Converging on Cancer at the Nanoscale


MIT-KI-Marble-Center-Faculty-00_0The Marble Center for Cancer Nanomedicine’s faculty is made up of Koch Institute members who are committed to fighting cancer with nanomedicine through research, education, and collaboration. Top row (l-r) Sangeeta Bhatia, director; Daniel Anderson; and Angela Belcher. Bottom row: Paula Hammond; Darrell Irvine; and Robert Langer. Photo: Koch Institute Marble Center for Cancer Nanomedicine

 Koch Institute – July 2017

Marking its first anniversary, the Koch Institute’s Marble Center for Cancer Nanomedicine goes full steam ahead.

This summer, the Koch Institute for Integrative Cancer Research at MIT marks the first anniversary of the launch of the Marble Center for Cancer Nanomedicine, established through a generous gift from Kathy and Curt Marble ’63.

Bringing together leading Koch Institute faculty members and their teams, the Marble Center for Cancer Nanomedicine focuses on grand challenges in cancer detection, treatment, and monitoring that can benefit from the emerging biology and physics of the nanoscale.

These challenges include detecting cancer earlier than existing methods allow, harnessing the immune system to fight cancer even as it evolves, using therapeutic insights from cancer biology to design therapies for previously undruggable targets, combining existing drugs for synergistic action, and creating tools for more accurate diagnosis and better surgical intervention. cancer-shapeshiftin

Koch Institute member Sangeeta N. Bhatia, the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, serves as the inaugural director for the center.

”A major goal for research at the Marble Center is to leverage the collaborative culture at the Koch Institute to use nanotechnology to improve cancer diagnosis and care in patients around the world,” Bhatia says.

Transforming nanomedicine

The Marble Center joins MIT’s broader efforts at the forefront of discovery and innovation to solve the urgent global challenge that is cancer. The concept of “convergence” — the blending of the life and physical sciences with engineering — is a hallmark of MIT, the founding principle of the Koch Institute, and at the heart of the Marble Center’s mission.

“The center galvanizes the MIT cancer research community in efforts to use nanomedicine as a translational platform for cancer care,” says Tyler Jacks, director of the Koch Institute and a David H. Koch Professor of Biology. “It’s transformative by applying these emerging technologies to push the boundaries of cancer detection, treatment, and monitoring — and translational by promoting their development and application in the clinic.”

The center’s faculty — six prominent MIT professors and Koch Institute members — are committed to fighting cancer with nanomedicine through research, education, and collaboration. They are:

Sangeeta Bhatia (director), the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science;

Daniel G. Anderson, the Samuel A. Goldblith Professor of Applied Biology in the Department of Chemical Engineering and the Institute for Medical Engineering and Science;

Angela M. Belcher, the James Mason Crafts Professor in the departments of Biological Engineering and Materials Science and Engineering;

Paula T. Hammond, the David H. Koch Professor of Engineering and head of the Department of Chemical Engineering;

Darrell J. Irvine, professor in the departments of Biological Engineering and Materials Science and Engineering; and

Robert S. Langer, the David H. Koch Institute Professor.

Extending their collaboration within the walls of the Institute, Marble Center members benefit greatly from the support of the Peterson (1957) Nanotechnology Materials Core Facility in the Koch Institute’s Robert A. Swanson (1969) Biotechnology Center. The Peterson Facility’s array of technological resources and expertise is unmatched in the United States, and gives members of the center, and of the Koch Institute, a distinct advantage in the development and application of nanoscale materials and technologies.

Looking ahead

Figure-1-11-Nanocarriers-for-cancer-theranostics-Nanoparticles-based-strategies-can-beThe Marble Center has wasted no time getting up to speed in its first year, and has provided support for innovative research projects including theranostic nanoparticles that can both detect and treat cancers, real-time imaging of interactions between cancer and immune cells to better understand response to cancer immunotherapies, and delivery technologies for several powerful RNA-based therapeutics able to engage specific cancer targets with precision.

As part of its efforts to help foster a multifaceted science and engineering research force, the center has provided fellowship support for trainees — as well as valuable opportunities for mentorship, scientific exchange, and professional development.

Promoting broader engagement, the Marble Center serves as a bridge to a wide network of nanomedicine resources, connecting its members to MIT.nano, other nanotechnology researchers, and clinical collaborators across Boston and beyond. The center has also convened a scientific advisory board, whose members hail from leading academic and clinical centers around the country, and will help shape the center’s future programs and continued expansion.

As the Marble Center begins another year of collaborations and innovation, there is a new milestone in sight for 2018. Nanomedicine has been selected as the central theme for the Koch Institute’s 17th Annual Cancer Research Symposium. Scheduled for June 15, 2018, the event will bring together national leaders in the field, providing an ideal forum for Marble Center members to share the discoveries and advancements made during its sophomore year.

“Having next year’s KI Annual Symposium dedicated to nanomedicine will be a wonderful way to further expose the cancer research community to the power of doing science at the nanoscale,” Bhatia says. “The interdisciplinary approach has the power to accelerate new ideas at this exciting interface of nanotechnology and medicine.”

To learn more about the people and projects of the Koch Institute Marble Center for Cancer Nanomedicine, visit nanomedicine.mit.edu.

