Researchers in Sweden have succeeded in taking the next step toward using man-made nanoscale compounds in the fight against cancer. A recent proof-of-concept study showed that dendrimers, which were first introduced in the 1980s, may be used to introduce compounds that essentially trick cancer cells into performing self-destructive tasks.
Dendrimers, or cascade molecules, are organically synthesized large molecules that match nature’s peptides and proteins with respect to size and structure. Researchers from KTH Royal Institute of Technology took advantage of these qualities – and cancer cells’ appetite for adsorbing large molecules – by loading the material with an organic sulfur compound (OSC) which is also a key ingredient in amino acids, peptides and proteins.
Applying these to cultured human cancer cells sets in motion a process that distracts cancer cells from their normal task of multiplying, and instead go to work on picking apart disulfide bonds in the dendrimers, says Michael Malkoch, a professor of fiber and polymer technology at KTH.
Malkoch says that this activity releases an increased concentration of reactive oxygen radicals (ROS), which eventually induces cell death. Unlike treatments like chemotherapy, the effect is selective toward cancer cells, leaving the healthy ones unaffected since healthy cells have a higher tolerance for ROS.
The nanomaterial is finally broken down by the body, he says.
The article was published in Journal of the American Chemical Society, and is co-authored by Malkoch, KTH doctoral student Oliver Andrén and Aristi P. Fernandes of Karolinska Institutet.
Their results show that the platform is worth continued research with clinical tests in which dendrimers are preprogrammed with large and specific numbers of organic disulfide bonds, Malkoch says.
“We’ve just scratched the surface for what you can do with dendrimers. We have previously tested using similar materials as a part of a leg patch – a type of adhesive that in some cases enables treatment of bone fractures without screws and plates,” he says. “You can imagine future applications where the material is used to coat implants around cancer tumors and thereby enable therapy treatment at a localized level.”
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 SPIOs
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.”
MIT is constructing, at the heart of the campus, a new 200,000-square-foot center for nanoscience and nanotechnology. This advanced facility will be a place for tinkering with atoms, one by one—and for constructing, from these fantastically small building blocks, the innovations of the future. Watch the MIT Video then Read More …
“Science is not only the disciple of Reason, but also one of Romance and Passion ~ Stephen B. Hawking
Nanotechnology is so small it’s measured in billionths of meters, and it is revolutionizing every aspect of our lives …
The past 70 years have seen the way we live and work transformed by two tiny inventions. The electronic transistor and the microchip are what make all modern electronics possible, and since their development in the 1940s they have been getting smaller. Today, one chip can contain as many as 5 billion transistors. If cars had followed the same development pathway, we would now be able to drive them at 300,000 mph and they would cost just $6.00 (US) each.
But to keep this progress going we need to be able to create circuits on the extremely small, nanometer scale. A nanometer (nm) is one billionth of a meter and so this kind of engineering involves manipulating individual atoms. We can do this, for example, by firing a beam of electrons at a material, or by vaporizing it and depositing the resulting gaseous atoms layer by layer onto a base.
Stanford researchers accidentally discovered that iron nanoparticles invented for anemia treatment have another use: triggering the immune system’s ability to destroy tumor cells.
Ironnanoparticles can activate the immune system to attack cancer cells, according to a study led by researchers at the Stanford University School of Medicine.
The nanoparticles, which are commercially available as the injectable iron supplement ferumoxytol, are approved by the Food and Drug Administration to treat iron deficiency anemia.
The mouse study found that ferumoxytol prompts immune cells called tumor-associated macrophages to destroy cancer cells, suggesting that the nanoparticles could complement existing cancer treatments. The discovery, described in a paper published online Sept. 26 in Nature Nanotechnology, was made by accident while testing whether the nanoparticles could serve as Trojan horses by sneaking chemotherapy into tumors in mice.
“It was really surprising to us that the nanoparticles activated macrophages so that they started to attack cancer cells in mice,” said Heike Daldrup-Link, MD, who is the study’s senior author and an associate professor of radiology at the School of Medicine. “We think this concept should hold in human patients, too.”
Daldrup-Link’s team conducted an experiment that used three groups of mice: an experimental group that got nanoparticles loaded with chemo, a control group that got nanoparticles without chemo and a control group that got neither. The researchers made the unexpected observation that the growth of the tumors in control animals that got nanoparticles only was suppressed compared with the other controls.
