Triple-threat cancer-fighting polymer capsules for guided drug delivery

drug delivery cancer 170330142230_1_540x360These micro-carriers may offer an entirely different approach to treating solid human tumors of numerous pathologic subtypes by delivering their encapsulated drug cargo to a tumor and protecting against collateral tissue damage.

Chemists at the University of Alabama at Birmingham have designed triple-threat cancer-fighting polymer capsules that bring the promise of guided drug delivery closer to preclinical testing.

These multilayer capsules show three traits that have been difficult to achieve in a single entity. They have good imaging contrast that allows detection with low-power ultrasound, they can stably and efficiently encapsulate the cancer drug doxorubicin, and both a low- and higher-power dose of ultrasound can trigger the release of that cargo.

These three features create a guided drug delivery system to target solid tumors. Therapeutic efficacy can be further improved through surface modifications to boost targeting capabilities. Diagnostic low-power ultrasound then could visualize the nanocapsules as they concentrated in a tumor, and therapeutic higher-dose ultrasound would release the drug at ground zero, sparing the rest of the body from dose-limiting toxicity.

This precise control of when and where doxorubicin or other cancer drugs are released could offer a noninvasive alternative to cancer surgery or systemic chemotherapy, the UAB researchers report in the journal ACS Nano, which has an impact factor of 13.3.

“We envision an entirely different approach to treating solid human tumors of numerous pathologic subtypes, including common metastatic malignancies such as breast, melanoma, colon, prostate and lung, utilizing these capsules as a delivery platform,” said Eugenia Kharlampieva, Ph.D., an associate professor in the Department of Chemistry, UAB College of Arts and Sciences. “These capsules can protect encapsulated therapeutics from degradation or clearance prior to reaching the target and have ultrasound contrast as a means of visualizing the drug release. They can release their encapsulated drug cargo in specific locations via externally applied ultrasound exposure.”

Kharlampieva — who creates her novel “smart” particles while working at the intersection of polymer chemistry, nanotechnology and biomedical science — says there is an urgent, and so far unmet, need for such an easily fabricated, guided drug delivery system.

The UAB researchers, led by Kharlampieva and co-first authors Jun Chen and Sithira Ratnayaka, use alternating layers of biocompatible tannic acid and poly(N-vinylpyrrolidone), or TA/PVPON, to build their microcarriers. The layers are formed around a sacrificial core of solid silica or porous calcium carbonate that is dissolved after the layers are complete.

By varying the number of layers, the molecular weight of PVPON or the ratio of shell thickness to capsule diameter, the researchers were able to alter the physical traits of the capsules and their sensitivity to diagnostic ultrasound, at power levels below the FDA maximum for clinical imaging and diagnosis.

For example, one-fourth of empty microcapsules made with four layers of TA/low-molecular weight PVPON were ruptured by three minutes of ultrasound, while capsules made of 15 layers of TA/low-molecular weight PVPON or capsules made from four layers of TA/high-molecular weight PVPON showed no rupture. The ruptured capsules had a lower mechanical rigidity that made them more sensitive to ultrasound pressure changes. Experiments showed that the ratio of the thickness of the capsule wall to the diameter of the capsule is a key variable for sensitivity to rupture.

To test the ultrasound imaging contrast of the microcapsules, the UAB researchers made capsules that were 5 micrometers wide, or about two times wider than the capsules used in the rupture experiments. This size is small enough to still pass through capillaries in the lung, while a larger size for various microparticles is known to greatly improve ultrasound contrast. Red blood cells, for a size comparison, have a diameter of about 6 to 8 micrometers.

Researchers found that 5-micrometer-wide, empty capsules that were made with eight layers of TA/low-molecular weight PVPON showed an ultrasound contrast comparable to the commercially available microsphere contrast agent Definity. When the UAB capsules — which have a shell thickness of about 50 nanometers — were loaded with doxorubicin, the ultrasound imaging contrast increased two- to eightfold compared to empty capsules, depending on the mode of ultrasound imaging used. These doxorubicin-loaded capsules were highly stable, with no change in ultrasound imaging contrast after six months of storage. Exposure to serum, known to deposit proteins on various microparticles, did not extinguish the ultrasound imaging contrast of the TA/PVPON microcapsules.

A therapeutic dose of ultrasound was able to rupture 50 percent of the 5-micrometer, doxorubicin-loaded microcapsules, releasing enough doxorubicin to induce 97 percent cytotoxicity in human breast adenocarcinoma cells in culture. Adenocarcinoma cells that were incubated with intact doxorubicin-loaded microcapsules remained viable.

Phenformin Nano Cancer Delivery id39449Thus, Kharlampieva says, these TA/PVPON capsules have strong potential as “theranostic” agents for efficient cancer therapy in conjunction with ultrasound. The term theranostic refers to nanoparticles or microcapsules that can double as diagnostic imaging agents and as therapeutic drug-delivery carriers.

The next important preclinical step, Kharlampieva says, in collaboration with Mark Bolding, Ph.D., assistant professor in the UAB Department of Radiology, and Jason Warram, Ph.D., assistant professor in the UAB Department of Otolaryngology, will be studies in animal models to explore how long the UAB capsules persist in blood circulation and where they distribute in the body.

