New Treatment To Kill Cancer

Raise your hand if you haven’t been touched by cancer,” says Mylisa Parette to a roomful of strangers. Parette, the research manager for Keystone Nano (KN), has occasional opportunities to present her company’s technologies to business groups and wants to emphasize the scope of the problem that still confronts society. “It’s easier to see the effects of cancer when nobody raises their hand,” she says. Despite 40 years of the War on Cancer, one in two men and one in three women will be diagnosed with the disease at some point in their lifetime. Parette and her Keystone Nano colleagues are working on a new approach to cancer treatment. The company was formed from the collaboration of two Penn State faculty members who realized that the nanoparticle research that the one was undertaking could be used to solve the drug delivery problems that the other was facing.

Mark Kester, a pharmacologist at Penn State College of Medicine in Hershey, was working with a new drug that showed real promise as a cancer therapy but that could be dangerous if injected directly into the bloodstream. Jim Adair, a materials scientist in University Park, was creating nontoxic nanoparticles that could enclose drugs that might normally be toxic or hydrophobic and were small enough to be taken up by cells.

The two combined their efforts and, licensing the resulting technology from Penn State, they joined with entrepreneur Jeff Davidson, founder of the Biotechnology Institute and the Pennsylvania Biotechnology Association, to form Keystone Nano. The new company’s first hire was Parette, whose job is to translate the lab-scale technology into something that can be ramped up to an industrial scale, and to prepare that technology for FDA approval leading to clinical trials.

Davidson, Parette, and KN’s research team work out of the Zetachron building, a long, one-story science incubator a mile from Penn State’s University Park campus. Operated by the Centre County Industrial Development Corporation, the building was originally the home of the successful Penn State spin-out company that gave it its name. A second Keystone Nano lab was recently opened in the Hershey Center for Applied Research, a biotech incubator adjacent to Penn State College of Medicine.

Our excitement is that we think our technology has shown efficacy in a whole range of animal models,” Davidson, Keystone CEO, remarks during a recent meeting in the shared conference room at Zetachron. “We understand the method of action, the active ingredient. We think it has every chance of being useful in treating disease. Our question is, how do we push this forward from where we are today to determining, one way or another, that it really does work?

Keystone Nano is pioneering two approaches to cancer therapy, both of which rely on advances in nanotechnology to infiltrate tumors and deliver a therapeutic agent. The approach nearest to clinical trials is a ceramide nanoliposome, or what Davidson calls a “nano fat ball around an active ingredient.” Kester, in whose lab the approach was developed, thinks of it as a basketball with a thick bilayer coating that contains 30 percent active ceramide and a hollow interior that can hold another cancer drug.


How To Use Potato Virus To Delay Tumor Progression

Researchers from Case Western Reserve University School of Medicine in collaboration with researchers from Dartmouth Geisel School of Medicine and RWTH Aachen University (Germany) have adapted virus particles—that normally infect potatoes—to serve as cancer drug delivery devices for mice. But in a recent article published in Nano Letters, the team showed injecting the virus particles alongside chemotherapy drugs, instead of packing the drugs inside, may provide an even more potent benefit.

The researchers discovered injecting potato virus particles into melanoma tumor sites activates an anti-tumor immune system response. And simultaneously injecting the nanoscale plant virus particles and a chemotherapy drugdoxorubicin—into tumor sites further helps halt tumor progression in mice. But surprisingly, when the researchers created and injected combination nanoparticles, where the chemo drug is physically attached to the virus particles, there was not a significant added benefit.

The results are the first to show “vaccinating” mice with potato virus nanoparticles at a cancer site can generate an anti-tumor response. But the results also suggest more complex nanoparticles may not correspond to added therapeutic benefit.

