They have two outstanding properties: they are fully biocompatible, which means that they can be used in body fluids such as blood and can be used for further medical studies.

In addition, biosupercapacitors can compensate for self-discharge behavior through bio-electrochemical reactions. In doing so, they even benefit from the body’s own reactions. This is because, in addition to typical charge storage reactions of a supercapacitor, redox enzymatic reactions and living cells naturally present in the blood increase the performance of the device by 40%.

Source: https://www.tu-chemnitz.de/

Cancer Vaccine Boosted

Scientists at Thomas Jefferson University who are developing a cancer vaccine to prevent recurrences of gastric, pancreatic, esophageal, and colon cancers say they have added a component that would make the vaccine more effective. The change makes the vaccine less prone to being cleared by the immune system before it can generate immunity against the tumor components.

The preclinical studies pave the way for a Phase II clinical trial opening to patients this fall, according to Adam Snook, PhD, assistant professor in the department of pharmacology and experimental therapeutics and researcher at the NCI-Designated Sidney Kimmel Cancer Center (SKCC)—Jefferson Health.

Our data show strong immune responses in mice that might otherwise clear the vaccine, and suggests this approach will be more effective in the human trials we are starting shortly,” he said. “Adenovirus serotype 5 (Ad5) is a commonly used viral vector for transient delivery of transgenes, primarily for vaccination against pathogen and tumor antigens. However, endemic infections with Ad5 produce virus-specific neutralizing antibodies (NAbs) that limit transgene delivery and constrain target-directed immunity following exposure to Ad5-based vaccines

Indeed, clinical trials have revealed the limitations that virus-specific NAbs impose on the efficacy of Ad5-based vaccines. In that context, the emerging focus on immunological approaches targeting cancer self-antigens or neoepitopes underscores the unmet therapeutic need for more efficacious vaccine vectors.

“Here, we evaluated the ability of a chimeric adenoviral vector (Ad5.F35) derived from the capsid of Ad5 and fiber of the rare adenovirus serotype 35 (Ad35) to induce immune responses to the tumor-associated antigen guanylyl cyclase C (GUCY2C).

In the absence of pre-existing immunity to Ad5, GUCY2C-specific T-cell responses and antitumor efficacy induced by Ad5.F35 were comparable to Ad5 in a mouse model of metastatic colorectal cancer. Furthermore, like Ad5, Ad5.F35 vector expressing GUCY2C was safe and produced no toxicity in tissues with, or without, GUCY2C expression. Importantly, this chimeric vector resisted neutralization in Ad5-immunized mice and by sera collected from patients with colorectal cancer naturally exposed to Ad5.

“These data suggest that Ad5.F35-based vaccines targeting GUCY2C, or other tumor or pathogen antigens, may produce clinically relevant immune responses in more (≥90%) patients compared with Ad5-based vaccines (~50%).”

Smart Tumor-Targeting DNA NanoRobots

Chinese researchers have developed biodegradable tumor-targeting nanoparticles, which provides a promising therapy for tumor treatment, according to the Chinese Academy of Sciences (CAS).

A joint research team with scientists from the CAS developed the tumor-targeting nanoparticles as a combination of tumor-infarction therapy and chemotherapy, said the CAS.

It has long been a challenge for researchers to find a safe and effective therapy for vascular thrombosis. Drugs that induce thrombosis in the tumor vasculature have not resulted in long-term tumor eradication.

The CAS research team developed the nanoparticle, a type of DNA nanorobot that can precisely send the thrombin to the tumor-vessel walls and the tumor stroma, leaving the tumor to “starve to death.”

Study results showed that the co-administration of a cytotoxic payload and a protease to elicit vascular infarction in tumors with biodegradable tumor-targeting nanoparticles represented a promising strategy for improving the therapeutic index of coagulation-based tumor therapy.

The study has been published online by the journal Nature Biomedical Engineering.

