22 Sep 2018
Ever wondered how groups of cells managed to build your tissues and organs while you were just an embryo?
Using state-of-the-art techniques he developed, UC Santa Barbara researcher Otger Campàs and his group have cracked this longstanding mystery, revealing the astonishing inner-workings of how embryos are physically constructed.
Not only does it bring a century-old hypothesis into the modern age, the study and its techniques provide the researchers a foundation to study other questions key to human health, such as how cancers form and spread or how to engineer organs.
“In a nutshell, we discovered a fundamental physical mechanism that cells use to mold embryonic tissues into their functional 3D shapes,” said Campàs, a professor of mechanical engineering in UCSB’s College of Engineering who holds the Duncan & Suzanne Mellichamp Chair in Systems Biology. His group investigates how living systems self organize to build the remarkable structures and shapes found in nature.
Cells coordinate by exchanging biochemical signals, but they also hold to and push on each other to build the body structures we need to live, such as the eyes, lungs and heart. And, as it turns out, sculpting the embryo is not far from glass molding or 3D printing. In their new work,”A fluid-to-solid jamming transition underlies vertebrate body axis elongation,” published in the journal Nature, Campàs and colleagues reveal that cell collectives switch from fluid to solid states in a controlled manner to build the vertebrate embryo, in a way similar to how we mold glass into vases or 3D print our favorite items. Or, if you like, we 3D print ourselves, from the inside.
Most objects begin as fluids. From metallic structures to gelatin desserts, their shape is made by pouring the molten original materials into molds, then cooling them to get the solid objects we use.
A fluid-to-solid jamming transition underlies vertebrate body axis elongation
As in a Chihuly glass sculpture, made by carefully melting portions of glass to slowly reshape it into life, cells in certain regions of the embryo are more active and ‘melt’ the tissue into a fluid state that can be restructured. Once done, cells ‘cool down’ to settle the tissue shape, Campàs explained.
“The transition from fluid to solid tissue states that we observed is known in physics as ‘jamming’,” Campàs said. “Jamming transitions are a very general phenomena that happens when particles in disordered systems, such as foams, emulsions or glasses, are forced together or cooled down.”
This discovery was enabled by techniques previously developed by Campàs and his group to measure the forces between cells inside embryos, and also to exert miniscule forces on the cells as they build tissues and organs. Using zebrafish embryos, favored for their optical transparency but developing much like their human counterparts, the researchers placed tiny droplets of a specially engineered ferromagnetic fluid between the cells of the growing tissue.
The spherical droplets deform as the cells around them push and pull, allowing researchers to see the forces that cells apply on each other. And, by making these droplets magnetic, they also could exert tiny stresses on surrounding cells to see how the tissue would respond.
“We were able to measure physical quantities that couldn’t be measured before, due to the challenge of inserting miniaturized probes in tiny developing embryos,” said postdoctoral fellow Alessandro Mongera, who is the lead author of the paper.
“Zebrafish, like other vertebrates, start off from a largely shapeless bunch of cells and need to transform the body into an elongated shape, with the head at one end and tail at the other,” Campàs said.
The physical reorganization of the cells behind this process had always been something of a mystery. Surprisingly, researchers found that the cell collectives making the tissue were physically like a foam (yes, as in beer froth) that jammed during development to ‘freeze’ the tissue architecture and set its shape.
These observations confirm a remarkable intuition made by Victorian-era Scottish mathematician D’Arcy Thompson 100 years ago in his seminal work “On Growth and Form.”
Read About: D’Arcy Wentworth Thompson
“He was convinced that some of the physical mechanisms that give shapes to inert materials were also at play to shape living organisms. Remarkably, he compared groups of cells to foams and even the shaping of cells and tissues to glassblowing,” Campàs said. A century ago, there were no instruments that could directly test the ideas Thompson proposed, Campàs added, though Thompson’s work continues to be cited to this day.
The new Nature paper also provides a jumping-off point from which the Campàs Group researchers can begin to address other processes of embryonic development and related fields, such as how tumors physically invade surrounding tissues and how to engineer organs with specific 3D shapes.
“One of the hallmarks of cancer is the transition between two different tissue architectures. This transition can in principle be explained as an anomalous switch from a solid-like to a fluid-like tissue state,” Mongera explained. “The present study can help elucidate the mechanisms underlying this switch and highlight some of the potential druggable targets to hinder it.”
Alessandro Mongera, Payam Rowghanian, Hannah J. Gustafson, Elijah Shelton, David A. Kealhofer, Emmet K. Carn, Friedhelm Serwane, Adam A. Lucio, James Giammona & Otger Campàs
IMAGE: SAMPLES OF NANOHYBRIDS OBTAINED IN NUST MISIS “INORGANIC NANOMATERIALS ” LABORATORY view more CREDIT: ©NUST MISIS
NATIONAL UNIVERSITY OF SCIENCE AND TECHNOLOGY MISIS
Scientists from the National University of Science and Technology MISIS (NUST MISIS), the State Research Center for Applied Microbiology and Biotechnology and the Queensland University (Brisbane, Australia) have created BN/Ag hybrid nanomaterials and have proved their effectiveness as catalysts and antibacterial agents as well as for treating oncological diseases. The results are published in the Beilstein Journal of Nanotechnology.