Getting macrophages back on track
The researchers conducted a series of follow-up tests to characterize what was happening. Experimenting with cells in a dish, they showed that immune cells called tumor-associated macrophages were required for the nanoparticles’ anti-cancer activity; in cell cultures without macrophages, the iron nanoparticles had no effect against cancer cells.
Before this study was done, it was already known that in healthy people, tumor-associated macrophages detect and eat individual tumor cells. However, large tumors can hijack the tumor-associated macrophages, causing them to stop attacking and instead begin secreting factors that promote the cancer’s growth.
The study showed that the iron nanoparticles switch the macrophages back to their cancer-attacking state, as evidenced by tracking the products of the macrophages’ metabolism and examining their patterns of gene expression.
Furthermore, in a mouse model of breast cancer, the researchers demonstrated that the ferumoxytol inhibited tumor growth when given in doses, adjusted for body weight, similar to those approved by the FDA for anemia treatment. Prior studies had shown that the nanoparticles are metabolized over a period of about six weeks, and the new study showed that the anti-cancer effect of a single dose of nanoparticles declined over about three weeks.
The scientists also tested whether the nanoparticles could stop cancer from spreading. In a mouse model of small-cell lung cancer, the nanoparticles reduced tumor formation in the liver, a common site of metastasis in both mice and humans. In a separate model of liver metastasis, pretreatment with nanoparticles before tumor cells were introduced greatly reduced the volume of liver tumors.
Potential clinical applications
The study’s results suggest several possible applications to test in human trials, Daldrup-Link said. For instance, after surgery to remove a potentially metastatic tumor, patients often need chemotherapy but must wait until they recover from the operation to tolerate the severe side effects of conventional chemo. The iron nanoparticles lack the toxic side effects of chemotherapy, suggesting they might be given to patients during the surgical recovery period.
“We think this could bridge the time when the patient is quite sick after surgery, and help keep the cancer from spreading until they are able to receive chemotherapy,” said Daldrup-Link.
The nanoparticles may also help cancer patients whose tumors can’t be completely removed. “If there are some tumor cells left after surgery, the situation that cancer surgeons call positive margins, we think it might work to inject iron nanoparticles there, and the smaller tumor seeds could potentially be taken care of by our immune system,” Daldrup-Link said.
The fact that the nanoparticles are already FDA-approved speeds the ability to test these applications in humans, she added.
The new findings will also help cancer researchers conduct more accurate evaluations of nanoparticle-drug combinations, Daldrup-Link said. “In many studies, researchers just consider nanoparticles as drug vehicles,” she said. “But they may have hidden intrinsic effects that we won’t appreciate unless we look at the nanoparticles themselves.”
Anaplastic thyroid cancer (ATC), the most aggressive form of thyroid cancer, has a mortality rate of nearly 100 percent and a median survival time of three to five months. One promising strategy for the treatment of these solid tumors and others is RNA interference (RNAi) nanotechnology, but delivering RNAi agents to the sites of tumors has proved challenging. Investigators at Brigham and Women’s Hospital, together with collaborators from Massachusetts General Hospital, have developed an innovative nanoplatform that allows them to effectively deliver RNAi agents to the sites of cancer and suppress tumor growth and reduce metastasis in preclinical models of ATC. Their results appear this week in Proceedings of the National Academy of Sciences.
“We call this a ‘theranostic’ platform because it brings a therapy and a diagnostic together in one functional nanoparticle,” said co-senior author Jinjun Shi, PhD, assistant professor of Anesthesia in the Anesthesia Department. “We expect this study to pave the way for the development of theranostic platforms for image-guided RNAi delivery to advanced cancers.”
RNAi, the discovery of which won the Nobel Prize in Physiology or Medicine 10 years ago, allows researchers to silence mutated genes, including those upon which cancers depend to grow and survive and metastasize. Many ATCs depend upon mutations in the commonly mutated cancer gene BRAF. By delivering RNAi agents that specifically target and silence this mutated gene, the investigators hoped to stop both the growth and the spread of ATC, which often metastasizes to the lungs and other organs.