Source: http://www.xinhuanet.com/

New Cancer Drug Halts Tumour Growth

A drug that could stop cancer cells repairing themselves has shown early signs of working. More than half of the 40 patients given berzosertib had the growth of their tumours halted. Berzosertib was even more effective when given alongside chemotherapy, the trial run by the Institute of Cancer Research (ICR) and the Royal Marsden NHS Trust in UK suggested. The trial was designed to test the safety of the drug. The drug is the first to be trialled of a new family of treatments, which block a protein involved in DNA repairBlocking this protein prevents cancers from mending damage to their cells. It’s part of a branch of treatment known as “precision medicine“, which targets specific genes or genetic changes.

The study involved patients with very advanced tumours, for whom no other treatment had worked. This was what is known as a “phase onetrial, which is only designed to test the safety of a treatment. But the ICR said the researchers did find some early indications that berzosertib could stop tumours growing. One of the study’s authors, Prof Chris Lord, a professor of cancer genomics at the ICR, said these early signs were “very promising”, adding that it was unusual in phase one trials to see a clinical response. Further trials will be needed to demonstrate the drug’s effectiveness, though.

This study involved only small numbers of patients…Therefore, it is too early to consider berzosertib a game changer in cancer treatment,” said Dr Darius Widera at the University of Reading. “Nevertheless, the unusually strong effects of berzosertib, especially in combination with conventional chemotherapy, give reasons to be optimistic regarding the outcomes of follow-up studies.”

One patient in the trial, with advanced bowel cancer, had his tumours completely disappear after treatment with berzosertib, and has remained cancer-free for two years. Another, whose ovarian cancer returned following a different course of treatment, saw her tumours shrink after combination treatment with the drug and chemotherapyChemotherapy works by damaging cancer cells’ DNA, so using it in conjunction with this new treatment, which stops the cells from repairing themselves, appears to give an even greater benefit. And berzosertib is able to target tumour cells without affecting other healthy cells, Prof Lord said.

Our new clinical trial is the first to test the safety of a brand-new family of targeted cancer drugs in people, and it’s encouraging to see some clinical responses even in at this early stage,” said Professor Johann de Bono, head of drug development at the ICR and the Royal Marsden.

Source: https://www.bbc.com/

How To Catch Aggressive Prostate Cancer Early

Two newly published studies are presenting novel diagnostic techniques to help catch the most aggressive forms of prostate cancer at an early stage. A University of East Anglia study presents an innovative way to measure gene expression in tumor samples and predict disease severity, while an Australian study details a new kind of imaging technique promising to detect metastasized prostate cancer with greater accuracy than ever before.

Two new techniques are designed to detect aggressive forms of prostate cancer and catch it when it metastasizes

Prostate cancer is the most common cancer in men in the UK,” explains Colin Cooper, lead researcher on a new study from the University of East Anglia. “It usually develops slowly and the majority of cancers will not require treatment in a man’s lifetime. However, doctors struggle to predict which tumors will become aggressive, making it hard to decide on treatment for many men.”

In order to develop a way for doctors to better identify the most aggressive tumors the researchers examined different gene expression patterns in nearly 2,000 prostate tumor samples. Applying a mathematical model called Latent Process Decomposition, the study homed in on a particular pattern of gene expression associated with the most aggressive clinical cases.

The pattern relates to a subtype of cells the team has labeled DESNT, and suggest the more tumor cells in a sample that are of that DESNT subtype, the faster a patient will progress through the disease. The hope is that this can act as a biomarker to stratify prostate cancer patients, identifying those needing more urgent invasive treatments.

If you have a tumor that is majority DESNT you are more likely to get metastatic disease, in other words it is more likely to spread to other parts of your body,” says Daniel Brewer, co-lead researcher on the project. “This is a much better indication of aggressive disease.”

Identifying when prostate cancer has metastasized is obviously of vital importance in guiding treatment. A team of Australian researchers just published the results of a clinical trial evaluating the efficacy of a new imaging technique developed to provide detailed data on the spread of the disease.

Around one in three prostate cancer patients will experience a disease relapse after surgery or radiotherapy,” says Declan Murphy, senior author on the new imaging study. “This is partly because current medical imaging techniques often fail to detect when the cancer has spread, which means some men are not given the additional treatments they need.”