The interest in the nanomaterials is related to the fact that when a particle is decreased to nanometers (1 nanometer = 10-9 meter) its electronic structure changes, and the material acquires new physical and chemical properties. For example, a magneto can lose its magnetism completely when decreased to ten nanometers.
Today, scientists are beginning to study combinations of various materials at the nanolevel instead of as separate nanoparticles (fullerenes and nanotubes). They have come up with a concept of hybrid nanomaterials, which combine the properties of individual components.
Hybridization makes it possible to combine properties that were incompatible before, for example, to create a material that can be a solid and a plastic at the same time. In addition, the scientists noted that combinations of nanomaterials often showed better or even new properties. Today the nanohybrid area is only beginning to develop.
MISIS scientists are studying the properties of BN hybrid nanomaterials. BN (boron nitride) was chosen as the base for new hybrid nanoparticles because it is chemically inert and biocompatible and has low relative density.
BN hybrid nanomaterials are used as prospective key components of the next generation advanced biomaterials, catalysts and sensors. These hybrids have advantageous combination of properties, such as biocompatibility, high tensile strength and thermal conductivity as well as superb chemical stability and electrical insulation. This explains their rich functionality for developing new biomedicines, reinforcement of ultralight metals and polymers and production of transparent superhydrophobic films and quantum devices.
“We have studied BN/Ag nanohybrid properties and have discovered a high potential for new applications. We were especially interested in an application for treating oncological diseases as well as their activity as catalysts and antibacterial agents,” said Andrei Matveyev, a research author, Senior Research Fellow at the MISIS Inorganic Materials Laboratory.
According to Matveyev, these nanohybrids can be used in cancer therapy as a base for drug delivery medicines. The nanohybrids with the drug become containers to be delivered inside cancer cells. Nanohybrids are chemically modified by attaching folic acid (vitamin ?9) to its surface through an Ag nanoparticle.
The modified nanohybrids with folic acid are mostly accumulated in cancer cells, because they have an increased number of folic acid receptors, so the concentration grows thousand times higher than in healthy cells. In addition, the acidity in a cancer cell is also higher than in the intercellular space, which leads to the drug’s release from its nanocontainer.
“This is why the drug is mostly released inside cancer cells, which decreases the general concentration of the drug in the organism, thus preventing toxicity,” Matveyev notes.
The authors believe that nanohybrids modified for drug delivery can be applied to uses in isotope and neuron capture cancer therapy.
The synthesized particles have also demonstrated high antibacterial activity against test bacteria: Escherichia coli live in dirty water, so water disinfection by nanohybrids may prove useful in emergencies or during war time.
Nanohybrids based on BN/Ag nanoparticles can also be used as an ultraviolet photoactive material.
29 Jan 2017
PEG-PDI, which incorporates a compound long used as a red dye, changes to greenish-blue with the addition of potassium superoxide as it converts the superoxide to dioxygen. Adding more further quenches the reactive oxygen species superoxide, turning the solution purple. Adding hydrogen peroxide in the last step clarifies the liquid, showing that a build-up of excess hydrogen peroxide can deactivate the structure. PEG-PDI, created at Rice University, shows potential as a biological antioxidant. Credit: Tour Group/Rice University
Treated particles of graphene derived from carbon nanotubes have demonstrated remarkable potential as life-saving antioxidants, but as small as they are, something even smaller had to be created to figure out why they work so well.
Researchers at Rice University, the McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth) and Baylor College of Medicine created single-molecule compounds that also quench damaging reactive oxygen species (ROS) but are far easier to analyze using standard scientific tools. The molecules may become the basis for new antioxidant therapies in their own right.
The research appears in the American Chemical Society journal ACS Nano.
The original compounds are hydrophilic carbon clusters functionalized with polyethylene glycol, known as PEG-HCCs and created by Rice and Baylor scientists five years ago. The particles help neutralize ROS molecules overexpressed by the body’s cells in response to an injury before they damage cells or cause mutations.
PEG-HCCs show promise for treating cancer, rebooting blood flow in the brain after traumatic injury and controlling chronic diseases.
The new particles, called PEG-PDI, consist of polyethylene glycol and perylene diimide, a compound used as a dye, the color in red car paint and in solar cells for its light-absorbing properties. Their ability to accept electrons from other molecules makes them functionally similar to PEG-HCCs.
They’re close enough to serve as an analog for experiments, according to Rice chemist James Tour, who led the study with University of Texas biochemist Ah-Lim Tsai.
The researchers wrote that the molecule is not only the first example of a small molecular analogue of PEG-HCCs, but also represents the first successful isolation of a PDI radical anion as a single crystal, which allows its structure to be captured with X-ray crystallography.
“This allows us to see the structure of these active particles,” Tour said. “We can get a view of every atom and the distances between them, and get a lot of information about how these molecules quench destructive oxidants in biological tissue.