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Materials provided by University of Alabama at Birmingham. Note: Content may be edited for style and length.

Journal Reference:

  1. Jun Chen, Sithira Ratnayaka, Aaron Alford, Veronika Kozlovskaya, Fei Liu, Bing Xue, Kenneth Hoyt, Eugenia Kharlampieva. Theranostic Multilayer Capsules for Ultrasound Imaging and Guided Drug Delivery. ACS Nano, 2017; 11 (3): 3135 DOI: 10.1021/acsnano.7b00151

Scientists discover mechanism that causes cancer cells to self-destruct

Many cancer patients struggle with the adverse effects of chemotherapy, still the most prescribed cancer treatment. For patients with pancreatic cancer and other aggressive cancers, the forecast is more grim: there is no known effective therapy.

A new Tel Aviv University study published last month in Oncotarget discloses the role of three proteins in killing fast-duplicating cancer cells while they’re dividing. The research, led by Prof. Malka Cohen-Armon of TAU’s Sackler School of Medicine, finds that these proteins can be specifically modified during the division process—mitosis—to unleash an inherent “death mechanism” that self-eradicates duplicating cancer cells.

“The discovery of an exclusive mechanism that kills cancer cells without impairing healthy cells, and the fact that this mechanism works on a variety of rapidly proliferating human cancer cells, is very exciting,” Prof. Cohen-Armon said. 
“According to the mechanism we discovered, the faster cancer cells proliferate, the faster and more efficiently they will be eradicated. The mechanism unleashed during mitosis may be suitable for treating aggressive cancers that are unaffected by traditional chemotherapy.

“Our experiments in cell cultures tested a variety of incurable human cancer types—breast, lung, ovary, colon, pancreas, blood, brain,” Prof. Cohen-Armon continued. “This discovery impacts existing cancer research by identifying a new specific target mechanism that exclusively and rapidly eradicates cancer cells without damaging normally proliferating human cells.”

The research was conducted in collaboration with Prof. Shai Izraeli and Dr. Talia Golan of the Cancer Research Center at Sheba Medical Center, Tel Hashomer, and Prof. Tamar Peretz, head of the Sharett Institute of Oncology at Hadassah Medical Center, Ein Kerem.

A new target for cancer research

The newly-discovered mechanism involves the modification of specific proteins that affect the construction and stability of the spindle, the microtubular structure that prepares duplicated chromosomes for segregation into “daughter” cells during cell division.

The researchers found that certain compounds called Phenanthridine derivatives were able to impair the activity of these proteins, which can distort the spindle structure and prevent the segregation of chromosomes. Once the proteins were modified, the cell was prevented from splitting, and this induced the cell’s rapid self-destruction.

“The mechanism we identified during the mitosis of cancer cells is specifically targeted by the Phenanthridine derivatives we tested,” Prof. Cohen-Armon said. “However, a variety of additional drugs that also modify these specific proteins may now be developed for cancer cell self-destruction during cell division. The faster the cancer cells proliferate, the more quickly they are expected to die.”

Research was conducted using both cancer cell cultures and mice transplanted with human cancer cells. The scientists harnessed biochemical, molecular biology and imaging technologies to observe the mechanism in real time. In addition, mice transplanted with triple negative breast cancer cells, currently resistant to available therapies, revealed the arrest of tumor growth.

“Identifying the mechanism and showing its relevance in treating developed tumors opens new avenues for the eradication of rapidly developing aggressive cancers without damaging healthy tissues,” said Prof. Cohen-Armon.
The researchers are currently investigating the potential of one of the Phenanthridine derivatives to treat two aggressive cancers known to be unresponsive to current chemotherapy: pancreatic cancer and triple negative breast cancer.

More information: Leonid Visochek et al, Exclusive destruction of mitotic spindles in human cancer cells, Oncotarget (2017). DOI: 10.18632/oncotarget.15343

Provided by: Tel Aviv University

Drug combination delivered by nanoparticles may help in melanoma treatment

Melenoma 170314140859_1_540x360Gavin Robertson, professor of pharmacology, pathology, dermatology, and surgery; director of the Penn State Melanoma and Skin Cancer Center and member of Penn State Cancer Institute, works with associates in the Melanoma Center.
Credit: Penn State College of Medicine

Summary: The first of a new class of medication that delivers a combination of drugs by nanoparticle may keep melanoma from becoming resistant to treatment, according to Penn State College of Medicine researchers.

CelePlum-777 combines a special ratio of the drugs Celecoxib, an anti-inflammatory, and Plumbagin, a toxin. By combining the drugs, the cells have difficulty overcoming the effect of having more than one active ingredient.

Celecoxib and Plumbagin work together to kill melanoma cells when used in a specific ratio. Researchers used microscopic particles called nanoparticles to deliver the drugs directly to the cancer cells. These particles are several hundred times smaller than the width of a hair and can be loaded with medications.