It’s attractive to want to create multifunctional nanoparticles that can ‘do it all,’” said Nicole F. Steinmetz, PhD, senior author on the study, George J. Picha Professor in Biomaterials, member of the Case Comprehensive Cancer Center, and Director of the Center for Bio-Nanotechnology at Case Western Reserve School of Medicine.But this study shows significant therapeutic efficacy, including prolonging survival, requires a more step-wise approach. When the plant-based virus particles and the drugs were able to work on their own, we saw the greatest benefit.”

Wrote the authors, “While the nanomedicine field strives to design multifunctional nanoparticles that integrate several functions and therapeutic regimens into single nanoparticle – our data suggest a paradigm shift; some therapeutics may need to be administered separately to synergize and achieve most potent therapeutic outcome.”


How To Boost Body’s Cancer Defenses

After radiation treatment, dying cancer cells spit out mutated proteins into the body. Scientists now know that immune system can detect these proteins and kill cancer in other parts of the body using these protein markers as a guide – a phenomenon that University of North Carolina Lineberger Comprehensive Cancer Center (UNC Lineberg) scientists are looking to harness to improve cancer treatment.

In the journal Nature Nanotechnology, the researchers report on strides made in the development of a strategy to improve the immune system’s detection of cancer proteins by using “stickynanoparticles called “antigen-capturing nanoparticles.” They believe these particles could work synergistically with immunotherapy drugs designed to boost the immune system’s response to cancer.

Our hypothesis was that if we use a nanoparticle to grab onto these cancer proteins, we’d probably get a more robust immune response to the cancer,” said the study’s senior author Andrew Z. Wang, MD, a UNC Lineberger member and associate professor in the UNC School of Medicine Department of Radiation Oncology. “We think it works because nanoparticles are attractive to the immune system. Immune cells don’t like anything that’s nano-sized; they think they are viruses, and will respond to them.”

Radiation therapy is commonly used to treat a wide array of cancers. Previously, doctors have observed a phenomenon they call the “abscopal effect,” in which a patient experiences tumor shrinkage outside of the primary site that was treated with radiation. This observation in a single patient with melanoma was reported in the New England Journal of Medicine in 2012.

Scientists believe this occurs because, after radiation, immune cells are recruited to the tumor site. Once they’ve arrived, these immune cells use mutated proteins released by dying cancer cells to train other immune cells to recognize and fight cancer elsewhere. This effect works synergistically with immunotherapy drugs called “checkpoint inhibitors,” which release the immune system’s brakes, thereby helping the body’s own defense system to attack the cancer.

Cancer cells discharge these mutated proteins – which become markers for the immune system — as a result of genetic mutations, said study co-author Jonathan Serody, MD, UNC Lineberger’s associate director for translational research.

The theory is that in cancer, tumors accumulate large numbers of mutations across their genomes, and those mutated genes can make mutant proteins, and any of those mutant proteins can be chopped up and presented to the immune system as a foreign,” said Serody, who is also the Elizabeth Thomas Professor in the UNC School of Medicine. “Your body is designed not to respond to its own proteins, but there’s no system that controls its response to new proteins, and you have a broad array of immune cells that could launch a response to them.

The UNC Lineberger researchers demonstrated in preclinical studies they could successfully design nanoparticles to capture mutated proteins released by tumors. Once these nanoparticles are taken up by immune cells, the tumor proteins attached to their surface can help immune cells recognize identify cancer cells across body.


Blood Cells Deliver Drugs To Kill Cancer

For the first time, WSU researchers have demonstrated a way to deliver a drug to a tumor by attaching it to a blood cell. The innovation could let doctors target tumors with anticancer drugs that might otherwise damage healthy tissues.

To develop the treatment, a team led by Zhenjia Wang, an assistant professor of pharmaceutical sciences, worked at the microscopic scale using a nanotherapeutic particle so small that 1,000 of them would fit across the width of a hair. By attaching a nanoscale particle to an infection-fighting white blood cell, the team showed they can get a drug past the armor of blood vessels that typically shield a tumor. This has been a major challenge in nanotechnology drug delivery.