“Lots of people get crystal structures for stable compounds, but this is a transient intermediate during a catalytic reaction,” he said. “To be able to crystallize a reactive intermediate like that is amazing.”
Antioxidant compounds mimic effective graphene agents, show potential for therapies
The crystal structure of PEG-PDI is achieved using cobaltocene as a reducing agent and omitting solvents and hydrogen atoms for clarity. Carbon atoms are gray, nitrogens are blue, oxygens red and cobalts purple. The molecules created by scientists at Rice University, the McGovern Medical School at the University of Texas Health Science Center at Houston and Baylor College of Medicine are efficient antioxidants and help scientists understand how larger nanoparticles quench damaging reactive oxygen species in the body. Credit: Tour Group
PEG-HCCs are about 3 nanometers wide and 30 to 40 nanometers long. By comparison, much simpler PEG-PDI molecules are less than a nanometer in width and length.
PEG-PDI molecules are true mimics of superoxide dismutase enzymes, protective antioxidants that break down toxic superoxide radicals into harmless molecular oxygen and hydrogen peroxide. The molecules pull electrons from unstable ROS and catalyze their transformation into less-reactive species.
Testing the PEG-PDI molecules can be as simple as putting them in a solution that contains reactive oxygen species molecules like potassium superoxide and watching the solution change color. Further characterization with electron paramagnetic resonance spectroscopy was more complicated, but the fact that it’s even possible makes them powerful tools in resolving mechanistic details, the researchers said.
Tour said adding polyethylene glycol makes the molecules soluble and also increases the amount of time they remain in the bloodstream. “Without PEG, they just go right out of the system through the kidneys,” he said.
When the PEG groups are added, the molecules circulate longer and continue to catalyze reactions.
He said PEG-PDI is just as effective as PEG-HCCs if measured by weight. “Because they have so much more surface area, PEG-HCC particles probably catalyze more parallel reactions per particle,” Tour said. “But if you compare them with PEG-PDI by weight, they are quite similar in total catalytic activity.”
Understanding the structure of PEG-PDI should allow researchers to customize the molecule for applications. “We should have a tremendous ability to modify the molecule’s structure,” he said. “We can add anything we want, exactly where we want, for specific therapies.”
The researchers said PEG-PDI may also be efficient metal- and protein-free catalysts for oxygen reduction reactions used in industry and essential to fuel cells. They are intrinsically more stable than enzymes and can function in much a wider pH range, Tsai said.
Co-author Thomas Kent, a professor of neurology at Baylor who has worked on the project from the start, noted small molecules have a better chance to get on the fast track to approval for therapy by the Food and Drug Administration than nanotube-based agents.
“A small molecule that is not derived from larger nanomaterial may have a better chance of approval to use in humans, assuming it is safe and effective,” he said.
Tour said PEG-PDI serves as a precise model for other graphene derivatives like graphene oxide and permits a more detailed study of graphene-based nanomaterials.
“Making nanomaterials smaller, from well-defined molecules, permits 150 years of synthetic chemistry methods to address the mechanistic questions within nanotechnology,” he said.
More information: Almaz S. Jalilov et al. Perylene Diimide as a Precise Graphene-Like Superoxide Dismutase Mimetic, ACS Nano (2017). DOI: 10.1021/acsnano.6b08211
Provided by: Rice University
The most difficult to treat and deadly of cancers may have met their match. Nanotechnology, at the forefront of cancer research, now has a new application, Medical News Today reports.
Mauro Ferrari, president and CEO of the Houston Methodist Research Institute in Texas, has found a way to inject metastatic tumors with nanoparticles, releasing cancer-fighting drugs directly into the tumors themselves.
Existing cancer drugs are limited in the fight against tumors in areas like the lungs and liver because of the body’s protective biological barriers. Basically, the cancer fighting drugs fail to reach their intended targets and wind up damaging healthy tissues.
“This may sound like science fiction, like we’ve penetrated and destroyed the Death Star, but what we discovered is transformational,” Ferrari tells Medical News Today. “I would never want to over-promise to the thousands of cancer patients looking for a cure, but the data is astounding.
“We’re talking about changing the landscape of curing metastatic disease, so it’s no longer a death sentence.”
“The Rest of the Story”
A few decades ago, the idea of developing any type of solution in the nanoscale was nothing more than a dream.
The word “nanotechnology” was only seen in print for the first time as recently as 1986.
Manipulating, creating and utilizing objects that are 100,000 times smaller than the width of a hair is science fiction turned science fact.
Today, nano-sized particles help golf balls fly straighter, make the surfaces of bowling balls more durable and give exterior varnishes a longer life.
Industry and manufacturing have taken nanoparticles to their bosom, but their abilities are also being tested for possible uses in the medical sphere; for instance, bandages infused with silver nanoparticles have been designed to help wounds heal faster.
Among the list of potential medical uses for nanotechnology are targeted drug delivery systems in the fight against diseases, including cancer.