“Loading multiple drugs into nanoparticles is one innovative approach to deliver multiple cancer drugs to a particular site where they need to act and have them released at that optimal cancer cell killing ratio,” said Raghavendra Gowda, assistant professor of pharmacology, who is the lead author on the study. “Another advantage is that by combining the drugs, lower concentrations of each that are more effective and less toxic can be used.”

Celecoxib and Plumbagin cannot be taken by mouth because the drugs do not enter the body well this way and cannot be used together in the ratio needed because of toxicity.

CelePlum-777 can be injected intravenously without toxicity. Because of its small size, it also accumulates inside the tumors where it then releases the drugs to kill the cancer cells. Researchers report their results in the journals Molecular Cancer Therapeutics and Cancer Letters.

“This drug is the first of a new class, loaded with multiple agents to more effectively kill melanoma cells, that has potential to reduce the possibility of resistance development,” said senior author Gavin Robertson, professor of pharmacology, pathology, dermatology, and surgery; director of the Penn State Melanoma and Skin Cancer Center and member of Penn State Cancer Institute. “There is no drug like it in the clinic today and it is likely that the next breakthrough in melanoma treatment will come from a drug like this one.”

The researchers showed the results of CelePlum-777 on killing cancer cells growing in culture dishes and in tumors growing in mice following intravenous injection. The drug prevented tumor development in mice with no detectable side effects and also prevented proteins from enabling uncontrolled cancer cell growth.

More research is required by the Food and Drug Administration before CelePlum-777 can be tested in humans through clinical trials. Penn State has patented this discovery and licensed it to Cipher Pharmaceuticals, which will perform the next series of FDA-required tests.

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Materials provided by Penn State College of Medicine. Note: Content may be edited for style and length.

UC Berkeley: Magnetic nano-particle imaging Research May Lead to Early Cancer Detection


Magnetic particle imaging is a new, up-and-coming, safe and highly sensitive tracer imaging technique that works by detecting super-para-magnetic iron oxide nano-particles with high image contrast (that is, no background tissue signal). The technique, which does not use any ionizing radiation, can be used to image anywhere inside the body, which means that it could be promising for detecting and monitoring tumors. Researchers in the US are now the first to have used MPI to passively detect cancer by basically exploiting the abnormal leakiness of tumor blood vessels – a finding that bodes well for the early detection of cancers like breast cancer in patients at risk for the disease.

Biomedical imaging is important at every stage of diagnosing and treating cancer, beginning with initial screening, through to diagnosis, treatment planning and monitoring. The biggest challenge here is to be able to reliably distinguish tumour tissue from healthy tissue, something that is not as easy as it sounds.

“Conventional anatomical techniques, such as X-ray, X-ray computed tomography (CT), ultrasound and magnetic resonance imaging (MRI), are very useful for detecting the tissue architecture changes that generally accompany cancer, but the native contrast of tumours may not differ sufficiently from healthy tissue for a confident diagnosis, especially for metastatic or so-called diffuse tumours” explains lead author of the study Elaine Yu, who is completing her Bioengineering PhD in Steven Conolly’s lab at the University of California at Berkeley (UCB). “This is why exogenous contrast agents, such as iodine (for X-ray and CT) and gadolinium (for MRI) are often administered to highlight crucial vascular differences between normal and cancerous tissue for more precise screening.”

Exploiting the EPR effect

Contrast agents are all injected intravenously, but the way they highlight tumours differs considerably. Nanosized agents are better than conventional low molecular weight agents in one respect because they are not immediately excreted by the kidneys if designed to be large enough. They are thus able to circulate in the blood for extended periods of time. The naturally leaky vasculature of some tumours also allows nanosized particles to preferentially end up in tumour tissue, where they can be held. This is known as the enhanced permeability and retention (EPR) effect.

“Our work is the first to exploit the EPR effect with the high sensitivity and contrast afforded by magnetic particle imaging (MPI),” says Yu. “We have succeeded in imaging tumours in rats with vivid tumour-to-background contrast. “Thanks to its high sensitivity and good signal throughout the entire body, we were able to clearly capture the nanoparticle dynamics in the tumour: so-called rim enhancement, peak particle uptake at six hours after administration and eventual clearance beyond 48 hours.”

Synthesizing the SPIOscancer-shapeshiftin

The MPI-tailored superparamagnetic iron oxide nanoparticle (SPIO) tracers were synthesized by team members at LodeSpin Labs and by Kannan Krishnan’s lab at the University of Washington (UW), and were designed for optimal imaging resolution and long blood circulation time. “The iron oxide nanoparticles were made by thermolysis of iron III oleate in 1-octadcene, with subsequent oxidation to achieve the desired magnetic behaviour and coated with the biocompatible coating MPAO-PEG,” explains Yu.

The researchers injected the nanoparticles into the tail veins of rats and then performed a series of MPI scans as the nanoparticles travelled through the circulation. Thanks to the EPR effect, the particles preferentially accumulated in tumours and were retained there for up to six days.