Working with colleagues in Spokane and China, Wang implanted a tumor on the flank of a mouse commonly chosen as a model for human diseases. The tumor was exposed to near-infrared light, causing an inflammation that released proteins to attract white blood cells, called neutrophils, into the tumor. The researchers then injected the mouse with gold nanoparticles treated with antibodies that mediate the union of the nanoparticles and neutrophils. When the tumor was exposed to infrared light, the light’s interaction with the gold nanoparticles produced heat that killed the tumor cells, Wang said. In the future, therapists could attach an anticancer drug like doxorubicin to the nanoparticle. This could let them deliver the drug directly to the tumor and avoid damaging nearby tissues, Wang said.

We have developed a new approach to deliver therapeutics into tumors using the white blood cells of our body,” Wang said. “This will be applied to deliver many anticancer drugs, such as doxorubicin, and we hope that it could increase the efficacy of cancer therapies compared to other delivery systems.”

Wang and Chu’s colleagues on the research are postdoctoral researcher Dafeng Chu, Ph.D. student Xinyue Dong, Jingkai Gu of Jilin University and Jingkai Gu of the University of Macau.

The researchers reported on the technique in the latest issue of the journal Advanced Materials.


Nanoparticle Shrinks Breast Tumor, Prevent Recurrence

A Mayo Clinic research team has developed a new type of cancer-fighting nanoparticle aimed at shrinking breast cancer tumors, while also preventing recurrence of the disease. A mice that received an injection with the nanoparticle showed a 70 to 80 percent reduction in tumor size. Most significantly, mice treated with these nanoparticles showed resistance to future tumor recurrence, even when exposed to cancer cells a month later.

The results show that the newly designed nanoparticle produced potent anti-tumor immune responses to HER2-positive breast cancers. Breast cancers with higher levels of HER2 protein are known to grow aggressively and spread more quickly than those without the mutation.

In this proof-of-concept study, we were astounded to find that the animals treated with these nanoparticles showed a lasting anti-cancer effect,” says Betty Y.S. Kim, M.D., Ph.D., principal investigator, and a neurosurgeon and neuroscientist who specializes in brain tumors at Mayo Clinic’s Florida campus. “Unlike existing cancer immunotherapies that target only a portion of the immune system, our custom-designed nanomaterials actively engage the entire immune system to kill cancer cells, prompting the body to create its own memory system to minimize tumor recurrence. These nanomedicines can be expanded to target different types of cancer and other human diseases, including neurovascular and neurodegenerative disorders.”

Dr. Kim’s team developed the nanoparticle, which she has named “Multivalent Bi-specific Nano-Bioconjugate Engager,” a patented technology with Mayo Clinic Ventures, a commercialization arm of Mayo Clinic.

The findings have been published in Nature Nanotechnology.


How To Capture Quickly Cancer Markers

A nanoscale product of human cells that was once considered junk is now known to play an important role in intercellular communication and in many disease processes, including cancer metastasis. Researchers at Penn State have developed nanoprobes to rapidly isolate these rare markers, called extracellular vesicles (EVs), for potential development of precision cancer diagnoses and personalized anticancer treatments.

Lipid nanoprobes

Most cells generate and secrete extracellular vesicles,” says Siyang Zheng, associate professor of biomedical engineering and electrical engineering. “But they are difficult for us to study. They are sub-micrometer particles, so we really need an electron microscope to see them. There are many technical challenges in the isolation of nanoscale EVs that we are trying to overcome for point-of-care cancer diagnostics.”

At one time, researchers believed that EVs were little more than garbage bags that were tossed out by cells. More recently, they have come to understand that these tiny fat-enclosed sacks — lipids — contain double-stranded DNA, RNA and proteins that are responsible for communicating between cells and can carry markers for their origin cells, including tumor cells. In the case of cancer, at least one function for EVs is to prepare distant tissue for metastasis.