Current cancer drug delivery
Metastases of cancers in the lung and liver are the primary causes of cancer deaths. In many cases, existing cancer drugs are of limited powerbecause of the body’s protective biological barriers. The chemicals fail to reach their intended targets in high enough concentrations and are distributed into healthy tissues, causing serious side effects.
Mauro Ferrari, president and CEO of the Houston Methodist Research Institute in Texas, has been working with nanomedicine for 20 years, and his latest research provides some of the most impressive results to date.
Ferrari and his team created a mechanism by which nanoparticles could move through these biological defenses and, once inside the tumor, release the toxic chemicals directly into the heart of the problem.
Injectable nanoparticle generator
The team used an injectable nanoparticle generator (iNPG), composed of the active drug – doxorubicin – packaged as thin strands of polymer within a nanoporous silicon material.
Once the iNPG enters the tumor, the silicon outer coating naturally degrades, releasing the polymer strands. The strands curl up into nano-scale balls and enter the cancer cells themselves. As the balls move freely around the cell and approach the nucleus, the pH becomes more acidic. This drop in pH triggers the strands to release the doxorubicin, which then kills the cell.
The iNPGs were trialed on mice with triple negative breast cancer that had metastasized into the tissues of the lungs. Triple negative cancers account for roughly 1 in 10 breast cancers. They are particularly difficult to treat and do not respond to hormonal therapy.
‘What we discovered is transformational’
Although the prognosis for triple negative cancer is poor, Ferrari and his team found that 50% of the mice treated by the iNPGs showed no traces of metastatic disease after an 8-month period, which is considered the equivalent of 24 human years.
“This may sound like science fiction, like we’ve penetrated and destroyed the Death Star, but what we discovered is transformational. We invented a method that actually makes the nanoparticles inside the cancer and releases the drug particles at the site of the cellular nucleus.”
The investigators are incredibly pleased with these results and hope they will shepherd in a new dawn of medical intervention. Any headway into the treatment of such an intractable disease is entirely welcome.
The authors say that “with this injectable nanoparticle generator, we were able to do what standard chemotherapy drugs, vaccines, radiation and other nanoparticles have all failed to do.” The Houston Methodist Research Institute are hoping to fast-track the research and secure FDA (US Food and Drug Administration) approval as soon as possible. They plan to trial the drugs in humans in 2017.
Although keen to keep the findings in perspective and not raise hopes unnecessarily, Ferrari has a difficult time keeping his positivity under wraps:
“I would never want to over-promise to the thousands of cancer patients looking for a cure, but the data is astounding. We’re talking about changing the landscape of curing metastatic disease, so it’s no longer a death sentence.”
Ferrari’s excitement is both palpable and understandable. Even if future research using human participants returns with survival rates that are only a fraction of those found in the present study, the results will be deemed a rousing success.
Medical News Today recently covered news of another “groundbreaking” cancer discovery that holds promise for personalizing cancer therapy.
Posted: Mar 01, 2016
Researchers involved in a national effort to develop cancer treatments that harness nanotechnology are recommending pivotal changes in the field because experiments with laboratory animals and efforts based on current assumptions about drug delivery have largely failed to translate into successful clinical results.
The assessment was advanced in a perspective piece that (“Targeting the Tumor Microenvironment”; pdf) appeared in the National Cancer Institute’s Cancer Nanotechnology Plan 2015, a 10-year roadmap concerning the use of nanotechnology to attack cancer.
The complex microenvironment of tumors is presenting a challenge in developing effective anticancer treatments
The complex microenvironment of tumors is presenting a challenge in developing effective anticancer treatments that attempt to harness nanotechnology. Researchers are recommending pivotal changes in the field of cancer nanotechnology because experiments with laboratory animals and efforts based on current assumptions about drug delivery have largely failed to translate into successful clinical results. (Image: Bumsoo Han, Kinam Park, Murray Korc) (click on image to enlarge)
Researchers are trying to perfect “targeted delivery” methods using various agents, including an assortment of tiny nanometer-size structures, to selectively attack tumor tissue. However, the current direction of research has brought only limited progress, according to the authors of the article.
“The bottom line is that so far there are only a few successful nanoparticle formulations approved and clinically used, so we need to start thinking out of the box,” said Bumsoo Han, a Purdue University associate professor of mechanical and biomedical engineering.
One approach pursued by researchers has been to design nanoparticles small enough to pass through pores in blood vessels surrounding tumors but too large to pass though the pores of vessels in healthy tissue. The endothelial cells that make up healthy blood vessels are well organized with tight junctions between them. However, the endothelial cells in blood vessels around tumors are irregular and misshapen, with loose gaps between the cells.
“We should realize that having a specific nanosize or functionality alone is not enough to guarantee good drug delivery to target tumors,” said Kinam Park, a professor of pharmaceutics and Purdue’s Showalter Distinguished Professor of Biomedical Engineering. “The tumor microenvironment is just too complex to overcome using this strategy alone.”
The two authored the article with Murray Korc, the Myles Brand Professor of Cancer Research at the Indiana University School of Medicine.