Imaging the SPIO electronic moment

MPI was first developed by Philips Research in 2005 and is a tracer imaging technique that directly measures the location and concentration of SPIO nanoparticles in vivo. It images the SPIO electronic moment, which is 22 million times more intense than nuclear MRI moments. When a time-varying exciting field is applied, it causes the moments of the SPIOs to instantaneously “flip”, thereby inducing a signal in a receiver coil.

“The advantages of MPI are its superb contrast and sensitivity, which could very soon rival the dose-limited sensitivity of nuclear medicine techniques,” Conolly tells “This is very exciting, since MPI does not rely on ionizing radiation. The scanner and iron oxide tracer are also thought to be safe for humans. Indeed, some SPIO agents are already FDA or EU safety approved for human use in other clinical applications.”

MPI tracers are excreted through the liver

Importantly, the MPI tracers are excreted through the liver, rather than through the kidneys, and there is evidence that SPIOs could be safer than iodine and gadolinium for patients with chronic kidney disease. “Given all these advantages, we are very hopeful that MPI could play an important role in early-stage cancer detection. Indeed, we are particularly focusing on early-stage breast cancer detection in the subpopulation of women with radiologically dense breast tissue and who are at high risk for cancer (because of, for example, BRCA1 or BRCA2 defects, or family history of the disease).”

Conolly says that he and his colleagues are now working hard to improve MPI in terms of resolution and sensitivity. “We are also studying MPI for stem-cell tracking, detecting pulmonary embolism, brain perfusion to detect and monitor strokes or traumatic brain injuries, and T-cell immunotherapy studies in collaboration with researchers at Berkeley, the University of California at San Francisco, UW, Case Western, Harvard and Stanford. We would also like to follow up on several promising demonstrations of MPI-guided magnetic fluid hyperthermia exploiting the unique ‘focusing’ capabilities of MPI to selectively heat tumours or to release chemotherapeutic agents specifically into a tumour. We are doing this work with University of Florida collaborators.”

The new MPI cancer imaging study is described in Nano Letters DOI: 10.1021/acs.nanolett.6b04865.

New class of materials could revolutionize biomedical, alternative energy industries: Cancer Therapies ~ Low Cost Solar Cells

poly-new-material-170125145735_1_540x360Polyarylboranes are a new class of materials that could be used in biomedical, personal computer and alternative energy applications. Credit: Mark Lee

Polyhedral boranes, or clusters of boron atoms bound to hydrogen atoms, are transforming the biomedical industry. These humanmade materials have become the basis for the creation of cancer therapies, enhanced drug delivery and new contrast agents needed for radioimaging and diagnosis. Now, a researcher at the University of Missouri has discovered an entirely new class of materials based on boranes that might have widespread potential applications, including improved diagnostic tools for cancer and other diseases as well as low-cost solar energy cells.

Mark Lee Jr., an assistant professor of chemistry in the MU College of Arts and Science, discovered the new class of hybrid nanomolecules by combining boranes with carbon and hydrogen. Boranes are chemically stable and have been tested at extreme heat of up to 900 degrees Celsius or 1,652 degrees Fahrenheit. It is the thermodynamic stability these molecules exhibit that make them non-toxic and attractive to the biomedical, personal computer and alternative energy industries.

“Despite their stability, we discovered that boranes react with aromatic hydrocarbons at mildly elevated temperatures, replacing many of the hydrogen atoms with rings of carbon,” Lee said. “Polyhedral boranes are incredibly inert, and it is their reaction with aromatic hydrocarbons like benzene that will make them more useful.”

Lee also showed that the attached hydrocarbons communicate with the borane core.

“The result is that these new materials are highly fluorescent in solution,” Lee said. “Fluorescence can be used in applications such as bio-imaging agents and organic light-emitting diodes like those in phones or television screens. Solar cells and other alternative energy sources also use fluorescence, so there are many practical uses for these new materials.”

Lee’s discovery is based on decades of research. Lee’s doctoral advisor, M. Frederick Hawthorne, MU Curators Distinguished Professor of Chemistry and Radiology, discovered several of these boron clusters as early as 1959. In the past, boranes have been used for medical imaging, drug delivery, neutron-based treatments for cancer and rheumatoid arthritis, catalysis and molecular motors. Borane researchers also have created a specific type of nanoparticle that selectively targets cancer cells.

“When these molecules were discovered years ago we never could have imagined that they would lead to so many advancements in biomedicine,” Lee said. “Now, my group is expanding on the scope of this new chemistry to examine the possibilities. These new materials, called ‘polyarylboranes,’ are much broader than we imagined, and now my students are systematically exploring the use of these new clusters.”

Story Source:

Materials provided by University of Missouri-Columbia. Note: Content may be edited for style and length.