The team’s initial challenge was to develop a method to isolate and purify EVs in blood samples that contain multiple other components. The use of liquid biopsy, or blood testing, for cancer diagnosis is a recent development that offers benefits over traditional biopsy, which requires removing a tumor or sticking a needle into a tumor to extract cancer cells. For lung cancer or brain cancers, such invasive techniques are difficult, expensive and can be painful.

Noninvasive techniques such as liquid biopsy are preferable for not only detection and discovery, but also for monitoring treatment,” explains Chandra Belani, professor of medicine and deputy director of the Cancer Institute,Penn State College of Medicine, and clinical collaborator on the study.

We invented a system of two micro/nano materials,” adds Zheng. “One is a labeling probe with two lipid tails that spontaneously insert into the lipid surface of the extracellular vesicle. At the other end of the probe we have a biotin molecule that will be recognized by an avidin molecule we have attached to a magnetic bead.”


Artificial Skin Breathes like Human Skin

A scientist in Chile is using microscopic algae to make skingreen skin. These very small, very simple plants are being used to develop a new artificial skin for humans. The problem with most current artificial skin is that there are no blood vessels – so the man-made skin cannot produce the oxygen it needs to live. But with algae, the skin can breathe through the process of photosynthesis.

artificial-skin-breathesCLICK ON THE IMAGE TO ENJOY THE VIDEO

What we’re basically doing is incorporating micro-algae, which are like microscopic plants into different types of materials. For example, when we apply artificial skin what we have is the characteristics of plants which means when it is lit up it can produce oxygen,” says Tomas Egana from the Chile’s Catholic University, professor at the Institute of biological engineering. And the benefits of the algae could go beyond just a cosmetic improvement. It may help human skin heal itself: “These micro-algae can be genetically modified. So that in addition to producing oxygen they will produce different factors, for example antibiotics, anti-inflammatories and pro-regenerative molecules. So, we are going to have material which is completely artificial and still, which is a structure that has material that is alive.

Professor Egana says the green-colored skin could eventually be used to help patients treat open wounds, tumors and possibly avoid amputations. But patients need not worry about looking like the Incredible Hulk. Egana believes the green color will fade over time as the algae dies. At the moment, animal testing has proven a success. Human trials are expected next year.


Triggered Immune Cells Attack Cancer

Stanford researchers accidentally discovered that iron nanoparticles invented for anemia treatment have another use: triggering the immune system’s ability to destroy tumor cellsIron nanoparticles can activate the immune system to attack cancer cells, according to a study led by researchers at the Stanford University School of Medicine. The nanoparticles, which are commercially available as the injectable iron supplement ferumoxytol, are approved by the Food and Drug Administration (FDA) to treat iron deficiency anemia.

The mouse study found that ferumoxytol prompts immune cells called tumor-associated macrophages to destroy cancer cells, suggesting that the nanoparticles could complement existing cancer treatments.

macrophages-attack-cancerA mouse study found that ferumoxytol prompts immune cells called tumor-associated macrophages to destroy tumor cells.

It was really surprising to us that the nanoparticles activated macrophages so that they started to attack cancer cells in mice,” said Heike Daldrup-Link, MD, who is the study’s senior author and an associate professor of radiology at the School of Medicine. “We think this concept should hold in human patients, too.

The study showed that the iron nanoparticles switch the macrophages back to their cancer-attacking state, as evidenced by tracking the products of the macrophages’ metabolism and examining their patterns of gene expression.

Furthermore, in a mouse model of breast cancer, the researchers demonstrated that the ferumoxytol inhibited tumor growth when given in doses, adjusted for body weight, similar to those approved by the FDA for anemia treatment.

Daldrup-Link’s team conducted an experiment that used three groups of mice: an experimental group that got nanoparticles loaded with chemo, a control group that got nanoparticles without chemo and a control group that got neither. The researchers made the unexpected observation that the growth of the tumors in control animals that got nanoparticles only was suppressed compared with the other controls.