When RNAi is delivered on its own, it is usually broken down by enzymes or filtered out by the kidneys before it reaches tumor cells. Even when RNAi agents make it as far as the tumor, they are often unable to penetrate or are rejected by the cancer cells. To overcome these barriers, the investigators used nanoparticles to deliver the RNAi molecules to ATC tumors. In addition, they coupled the nanoparticles with a near-infrared fluorescent polymer, which allowed them to see where the nanoparticles accumulated in a mouse model of ATC.
By measuring the glow from the near-infrared fluorescent polymer, the team verified that nanoparticles had reached the primary site of ATC in the thyroid. The team found that the nanoparticles circulated for long periods of time in the blood stream and accumulated at high concentrations in the tumors.
In addition, the team reports evidence that BRAF had been successfully silenced at these sites. They found that, for cells grown in a dish and treated with the nanoparticles containing RNAi agents, cell growth was drastically slowed and the number of cancer cells that were able to migrate decreased by as much as 15-fold. In mouse models, tumor growth was also slowed and fewer metastases formed.
In order to translate the new platform into clinical applications, the research team notes the importance of having an imaging diagnostic that will allow them to quickly assess which patients most likely to benefit from RNAi nanotherapeutics.
“Most patients who present to surgeons with anaplastic thyroid cancer are out of options and this new research gives these patients some options. Having an approach that allows us to rapidly visualize and simultaneously deliver a targeted therapy could be critical for the efficient treatment of this disease and other lethal cancers with a poor prognosis,” said co-senior author, Sareh Parangi, MD, associate professor in the MGH Department of Surgery.
In one of the first efforts to date to apply nanotechnology to targeted cancer therapeutics, researchers have created a nanoparticle formulation of a cancer drug that is both effective and nontoxic — qualities harder to achieve with the free drug. Their nanoparticle creation releases the potent but toxic targeted cancer drug directly to tumors, while sparing healthy tissue.
The findings in rodents with human tumors have helped launch clinical trials of the nanoparticle-encapsulated version of the drug, which are currently underway. Aurora kinase inhibitors are molecularly targeted agents that disrupt cancer’s cell cycle.
While effective, the inhibitors have proven highly toxic to patients and have stalled in late-stage trials. Development of several other targeted cancer drugs has been abandoned because of unacceptable toxicity. To improve drug safety and efficacy, Susan Ashton and colleagues designed polymeric nanoparticles called Accurins to deliver an Aurora kinase B inhibitor currently in clinical trials.
The nanoparticle formulation used ion pairing to efficiently encapsulate and control the release of the drug. In colorectal tumor-bearing rats and mice with diffuse large B cell lymphoma, the nanoparticles accumulated specifically in tumors, where they slowly released the drug to cancer cells. Compared to the free drug, the nanoparticle-encapsulated inhibitor blocked tumor growth more effectively at one half the drug dose and caused fewer side effects in the rodents.
The polymeric nanoparticle Accurin encapsulates the clinical candidate AZD2811, an Aurora B kinase inhibitor. This material relates to a paper that appeared in the Feb. 10, 2016 issue of Science Translational Medicine, published by AAAS. The paper, by S. Ashton at institution in location, and colleagues was titled, “Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo.”
Credit: Ashton et al., Science Translational Medicine (2016)
A related Focus by David Bearss offers more insights on how Accurin nanoparticles may help enhance the safety and antitumor activity of Aurora kinase inhibitors and other molecularly targeted drugs.
Susan Ashton, Young Ho Song, Jim Nolan, Elaine Cadogan, Jim Murray, Rajesh Odedra, John Foster, Peter A. Hall, Susan Low, Paula Taylor, Rebecca Ellston, Urszula M. Polanska, Joanne Wilson, Colin Howes, Aaron Smith, Richard J. A. Goodwin, John G. Swales, Nicole Strittmatter, Zoltán Takáts, Anna Nilsson, Per Andren, Dawn Trueman, Mike Walker, Corinne L. Reimer, Greg Troiano, Donald Parsons, David De Witt, Marianne Ashford, Jeff Hrkach, Stephen Zale, Philip J. Jewsbury, and Simon T. Barry. Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo. Science Translational Medicine, 2016 DOI: 10.1126/scitranslmed.aad2355
The DNA sequencing giant will launch a new company, Grail, to develop blood tests to detect cancer.
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.