Journal Reference:

  1. Mark W. Lee. Catalyst-Free Polyhydroboration of Dodecaborate Yields Highly Photoluminescent Ionic Polyarylated Clusters. Angewandte Chemie, 2017; 129 (1): 144 DOI: 10.1002/ange.201608249

In one-two punch, researchers load ‘nanocarriers’ to deliver cancer-fighting drugs and imaging molecules to tumors

nano-carriers-161129161516_1_540x360Zhang’s group created this nanocarrier using a “load during assembly” approach, shown along the top. Images b, c and d are microscopic views of the nanocarriers at each major step of the assembly and loading process. Credit: Miqin Zhang

In one-two punch, researchers load ‘nanocarriers’ to deliver cancer-fighting drugs and imaging molecules to tumors

A conundrum of cancer is the tumor’s ability to use our bodies as human shields to deflect treatment. Tumors grow among normal tissues and organs, often giving doctors few options but to damage, poison or remove healthy parts of our body in attempts to beat back the cancer with surgery, chemotherapy or radiation.

But in a paper published Sept. 27 in the journal Small, scientists at the University of Washington describe a new system to encase chemotherapy drugs within tiny, synthetic “nanocarrier” packages, which could be injected into patients and disassembled at the tumor site to release their toxic cargo.

The group, led by UW professor of materials science and engineering Miqin Zhang, is not the first to work on nanocarriers. But the nanocarrier package developed by Zhang’s team is a hybrid of synthetic materials, which gives the nanocarrier the unique ability to ferry not just drugs, but also tiny fluorescent or magnetic particles to stain the tumor and make it visible to surgeons.

“Our nanocarrier system is really a hybrid addressing two needs — drug delivery and tumor imaging,” said Zhang, who is senior author on the paper. “First, this nanocarrier can deliver chemotherapy drugs and release them in the tumor area, which spares healthy tissue from toxic side effects. Second, we load the nanocarrier with materials to help doctors visualize the tumor, either using a microscope or by MRI scan.”

Their hybrid nanocarrier builds on years of research into the types of synthetic materials that could package drugs for delivery into a specific part of a patient’s body. In previous attempts, scientists would often first try make an empty nanocarrier out of a synthetic material. Once assembled, they would load the nanocarrier with a therapeutic drug. But this approach was inefficient, and carried a high risk of damaging the fragile drugs and rendering them ineffective.

“Most chemotherapy drugs have complex structures — essentially, they’re very fragile — and they do no good if they are broken by the time they reach the tumor,” said Zhang.

Nano Body II 43a262816377a448922f9811e069be13Zhang’s team worked around this problem by designing a nanocarrier that could be assembled and loaded simultaneously. Their approach is akin to laying cargo within a shipping container even as the container’s walls, floor and roof are being assembled and bolted together.

This “load during assembly” technique also let Zhang’s team incorporate multiple chemical components into the nanocarrier’s structure, which could help hold cargo in place and make the tumor easy to image in clinical settings.

Their nanocarrier sports a core of iron oxide, which provides structure but can also be used as an imaging agent in MRI scans. A shell of silica surrounds the core, and was designed to efficiently stack the chemotherapy drug paclitaxel. They also included space in the nanocarrier for carbon dots, tiny particles that can “stain” tissue and make it easier to see under a microscope, helping doctors resolve the boundaries between cancerous and healthy tissue for further treatment or surgery. The intensity of many imaging agents fades over time, but Zhang said this nanocarrier can provide sustained imaging for months.

Yet despite holding so much cargo, the fully loaded nanocarriers are less than the thickness of a sheet of flimsy notebook paper.

The silica shell keeps the nanocarriers watertight. In addition, they do not interfere with healthy tissue, as Zhang’s team showed by injecting healthy mice with empty nanocarriers or nanocarriers loaded with drug cargo. Five days after injection, they checked vital organs in the mice for evidence of toxicity and found none.

“This would indicate that the nanocarriers themselves do not trigger an adverse reaction in the body, and that the loaded nanocarriers are keeping their toxic cargo shielded from the body,” said Zhang.

The UW team also designed the nanocarriers to be easily disassembled once they reached a desired location. Gentle heating from low-level infrared light was sufficient to make the nanocarriers break apart and disgorge their cargo, which is something doctors could apply to the tumor site during treatment.

As their final test of the nanocarrier effectiveness, Zhang’s team turned to mice with a form of transmissible cancer. Mice that they injected with empty nanocarriers showed no reduction in tumor size. But tumors shrank significantly in mice injected with nanocarriers that were loaded with paclitaxel. They saw a similar affect on human cancer cells cultured and tested in the lab.

“These results show that the nanocarriers can deliver their cargo intact to the tumor site,” said Zhang. “And while we designed this nanocarrier specifically to accommodate paclitaxel, it is possible to adjust this technique for other drugs.”

There are still mountains to climb before this technology is proven safe and effective for humans. But Zhang hopes her team’s approach and promising results will accelerate the ascent.

Story Source:

Materials provided by University of Washington. Original written by James Urton. Note: Content may be edited for style and length.