Source: https://newatlas.com/

How To Turn Tumors Into Cancer Vaccine Factories

Researchers at Mount Sinai have developed last year a novel approach to cancer immunotherapy, injecting immune stimulants directly into a tumor to teach the immune system to destroy it and other tumor cells throughout the body.
The “in situ vaccination” worked so well in patients with advanced-stage lymphoma that it is also undergoing trials in breast and head and neck cancer patients, according to a study published in Nature Medicine in April.
The treatment consists of administering a series of immune stimulants directly into one tumor site. The first stimulant recruits important immune cells called dendritic cells that act like generals of the immune army. The second stimulant activates the dendritic cells, which then instruct T cells, the immune system’s soldiers, to kill cancer cells and spare non-cancer cells. This immune army learns to recognize features of the tumor cells so it can seek them out and destroy them throughout the body, essentially turning the tumor into a cancer vaccine factory.

The in situ vaccine approach has broad implications for multiple types of cancer,” said lead author Joshua Brody, MD, Director of the Lymphoma Immunotherapy Program at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai. “This method could also increase the success of other immunotherapies such as checkpoint blockade.”

After testing the lymphoma vaccine in the lab, it was tested in 11 patients in a clinical trial. Some patients had full remission from months to years. In lab tests in mice, the vaccine drastically increased the success of checkpoint blockade immunotherapy, the type of immunotherapy responsible for the complete remission of former President Jimmy Carter’s cancer and the focus of the 2018 Nobel Prize in Medicine.

Source: https://www.mountsinai.org/

How To Starve Cancer Tumors and Beef Up The Immune Cells

Tumors are hogs, gobbling nutrients to fuel their runaway growth, and for decades researchers have tried to develop drugs that cut off their food supply. A study out today shows that an updated version of a failed cancer drug can not only prevent tumor cells from using an essential nutrient, but also spur immune cells to attack the growths.

T lymphocyte cells attacking a cancer cell, computer illustration. T lymphocytes are a type of white blood cell that recognise a specific site (antigen) on the surface of cancer cells or pathogens and bind to it. Some T lymphocytes then signal for other immune system cells to eliminate the cell. The genetic changes that cause a cell to become cancerous lead to the presentation of tumour antigens on the cell’s surface.

It’s a pretty striking paper,” says cancer biologist Ralph DeBerardinis of the University of Texas Southwestern Medical Center in Dallas, who wasn’t connected to the study. “With a single drug, you can in effect starve the tumor and beef up the immune cells.”

Cancer cells eat to obtain molecules vital for survival and replication, but their gluttony also turns their surroundings into an acidic, oxygen-deprived moat that stymies immune cells trying to eliminate them. One of the nutrients many tumors need in abundance is the amino acid glutamine, which provides the building blocks for fabricating molecules such as DNA, proteins, and lipids. “Glutamine is incredibly important for cellular metabolism,” says immunologist Jonathan Powell of the Johns Hopkins School of Medicine in Baltimore, Maryland.

Starting in the 1950s, researchers tried to turn tumors’ glutamine dependence against them, developing drugs to block its metabolism. A bacteria-derived compound called DON, for instance, kills tumors by inhibiting several enzymes that allow cancer cells to use glutamine. In clinical trials, however, the drug provoked severe nausea and vomiting, and it was never approved.

Now, Powell and colleagues have crafted a new version of DON that may be easier to stomach. It carries two chemical groups that keep it inert until it reaches the tumor’s neighborhood. There, enzymes that normally loiter around tumors remove these molecular handcuffs, unleashing the drug on the cancerous cells. With this approach, “the vast majority of the active drug is where we want,” Powell says.

To test their new compound, he and colleagues injected four types of cancer cells into mice, inducing tumors. They then dosed some of the animals with their next-generation DON. The drug worked against all four kinds of tumors, the scientists report today in Science. In untreated mice, for example, colon cancer tumors had grown more than five times larger after about 3 weeks. But in rodents that received DON, the tumors shrank and almost disappeared. The researchers found that the drug wasn’t just throttling glutamine metabolism. It was also disrupting other aspects of the cellsbiochemistry, such as their ability to use the sugar glucose.

Source: https://www.sciencemag.org/