The authors pointed out that research with laboratory mice has rarely translated into successful clinical results in humans, suggesting that a more effective approach might be to concentrate on research using in-vitro experiments that mimic human physiology. For example, one new system under development, called a tumor-microenvironment-on-chip (T-MOC) device, could allow researchers to study the complex environment surrounding tumors and the barriers that prevent the targeted delivery of therapeutic agents.
The approach could help drug makers solve a daunting obstacle: even if drugs are delivered to areas near the target tumor cells, the treatment still is hindered by the complex microenvironment of tumors.
“We used to think that if we just killed the tumor cell it would cure the cancer, but now we know it’s not just the cancer cells alone that we have to deal with,” Korc said. “There are a lot of different cells and blood vessel structure, making for a complex environment that supports the cancer cells.”
An “extracellular matrix” near tumors includes dense collagen bundles and a variety of enzymes, growth factors and cells. For example, surrounding pancreatic tumors is a “stromal compartment” containing a mixture of cells called stromal cells, activated cancer-associated fibroblasts and inflammatory immune cells.
“Particularly for pancreatic cancer, the stromal tissue is much bigger than the tumor itself,” Korc said.
In addition, a compound called hyaluronic acid in this stromal layer increases the toughness of tumor microenvironment tissue, making it difficult for nanoparticles and drugs to penetrate.
“It’s dense, like scar tissue, so it’s more difficult for drugs coming out of the blood vessel to diffuse through this tissue,” Han said.
Another challenge is to develop water-soluble drugs to effectively deliver medicines.
“The cancer drugs need to be aqueous because the body resorbs them better, but a lot of the current chemotherapy drugs have low solubility and usually need different types of solvents to increase their solubility,” Park said.
The T-MOC approach offers some hope of learning how to design more effective cancer treatments.
“Recent advances in tissue engineering and microfluidic technologies present an opportunity to realize in-vitro platforms as alternatives to animal testing,” Park said. “Tumor cells can be grown in 3D matrices with other relevant stromal cells to more closely mirror the complexity of solid tumors in patients. The current ability of forming 3D-perfused tumor tissue needs to be advanced further to create an accurate tumor microenvironment.”
Such a major shift in research focus could play a role in developing personalized medicine, or precision medicine, tailored to a particular type of cancer and specific patients. More effective treatment might require various “priming agents” in combination with several drugs to be administered simultaneously or sequentially.
“This kind of research currently involves a very large number of experiments, and it makes animal testing expensive and time consuming,” Park said. “Moreover, small animal data have not been good predictors of clinical outcome. Thus, it is essential to develop in-vitro test methods that can represent the microenvironment of human tumors.”
Source: By Emil Venere, Purdue University
Chemotherapy isn’t supposed to make your hair fall out—it’s supposed to kill cancer cells. A new molecular delivery system created at U of T could help ensure that chemotherapy drugs get to their target while minimizing collateral damage.
Many cancer drugs target fast-growing cells. Injected into a patient, they swirl around in the bloodstream acting on fast-growing cells wherever they find them. That includes tumours, but unfortunately also hair follicles, the lining of your digestive system, and your skin.
Professor Warren Chan (IBBME, ChemE, MSE) has spent the last decade figuring out how to deliver chemotherapy drugs into tumours—and nowhere else. Now his lab has designed a set of nanoparticles attached to strands of DNA that can change shape to gain access to diseased tissue.
“Your body is basically a series of compartments,” says Chan. “Think of it as a giant house with rooms inside. We’re trying to figure out how to get something that’s outside, into one specific room. One has to develop a map and a system that can move through the house where each path to the final room may have different restrictions such as height and width.”
One thing we know about cancer: no two tumours are identical. Early-stage breast cancer, for example, may react differently to a given treatment than pancreatic cancer, or even breast cancer at a more advanced stage. Which particles can get inside which tumours depends on multiple factors such as the particle’s size, shape and surface chemistry.
Chan and his research group have studied how these factors dictate the delivery of small molecules and nanotechnologies to tumours, and have now designed a targeted molecular delivery system that uses modular nanoparticles whose shape, size and chemistry can be altered by the presence of specific DNA sequences.
“We’re making shape-changing nanoparticles,” says Chan. “They’re a series of building blocks, kind of like a LEGO set.” The component pieces can be built into many shapes, with binding sites exposed or hidden. They are designed to respond to biological molecules by changing shape, like a key fitting into a lock.
These shape-shifters are made of minuscule chunks of metal with strands of DNA attached to them. Chan envisions that the nanoparticles will float around harmlessly in the blood stream, until a DNA strand binds to a sequence of DNA known to be a marker for cancer. When this happens, the particle changes shape, then carries out its function: it can target the cancer cells, expose a drug molecule to the cancerous cell, tag the cancerous cells with a signal molecule, or whatever task Chan’s team has designed the nanoparticle to carry out.
Their work was published this week in two key studies in the Proceedings of the National Academy of Sciences and the leading journal Science.
“We were inspired by the ability of proteins to alter their conformation—they somehow figure out how to alleviate all these delivery issues inside the body,” says Chan. “Using this idea, we thought, ‘Can we engineer a nanoparticle to function like a protein, but one that can be programmed outside the body with medical capabilities?'”