Journal Reference:

  1. Hui Wang, Kui Wang, Bowei Tian, Richard Revia, Qingxin Mu, Mike Jeon, Fei-Chien Chang, Miqin Zhang. Preloading of Hydrophobic Anticancer Drug into Multifunctional Nanocarrier for Multimodal Imaging, NIR-Responsive Drug Release, and Synergistic Therapy. Small, 2016; DOI: 10.1002/smll.201602263

MIT: Nanosensors could help determine tumors’ ability to remodel tissue – Nanosensors that can ‘profile’ tumors

mit-nanosensorsc-093016MIT researchers have designed nanosensors that can profile tumors and may yield insight into how they will respond to certain therapies. Credit: Christine Daniloff/MIT

MIT researchers have designed nanosensors that can profile tumors and may yield insight into how they will respond to certain therapies. The system is based on levels of enzymes called proteases, which cancer cells use to remodel their surroundings.

Once adapted for humans, this type of sensor could be used to determine how aggressive a tumor is and help doctors choose the best treatment, says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science and a member of MIT’s Koch Institute for Integrative Cancer Research.

“This approach is exciting because people are developing therapies that are protease-activated,” Bhatia says. “Ideally you’d like to be able to stratify patients based on their protease activity and identify which ones would be good candidates for these therapies.”

Once injected into the tumor site, the nanosensors are activated by a  that is harmless to healthy tissue. After interacting with and being modified by the target tumor proteins, the sensors are secreted in the urine, where they can be easily detected in less than an hour.

Bhatia and Polina Anikeeva, the Class of 1942 Associate Professor of Materials Science and Engineering, are the senior authors of the paper, which appears in the journal Nano Letters. The paper’s lead authors are Koch Institute postdoc Simone Schurle and graduate student Jaideep Dudani.

Heat and release

Tumors, especially aggressive ones, often have elevated protease levels. These enzymes help tumors spread by cleaving proteins that compose the extracellular matrix, which normally surrounds cells and holds them in place.

In 2014, Bhatia and colleagues reported using nanoparticles that interact with a type of protease known as matrix metalloproteinases (MMPs) to diagnose cancer. In that study, the researchers delivered nanoparticles carrying peptides, or short protein fragments, designed to be cleaved by the MMPs. If MMPs were present, hundreds of cleaved peptides would be excreted in the urine, where they could be detected with a simple paper test similar to a pregnancy test.

In the new study, the researchers wanted to adapt the sensors so that they could report on the traits of tumors in a known location. To do that, they needed to ensure that the sensors were only producing a signal from the target organ, unaffected by background signals that might be produced in the bloodstream. They first designed sensors that could be activated with light once they reached their target. That required the use of ultraviolet light, however, which doesn’t penetrate very far into tissue.

“We started thinking about what kinds of energy we might use that could penetrate further into the body,” says Bhatia, who is also a member of MIT’s Institute for Medical Engineering and Science.

To achieve that, Bhatia teamed up with Anikeeva, who specializes in using magnetic fields to remotely activate materials. The researchers decided to encapsulate Bhatia’s protease-sensing nanoparticles along with magnetic particles that heat up when exposed to an alternating magnetic field. The field is produced by a small magnetic coil that changes polarity some half million times per second.

The heat-sensitive material that encapsulates the particles disintegrates as the magnetic particles heat up, allowing the protease sensors to be released. However, the particles do not produce enough heat to damage nearby tissue.

“It has been challenging to examine tumor-specific protease activities from patients’ biofluids because these proteases are also present in blood and other organs,” says Ji Ho (Joe) Park, an associate professor of bio and brain engineering at the Korea Advanced Institute of Science and Technology.

“The strength of this work is the magnetothermally responsive protease nanosensors with spatiotemporal controllability,” says Park, who was not involved in the research. “With these nanosensors, the MIT researchers could assay protease activities involved more in tumor progression by reducing off-target activation significantly.”

Choosing treatments

In a study of mice, the researchers showed that they could use these particles to correctly profile different types of colon tumors based on how much protease they produce.

Cancer treatments based on proteases, now in clinical trials, consist of antibodies that target a tumor protein but have “veils” that prevent them from being activated before reaching the tumor. The veils are cleaved by proteases, so this therapy would be most effective for patients with high  levels.

The MIT team is also exploring using this type of sensor to image cancerous lesions that spread to the liver from other organs. Surgically removing such lesions works best if there are fewer than four, so measuring them could help doctors choose the best treatment.

Bhatia says this type of sensor could be adapted to other tumors as well, because the magnetic field can penetrate deep into the body. This approach could also be expanded to make diagnoses based on detecting other kinds of enzymes, including those that cut sugar chains or lipids.

Explore further: Nanoparticles amplify tumor signals, making them much easier to detect in the urine

More information: Simone Schuerle et al. Magnetically Actuated Protease Sensors for in Vivo Tumor Profiling, Nano Letters (2016). DOI: 10.1021/acs.nanolett.6b02670



Argonne National Laboratory-led projects among $39.8 million in first-round “Exascale” Computing Project awards -Enabled Precision Medicine for Cancer

doe-iii-doeThe U.S. Department of Energy’s (DOE’s) Exascale Computing Project (ECP) today announced its first round of funding with the selection of 15 application development proposals for full funding and seven proposals for seed funding, representing teams from 45 research and academic organizations.

Exascale refers to high-performance computing systems capable of at least a billion billion calculations per second, or a factor of 50 to 100 times faster than the nation’s most powerful supercomputers in use today.