Ginseng nanoparticles for cancer treatment



A recent editorial in Nanomedicine (“Ginseng nanoparticles: a budding tool for cancer treatment”) by scientists in Korea states that use of ginsenoside nanoconjugates could be a promising candidate against cancer and various other diseases, such as inflammation, osteoporosis and obesity in the future.

Researchers have found that nanoparticles of ginsenoside by various nanocarriers, such as, polymers, proteins, micelles and liposomes result in an increased water solubility and anticancer activity.

In addition, the cytotoxicity of the conjugates is often similar or superior compared with bare ginsenosides in cancer cells with relatively low cytotoxicity in normal cells.


Ginseng

Ginseng has been considered one of the highly valued medicinal plants in traditional Chinese medicine for more than thousands of years.

Ginseng phytochemicals, such as, ginsenoside (unique triterpenoid saponins), phenols and acidic polysaccharides have been known to exhibit numerous pharmacological efficacies including anticancer, anti-inflammatory, antidiabetic, antiaging, enhanced immunization and liver functions and protective effects against Alzheimer’s disease. Their administration often results in adaptogenic effects.

Regular intake of ginseng products has been demonstrated to prevent the occurrence of various cancers, ameliorate cancer-related fatigue and enhance life span.

Among ginseng phytochemicals, ginsenosides have been thoroughly researched and scrutinized over the years to flaunt various pharmacological activities.

As the scientists point out, though, there are considerable limitation sto these benefits: After oral administration, crude and major ginsenosides are mainly converted into minor ginsenosides due to hydrolysis of glucose molecules by intestinal microbiota.

Biomolecular conjugations of ginsenosides and drug delivery techniques play significant roles to solve these problematic issues.

Most reported nanodrug delivery carriers, such as, polymer–drug conjugates, nanoparticles, liposomes and metal nanoparticles are designed to increase solubility, improve lipid membrane penetration, enhance anticancer efficacy, ameliorate sustainability in gastrointestinal environment and reduce or eliminate loss during oral administration.

Polymer–ginsenoside nanoconjugates have been recently studied as a potential drug carrier to tumor sites owing to the improved solubility and efficient drug-release mechanisms.

The enhanced oral bioavailability, oncogene MDM2 targeting and anticancer activities were reported in both in vitro and in vivo of PEG-PLGA loaded 25–OCH3–PPD nanoparticles than nonloaded drug.

The phytochemicals in plant extracts have a direct relationship in the efficacy of tailor-made nanoparticles used as drug delivery and as therapeutic agents.

The phytochemicals in ginseng provide binary functions in the nanoparticle synthesis as competent reducing agents to convert macrosized salts into nanosized metal nanoparticles as well as stabilizers to cater a potent coating on the metal nanoparticles.

Source: Future Medicine

Mayo Clinic Researchers develop new tumor-shrinking nanoparticle to fight breast cancer – prevent recurrence


Cancer New Nano Particle 58e378ef3aa34Credit: CC0 Public Domain

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. In the study, published today in Nature Nanotechnology, 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- 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- 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 , 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. It’s coated with antibodies that target the HER2 receptor, a common molecule found on 40 percent of breast cancers. It’s also coated with molecules that engage two distinct facets of the body’s immune system. The nanoparticle hones in on the tumor by recognizing HER2 and then helps the identify the tumor cells to attack them.

The molecules attached to the nanoparticle rev up the body’s nonspecific, clean-up cells (known as macrophages and phagocytes) in the immune system that engulf and destroy any foreign material. The design of the nanoparticle prompts these cells to appear in abundance and clear up abnormal cancer cells. These clean-up cells then relay information about the cancer cells to highly specialized T-cells in the immune system that help eradicate remaining , while maintaining a memory of these cells to prevent cancer recurrence. It’s the establishment of disease-fighting memory in the cells that makes the nanoparticle similar to a cancer vaccine. Ultimately, the body’s own cells become capable of recognizing and destroying recurrent tumors.

Since the late 1990s, the field of nanomedicine has focused on developing as simple drug delivery vehicles that can propel chemotherapy drugs to tumors. One pitfall is that the body tends to purge the particles before they reach their destination.

“Our study represents a novel concept of designing nanomedicine that can actively interact with the immune cells in our body and modulate their functions to treat human diseases,” says Dr. Kim. “It builds on recent developments in cancer immunotherapy, which have been successful in treating some types of tumors; however, most immunotherapy developed so far does not harness the power of the entire immune system. We’ve developed a new platform that reaches and also recruits abundant clean-up cells for a fully potent immune response.”

Future studies in the lab will explore the ability of the nanoparticle to prevent long-term recurrence of tumors, including metastases at sites distant from the primary tumor. What’s more, the nanoparticle is designed to be modular, meaning it can carry molecules to fight other types of disease. “This approach hopefully will open new doors in the design of new nanomedicine-based immunotherapies,” she says.

Explore further: Nanoparticles target and kill cancer stem cells that drive tumor growth

More information: Multivalent Bi-Specific Nano-Bioconjugate Engager for Targeted Cancer Immunotherapy, Nature Nanotechnology (2017). nature.com/articles/doi:10.1038/nnano.2017.69

 

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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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 nanotechweb.org. “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:

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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

 

 

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