The discovery, described in a paper published online in Nature Nanotechnology, was made by accident while testing whether the nanoparticles could serve as Trojan horses by sneaking chemotherapy into tumors in mice.

How Anthrax Toxin Kills Tumors

Over the past decades, researchers have become particularly interested in the idea of hijacking the cell-killing capacity of bacterial toxins to target tumor cells. So far, engineered toxins from Pseudomonas, anthrax toxin, and ricin showed promising results in treating tumors in mice. But the mechanism of action of these toxins remains elusive. Now a new study in the journal Proceedings of the National Academy of Science sheds light on tumor proteins used by Bacillus anthracis to kill tumors.

anthrax-tumorModified anthrax toxin specifically targets the tumor vasculature to exert anti-tumor effects

As we worked more and more on anthrax toxin, we discovered, along with others, features of it that made it attractive as another bacterial protein toxin that could be redirected for curing cancer,” said Stephen Leppla from the National Institute of Allergy and Infectious Disease, senior author of the study.

Anthrax toxin has three sub-components that assemble within host cells before exerting their toxicity. PA, the cell-binding component of anthrax toxin, interacts with two cell surface proteins: tumor endothelium-marker 8 (TEM8) and capillary morphogenesis protein-2 (CMG2).

Finding that anthrax toxin specifically acts on tumor vasculature is particularly promising, given the stability of tumor endothelial cells compared to mutation-prone stromal cells. Anthrax toxin could thus be used to treat widely different tumors. “We would like to get to phase I human trials,” said Leppla. “We have collaborators who are testing our reagents in both cats and dogs who also get cancer but don’t have good treatment options. We’re hoping that this will provide further evidence that these reagents are effective.


Cancer: How To Shrink Tumors

Math, biology and nanotechnology are becoming strange, yet effective bed-fellows in the fight against cancer treatment resistance. Researchers at the University of Waterloo and Harvard Medical School have engineered a revolutionary new approach to cancer treatment that pits a lethal combination of drugs together into a single nanoparticle. Their work, published online on June 3, 2016 in the  journal ACS Nano, finds a new method of shrinking tumors and prevents resistance in aggressive cancers by activating two drugs within the same cell at the same time. Every year thousands of patients die from recurrent cancers that have become resistant to therapy, resulting in one of the greatest unsolved challenges in cancer treatment. By tracking the fate of individual cancer cells under pressure of chemotherapy, biologists and bioengineers at Harvard Medical School studied a network of signals and molecular pathways that allow the cells to generate resistance over the course of treatment.

anti cancer nanoparticle

Using this information, a team of applied mathematicians led by Professor Mohammad Kohandel at the University of Waterloo (Canada), developed a mathematical model that incorporated algorithms that define the phenotypic cell state transitions of cancer cells in real-time while under attack by an anticancer agent. The mathematical simulations enabled them to define the exact molecular behavior and pathway of signals, which allow cancer cells to survive treatment over time.

They discovered that the PI3K/AKT kinase, which is often over-activated in cancers, enables cells to undergo a resistance program when pressured with the cytotoxic chemotherapy known as Taxanes, which are conventionally used to treat aggressive breast cancers. This revolutionary window into the life of a cell reveals that vulnerabilities to small molecule PI3K/AKT kinase inhibitors exist, and can be targeted if they are applied in the right sequence with combinations of other drugs.

Previously theories of drug resistance have relied on the hypothesis that only certain, “privileged” cells can overcome therapy. The mathematical simulations demonstrate that, under the right conditions and signaling events, any cell can develop a resistance program.

Only recently have we begun to appreciate how important mathematics and physics are to understanding the biology and evolution of cancer,” said Professor Kohandel. “In fact, there is now increasing synergy between these disciplines, and we are beginning to appreciate how critical this information can be to create the right recipes to treat cancer.”