Applying nanotechnology and materials science to medicine, and particularly to targeted drug delivery, is still a relatively new concept, but one Chan sees as full of promise. The real problem is how to deliver enough of the nanoparticles directly to the cancer to produce an effective treatment.
“Here’s how we look at these problems: it’s like you’re going to Vancouver from Toronto, but no one tells you how to get there, no one gives you a map, or a plane ticket, or a car—that’s where we are in this field,” he says. “The idea of targeting drugs to tumours is like figuring out how to go to Vancouver. It’s a simple concept, but to get there isn’t simple if not enough information is provided.”
“We’ve only scratched the surface of how nanotechnology ‘delivery’ works in the body, so now we’re continuing to explore different details of why and how tumours and other organs allow or block certain things from getting in,” adds Chan.
He and his group plan to apply the delivery system they’ve designed toward personalized nanomedicine—further tailoring their particles to deliver drugs to your precise type oftumour, and nowhere else.
Explore further: Cylindrical nanoparticles more deadly to breast cancer
More information: Edward A. Sykes et al. Tailoring nanoparticle designs to target cancer based on tumor pathophysiology, Proceedings of the National Academy of Sciences(2016). DOI: 10.1073/pnas.1521265113
Some drug regimens, such as those designed to eliminate tumors, are notorious for nasty side effects. Unwanted symptoms are often the result of medicine going where it’s not needed and harming healthy cells. To minimize this risk, researchers in Quebec have developed nanoparticles that only release a drug when exposed to near-infrared light, which doctors could beam onto a specific site. Their report appears in the Journal of the American Chemical Society.
For years, scientists have been striving to develop localized treatments to reduce side effects of therapeutic drugs. They have designed drug-delivery systems that respond to light, temperature, ultrasound and pH changes. One promising approach involved drug-carrying materials that are sensitive to ultraviolet (UV) light. Shining a beam in this part of the light spectrum causes the materials to release their therapeutic cargo at a designated location. But UV light has major limitations. It can’t penetrate body tissues, and it is carcinogenic. Near-infrared (NIR) light can go through 1 to 2 centimeters of tissue and would be a safer alternative, but photosensitive drug-carriers don’t react to it. McGill University engineering professor Marta Cerruti and colleagues sought a way to bring the two kinds of light together in one possible solution.
The researchers started with nanoparticles that convert NIR light into UV light and coated them in a UV-sensitive hydrogel shell infused with a fluorescent protein, a stand-in for drug molecules. When exposed to NIR light, the nanoparticles instantaneously converted it to UV, which induced the shell to release the protein payload. The researchers note that their on-demand delivery system could not only supply drug molecules but also agents for imaging and diagnostics.
- Ghulam Jalani, Rafik Naccache, Derek H. Rosenzweig, Lisbet Haglund, Fiorenzo Vetrone, Marta Cerruti.Photocleavable Hydrogel-Coated Upconverting Nanoparticles: A Multifunctional Theranostic Platform for NIR Imaging and On-Demand Macromolecular Delivery. Journal of the American Chemical Society, 2016; DOI: 10.1021/jacs.5b12357
11 Jan 2016
The world’s largest DNA sequencing company says it will form a new company to develop blood tests that cost $1,000 or less and can detect many types of cancer before symptoms arise.
Illumina, based in San Diego, said its blood tests should reach the market by 2019, and would be offered through doctors’ offices or possibly a network of testing centers.
The spin-off’s name, Grail, reflects surging expectations around new types of DNA tests that might do more to defeat cancer than the more than $90 billion spent each year by doctors and hospitals on cancer drugs. Illumina CEO Jay Flatley says he hopes the tests could be a “turning point in the war on cancer.”
The startup will be based in San Francisco and has raised more than $100 million from Illumina as well as Bill Gates, Jeff Bezos’s venture fund, Bezos Expeditions, and Arch Venture Partners. Illumina will retain majority control.
The testing concept being pursued by Illumina, sometimes called a “liquid biopsy,” is to use high-speed DNA sequencing machines to scour a person’s blood for fragments of DNA released by cancer cells. If DNA with cancer-causing mutations is present, it often indicates a tumor is already forming, even if it’s too small to cause symptoms or be seen on an imaging machine.
Illumina didn’t invent the idea for the tests, which were first developed by academic centers including at Johns Hopkins University (see “Spotting Cancer in a Vial of Blood”) and in Hong Kong (see “Liquid Biopsy”). But Flatley says only recently has gene-sequencing become inexpensive enough to try to make the cancer screening tests affordable.
Illumina, which is based in San Diego, has established spin-offs in Silicon Valley to address consumer markets for DNA data.
A DNA test able to pick up many kinds of cancer could be revolutionary because tumors caught early can often be cured with surgery or radiation. Since the 1970s, the largest declines in cancer deaths rates are due to either behavioral changes, like declining tobacco use, or because of effective screening tests, principally colonoscopies and pap smear. New drugs have helped, too, though their impact on survival has generally been modest.