The 15 awards being announced total $39.8 million, targeting advanced modeling and simulation solutions to specific challenges supporting key DOE missions in science, clean energy and national security, as well as collaborations such as the Precision Medicine Initiative with the National Institutes of Health’s National Cancer Institute.

Of the proposals announced that are receiving full funding, two are being led by principal investigators at the DOE’s Argonne National Laboratory:

  1. Computing the Sky at Extreme Scales equips cosmologists with the ability to design foundational simulations to create “virtual universes” on demand at the extreme fidelities demanded by future multi-wavelength sky surveys. The new discoveries that will emerge from the combination of sky surveys and advanced simulation provided by the ECP will shed more light on three key ingredients of our universe: dark energy, dark matter and inflation. All three of these concepts reach beyond the known boundaries of the Standard Model of particle physics.Salman Habib, Principal Investigator, Argonne National Laboratory, with Los Alamos National Laboratory and Lawrence Berkeley National Laboratory.argone-ii-nl-mira_-_blue_gene_q_at_argonne_national_laboratory
  1. Exascale Deep Learning and Simulation Enabled Precision Medicine for Cancer focuses on building a scalable deep neural network code called the CANcer Distributed Learning Environment (CANDLE) that addresses three top challenges of the National Cancer Institute: understanding the molecular basis of key protein interactions, developing predictive models for drug response and automating the analysis and extraction of information from millions of cancer patient records to determine optimal cancer treatment strategies.Rick Stevens, Principal Investigator, Argonne National Laboratory, with Los Alamos National Laboratory, Lawrence Livermore National Laboratory, Oak Ridge National Laboratory and the National Cancer Institute.

Additionally, a third project led by Argonne will be receiving seed funding:

  1. Multiscale Coupled Urban Systems will create an integrated modeling framework comprising data curation, analytics, modeling and simulation components that will equip city designers, planners and managers to scientifically develop and evaluate solutions to issues that affect cities now and in the future. The framework will focus first on integrating urban atmosphere and infrastructure heat exchange and air flow; building energy demand at district or city-scale, generation and use; urban dynamics and socioeconomic models; population mobility and transportation; and hooks to expand to include energy systems (biofuels, electricity and natural gas) and water resources.Charlie Catlett, Principal Investigator, Argonne National Laboratory, with Lawrence Berkeley National Laboratory, National Renewable Energy Laboratory, Oak Ridge National Laboratory and Pacific Northwest National Laboratory.

The application efforts will help guide DOE’s development of a U.S. exascale ecosystem as part of President Obama’s National Strategic Computing Initiative. DOE, the U.S. Department of Defense and the National Science Foundation have been designated as lead agencies, and ECP is the primary DOE contribution to the initiative.

The ECP’s multiyear mission is to maximize the benefits of high-performance computing for U.S. economic competitiveness, national security and scientific discovery. In addition to applications, the DOE project addresses hardware, software, platforms and workforce development needs critical to the effective development and deployment of future exascale systems.

argone-nl-090115-114727Leadership of the ECP comes from six DOE national laboratories: the Office of Science’s Oak Ridge, Argonne and Lawrence Berkeley national labs and the National Nuclear Security Administration’s (NNSA’s) Lawrence Livermore, Los Alamos and Sandia national labs.

The Exascale Computing Project is a collaborative effort of two DOE organizations — the Office of Science and the NNSA. As part of President Obama’s National Strategic Computing initiative, ECP was established to develop a capable exascale ecosystem, encompassing applications, system software, hardware technologies and architectures, and workforce development to meet the scientific and national security mission needs of DOE in the mid-2020s timeframe.

Established by Congress in 2000, NNSA is a semi-autonomous agency within DOE responsible for enhancing national security through the military application of nuclear science. NNSA maintains and enhances the safety, security, and effectiveness of the U.S. nuclear weapons stockpile without nuclear explosive testing; works to reduce the global danger from weapons of mass destruction; provides the U.S. Navy with safe and effective nuclear propulsion; and responds to nuclear and radiological emergencies in the United States and abroad.

Argonne National Laboratory seeks solutions to pressing national problems in science and technology. The nation’s first national laboratory, Argonne conducts leading-edge basic and applied scientific research in virtually every scientific discipline. Argonne researchers work closely with researchers from hundreds of companies, universities, and federal, state and municipal agencies to help them solve their specific problems, advance America’s scientific leadership and prepare the nation for a better future. With employees from more than 60 nations, Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science.

The U.S. Department of Energy’s Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information, visit the Office of Science website.

Nanorobots target cancerous tumours with precision

Nanorobots 081916 legionsofnanThe legions of nanorobotic agents are actually composed of more than 100 million flagellated bacteria — and therefore self-propelled — and loaded with drugs that moved by taking the most direct path between the drug’s injection point and …more

Researchers from Polytechnique Montréal, Université de Montréal and McGill University have just achieved a spectacular breakthrough in cancer research. They have developed new nanorobotic agents capable of navigating through the bloodstream to administer a drug with precision by specifically targeting the active cancerous cells of tumours. This way of injecting medication ensures the optimal targeting of a tumour and avoids jeopardizing the integrity of organs and surrounding healthy tissues. As a result, the drug dosage that is highly toxic for the human organism could be significantly reduced.