Gentle Cancer Treatment Using Nanoparticles

Cancer treatments based on laser irradiation of tiny nanoparticles that are injected directly into the cancer tumor are working and can destroy the cancer from within. Researchers from the Niels Bohr Institute and the Faculty of Health Sciences at the University of Copenhagen  (Denmark) have developed a method that kills cancer cells using nanoparticles and lasers. The treatment has been tested on mice and it has been demonstrated that the cancer tumors are considerably damaged.

mouse with cancer treatment

The drawing shows a mouse with a cancerous tumor on its hind leg. The nanoparticles are injected directly into the tumor, which is then flashed with near infrared laser light. Near infrared laser light penetrates through the tissue well and causes no burn damage


Traditional cancer treatments like radiation and chemotherapy have major side affects, because they not only affect the cancer tumors, but also the healthy parts of the body. A large interdisciplinary research project between physicists at the Niels Bohr Institute and doctors and human biologists at the Panum Institute and Rigshospitalet has developed a new treatment that only affects cancer tumors locally and therefore is much more gentle on the body. The project is called Laser Activated Nanoparticles for Tumor Elimination (LANTERN). The head of the project is Professor Lene Oddershede, a biophysicist and head of the research group Optical Tweezers at the Niels Bohr Institute at the University of Copenhagen in collaboration with Professor Andreas Kjær, head of the Cluster for Molecular Imaging, Panum Institute.

After experimenting with biological membranes, the researchers have now tested the method on living mice. In the experiments, the mice are given cancer tumors of laboratory cultured human cancer cells“The treatment involves injecting tiny nanoparticles directly into the cancer. Then you heat up the nanoparticles from outside using lasers. There is a strong interaction between the nanoparticles and the laser light, which causes the particles to heat up. What then happens is that the heated particles damage or kill the cancer cells,” explains Lene Oddershede.

The results are published in the scientific journal, Scientific Reports.

Nanoparticle Attacks Agressive Thyroid Cancer

Anaplastic thyroid cancer (ATC), the most aggressive form of thyroid cancer, has a mortality rate of nearly 100 percent and a median survival time of three to five months. One promising strategy for the treatment of these solid tumors and others is RNA interference (RNAi) nanotechnology, but delivering RNAi agents to the sites of tumors has proved challenging. Investigators at Brigham and Women’s Hospital, together with collaborators from Massachusetts General Hospital, have developed an innovative nanoplatform that allows them to effectively deliver RNAi agents to the sites of cancer and suppress tumor growth and reduce metastasis in preclinical models of ATC.

thyroid cancer

We call this a ‘theranostic’ platform because it brings a therapy and a diagnostic together in one functional nanoparticle,” said co-senior author Jinjun Shi, PhD, assistant professor of Anesthesia in the Anesthesia Department. “We expect this study to pave the way for the development of theranostic platforms for image-guided RNAi delivery to advanced cancers.”

RNAi, the discovery of which won the Nobel Prize in Physiology or Medicine 10 years ago, allows researchers to silence mutated genes, including those upon which cancers depend to grow and survive and metastasize. Many ATCs depend upon mutations in the commonly mutated cancer gene BRAF. By delivering RNAi agents that specifically target and silence this mutated gene, the investigators hoped to stop both the growth and the spread of ATC, which often metastasizes to the lungs and other organs.

When RNAi is delivered on its own, it is usually broken down by enzymes or filtered out by the kidneys before it reaches tumor cells. Even when RNAi agents make it as far as the tumor, they are often unable to penetrate or are rejected by the cancer cells. To overcome these barriers, the investigators used nanoparticles to deliver the RNAi molecules to ATC tumors. In addition, they coupled the nanoparticles with a near-infrared fluorescent polymer, which allowed them to see where the nanoparticles accumulated in a mouse model of ATC.

The results have appeared in the journal  Proceedings of the National Academy of Sciences.