Expectations that cancer blood tests will quickly turn into a multibillion-dollar industry has attracted growing interest from investors. For instance, last week, a startup called Guardant, run by former Illumina executives, also said it had raised $100 million.
Guardant’s test isn’t an early detection test, but is instead used to measure tumor DNA in patients already battling cancer and can be prescribed in place of an invasive tissue biopsy (see “The Great Cancer Test Experiment”). Other companies bidding for a share of the testing market include Personal Genome Diagnostics, a spin-off of Johns Hopkins University, as well as Trovagene, Boreal Genomics, and Natera.
In the U.S., the only early-detection liquid biopsy test on the market is from Pathway Genomics, and it costs $699. But since it remains unclear how well these types of tests work, that company received a warning letter from the U.S. Food and Drug Administration questioning its marketing claims (see “Why You Shouldn’t Bother with a $699 Cancer Test”).
Any developer of a presymptomatic screening test for cancer faces daunting obstacles. How often will the test find cancer, and how often will it give a wrong result? What’s more, even tests that do discover cancer early can turn into medical disasters if patients end up getting aggressive and costly treatment for cancers that won’t kill them.
“The hardest part is not only demonstrating the ability to detect cancer early, but being able to say this knowledge is in fact meaningful in terms of patient outcomes,” says J. Leonard Lichtenfeld, deputy chief medical officer of the American Cancer Society. “I can’t tell you how many times we’ve said, ‘Oh, all we have to do is find every cancer early and we would solve the problem.’”
Flatley agrees that most screening tests have failed to help patients and that many companies developing them had suffered reversals as a result. “If you look at this business, it’s littered with failures. With a few exceptions, screening tests have been invariably horrible,” he says. “It’s a big challenge.”
To prove early detection is possible, Flatley says, Grail will spend millions on organizing clinical trials involving as many as 30,000 people. It will test all of them and then see if the tests are able to catch cancer earlier than established methods.
Flatley estimates that the amount of DNA sequencing required for the studies would be the equivalent of decoding the genomes of about 400,000 people at high quality. That makes the project about three times as large as Genomics England, a national effort to study cancer and disease in the U.K.
Flatley says he believes that, right now, Illumina is the only company currently able to implement sequencing technology at a cost that’s low enough to carry out such studies and bring an inexpensive test to market. “In this case, we didn’t think the market could do it fast enough, unless we destroyed our [business] by giving away sequencing,” said Flatley. “We don’t think anyone else can do it at scale. And there are millions of lives at stake.”
Illumina has a price advantage because it makes and sells more than about $2 billion worth of DNA sequencing instruments, chemicals, and test kits annually to university scientists and other labs. But recently it has also sought to jump directly into what it thinks will be key applications for that DNA data. In 2013, it paid almost half a billion dollars to acquire prenatal testing company Verinta (see “Prenatal DNA Sequencing”), and last August said it would partner with investors to create a vast DNA “app store” aimed at consumers. (see “Inside Illumina’s Plans to Lure Consumers with an App Store for Genomes”).
Flatley says Grail’s objective is a “pan-cancer” test able to detect most types of cancer from a single blood draw, but he says early detection of lung and breast cancer could be the first tests to reach the market. Flatley himself says he took an early version of the test, which came back without any problems.
“I was clear,” says Flatley. “But if I have cancer I want to know about it.”
Jay Flatley, the CEO of Illumina, with a DNA sequencing machine. Illumina sequencers account for most of the DNA data generated globally.
A schematic of targeted drug delivery towards breast cancer is shown. Nanodiamonds are encapsulated within liposomes that are functionalized with targeting antibodies. Credit: Dr. Laura Moore (Prof. Dean Ho Group)
A trio of researchers, Dean Ho, with UCLA in the U.S., Chung-Huei Katherine Wang, with BRIM Biotechnology Inc., in Taipei and Edward Kai-Hua Chow with the National University of Singapore, has published a review in Science Advances, of the ways nanodiamonds are being used in cancer research and offer insights into the ways they may be used in the future.
As the research trio note, significant progress has been made over the past several decades in the development of nano-materials for use in treating cancer and other ailments. The central idea is to use very tiny particles to carry tumor fighting drugs to tumors (they are not as easily repelled as the larger varieties) thereby healing the patient. The list includes metallic particles, nanotubes, polymers and even lipids. More recently, scientists have been looking into using nanodiamonds as more is learned about the electrostatic capabilities of their facet surfaces when they carry chemicals in a biological system, the ways their inert core can be useful in certain applications and as a means to capitalize on their tunable surfaces.
The authors note that nanodiamonds used in medical applications fall into two main categories, detonation nanodiamonds (DNDs) and fluorescent nanodiamonds (FNDs) as part of highlighting the major ways that nanodiamonds are currently being used:
Imaging—both DNDs and FNDs, the researchers note are increasingly being eyed as a way to improve magnetic resonance imaging and more recently FNDs are also being seen as a way to track stem cells to learn more about their regenerative potential.
Drug Delivery—a lot of research is currently going on to learn more about which types of drugs adhere well to nanodiamond facets, most specifically those used in chemotherapy applications.