This scientific breakthrough has just been published in the prestigious journal Nature Nanotechnology in an article titled “Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions.” The article notes the results of the research done on mice, which were successfully administered nanorobotic agents into colorectal tumours.

“These legions of nanorobotic agents were actually composed of more than 100 million flagellated bacteria – and therefore self-propelled – and loaded with drugs that moved by taking the most direct path between the drug’s injection point and the area of the body to cure,” explains Professor Sylvain Martel, holder of the Canada Research Chair in Medical Nanorobotics and Director of the Polytechnique Montréal Nanorobotics Laboratory, who heads the research team’s work. “The drug’s propelling force was enough to travel efficiently and enter deep inside the tumours.”

When they enter a tumour, the nanorobotic agents can detect in a wholly autonomous fashion the oxygen-depleted tumour areas, known as hypoxic zones, and deliver the drug to them. This hypoxic zone is created by the substantial consumption of oxygen by rapidly proliferative tumour cells. Hypoxic zones are known to be resistant to most therapies, including radiotherapy.

But gaining access to tumours by taking paths as minute as a and crossing complex physiological micro-environments does not come without challenges. So Professor Martel and his team used nanotechnology to do it.

Bacteria with compass

To move around, bacteria used by Professor Martel’s team rely on two natural systems. A kind of compass created by the synthesis of a chain of magnetic nanoparticles allows them to move in the direction of a magnetic field, while a sensor measuring oxygen concentration enables them to reach and remain in the tumour’s active regions. By harnessing these two transportation systems and by exposing the bacteria to a computer-controlled magnetic field, researchers showed that these bacteria could perfectly replicate artificial nanorobots of the future designed for this kind of task.

“This innovative use of nanotransporters will have an impact not only on creating more advanced engineering concepts and original intervention methods, but it also throws the door wide open to the synthesis of new vehicles for therapeutic, imaging and diagnostic agents,” Professor Martel adds. “Chemotherapy, which is so toxic for the entire human body, could make use of these natural nanorobots to move drugs directly to the targeted area, eliminating the harmful side effects while also boosting its therapeutic effectiveness.”

Explore further: Fantastic voyage: From science fiction to reality

More information: Ouajdi Felfoul et al, Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions, Nature Nanotechnology (2016). DOI: 10.1038/NNANO.2016.137


University of Copenhagen: Nanoparticles Provide Gentle Cancer Treatment that Works!

Coppen Cancer 081116 160803103750_1_540x360The images show PET scans of a mouse with a large tumor (by the white arrow). The tumor is treated with nanoparticles, which are injected directly into the tumor and are then flashed with near infrared laser light. The laser light heats the nanoparticles, thus damaging or killing the cancer cells (red arrows).
Credit: Kamilla Nørregaard and Jesper Tranekjær Jørgensen, Panum Inst.

Cancer treatments based on laser irridation 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 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. The results are published in the scientific journal,Scientific Reports.

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. It 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.

Design and effect

The small nanoparticles are between 80 and 150 nanometers in diameter (a nanometer is a millionth of a millimeter). The tested particles consist of either solid gold or a shell structure consisting of a glass core with a thin shell of gold around it. Some of the experiments aimed to find out which particles are most effective in reducing tumors.

“As physicists we have great expertise in the interaction between light and nanoparticles and we can very accurately measure the temperature of the heated nanoparticles. The effectiveness depends on the right combination between the structure and material of the particles, their physical size and the wavelength of the light,” explains Lene Oddershede.

The experiments showed that the researchers got the best results with nanoparticles that were 150 nanometers in size and consisted of a core of glass coated with gold. The nanoparticles were illuminated with near-infrared laser light, which is the best at penetrating through the tissue. In contrast to conventional radiation therapy, the near-infrared laser light causes no burn damage to the tissue that it passes through. Just an hour after the treatment, they could already directly see with PET scans that the cancer cells had been killed and the effect continued for at least two days after the treatment.

“Now we have proven that the method works. In the longer term, we would like the method to work by injecting the nanoparticles into the bloodstream, where they end up in the tumors that may have metastasized. With the PET scans we can see where the tumors are and irridate them with lasers, while also effectively assessing how well the treatment has worked shortly after the irradiation. In addition, we will coat the particles with chemotherapy, which is released by the heat and which will also help kill the cancer cells,” explains Lene Oddershede.

Story Source:

The above post is reprinted from materials provided byUniversity of Copenhagen – Niels Bohr Institute. Note: Content may be edited for style and length.

Journal Reference:

  1. Jesper Tranekjær Jørgensen, Kamilla Norregaard, Pengfei Tian, Poul Martin Bendix, Andreas Kjaer, Lene B. Oddershede. Single Particle and PET-based Platform for Identifying Optimal Plasmonic Nano-Heaters for Photothermal Cancer Therapy. Scientific Reports, 2016; 6: 30076 DOI: 10.1038/srep30076
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