Biodistribution and Toxicity—similarly, a lot of research is being conducted to learn more about the ways nanodiamonds can be placed into a living organism (injection, consumption, though the skin, etc.) and whether there is a danger of toxicity.
The researchers note that another area of study involves using nanodiamonds as part of drug testing—if medications can be carried to specific sites, they note, there might be less side-effects.
Another benefit of using nanodiamonds, they note, is that despite being associated with precious gems, nanodiamonds would be quite cheap to procure and use because they can be obtained from mining waste.
Explore further: Tiny diamonds to boost treatment of chemoresistant leukemia
More information: Nanodiamonds: The intersection of nanotechnology, drug development, and personalized medicine, Science Advances 21 Aug 2015: Vol. 1, no. 7, e1500439. DOI: 10.1126/sciadv.1500439
The implementation of nanomedicine in cellular, preclinical, and clinical studies has led to exciting advances ranging from fundamental to translational, particularly in the field of cancer. Many of the current barriers in cancer treatment are being successfully addressed using nanotechnology-modified compounds. These barriers include drug resistance leading to suboptimal intratumoral retention, poor circulation times resulting in decreased efficacy, and off-target toxicity, among others.
The first clinical nanomedicine advances to overcome these issues were based on monotherapy, where small-molecule and nucleic acid delivery demonstrated substantial improvements over unmodified drug administration. Recent preclinical studies have shown that combination nanotherapies, composed of either multiple classes of nanomaterials or a single nanoplatform functionalized with several therapeutic agents, can image and treat tumors with improved efficacy over single-compound delivery. Among the many promising nanomaterials that are being developed, nanodiamonds have received increasing attention because of the unique chemical-mechanical properties on their faceted surfaces.
More recently, nanodiamond-based drug delivery has been included in the rational and systematic design of optimal therapeutic combinations using an implicitly de-risked drug development platform technology, termed Phenotypic Personalized Medicine–Drug Development (PPM-DD). The application of PPM-DD to rapidly identify globally optimized drug combinations successfully addressed a pervasive challenge confronting all aspects of drug development, both nano and non-nano. This review will examine various nanomaterials and the use of PPM-DD to optimize the efficacy and safety of current and future cancer treatment. How this platform can accelerate combinatorial nanomedicine and the broader pharmaceutical industry toward unprecedented clinical impact will also be discussed.
12 Jun 2015
Cornell Univ. engineers have created a functional, synthetic immune organ that produces antibodies and can be controlled in the lab, completely separate from a living organism. The engineered organ has implications for everything from rapid production of immune therapies to new frontiers in cancer or infectious disease research.
The immune organoid was created in the lab of Ankur Singh, assistant professor of mechanical and aerospace engineering, who applies engineering principles to the study and manipulation of the human immune system. The work was published online in Biomaterials and will appear later in print.
The synthetic organ is bio-inspired by secondary immune organs like the lymph node or spleen. It is made from gelatin-based biomaterials reinforced with nanoparticles and seeded with cells, and it mimics the anatomical microenvironment of lymphoid tissue. Like a real organ, the organoid converts B cells—which make antibodies that respond to infectious invaders—into germinal centers, which are clusters of B cells that activate, mature and mutate their antibody genes when the body is under attack. Germinal centers are a sign of infection and are not present in healthy immune organs.
The engineers have demonstrated how they can control this immune response in the organ and tune how quickly the B cells proliferate, get activated and change their antibody types. According to their paper, their 3-D organ outperforms existing 2-D cultures and can produce activated B cells up to 100 times faster.
The immune organ, made of a hydrogel, is a soft, nanocomposite biomaterial. The engineers reinforced the material with silicate nanoparticles to keep the structure from melting at the physiologically relevant temperature of 98.6 degrees.
When exposed to a foreign agent, such as an immunogenic protein, B cells in lymphoid organs undergo germinal center reactions. The image on the left is an immunized mouse spleen with activated B cells (brown) that produce antibodies. At right, top: a scanning electron micrograph of porous synthetic immune organs that enable rapid proliferation and activation of B cells into antibody-producing cells. At right, bottom: primary B cell viability and distribution is visible 24 hrs following encapsulation procedure. Images: Singh lab
The organ could lead to increased understanding of B cell functions, an area of study that typically relies on animal models to observe how the cells develop and mature.
What’s more, Singh said, the organ could be used to study specific infections and how the body produces antibodies to fight those infections—from Ebola to HIV.
“You can use our system to force the production of immunotherapeutics at much faster rates,” he said. Such a system also could be used to test toxic chemicals and environmental factors that contribute to infections or organ malfunctions.
The process of B cells becoming germinal centers is not well understood, and in fact, when the body makes mistakes in the genetic rearrangement related to this process, blood cancer can result.
“In the long run, we anticipate that the ability to drive immune reaction ex vivo at controllable rates grants us the ability to reproduce immunological events with tunable parameters for better mechanistic understanding of B cell development and generation of B cell tumors, as well as screening and translation of new classes of drugs,” Singh said.
Source: Cornell Univ.