Childhood Cancer: Novel Nanoparticle Shows Early Promise for Brain Tumor
Posted on by Lawrence Tabak, D.D.S., Ph.D.
The human brain is profoundly complex, consisting of tens of billions of neurons that form trillions of interconnections. This complex neural wiring that allows us to think, feel, move, and act is surrounded by what’s called the blood-brain barrier (BBB), a dense sheet of cells and blood vessels. The BBB blocks dangerous toxins and infectious agents from entering the brain, while allowing nutrients and other essential small molecules to pass right through.
This gatekeeping function helps to keep the brain healthy, but not when the barrier prevents potentially life-saving drugs from reaching aggressive, inoperable brain tumors. Now, an NIH-funded team reporting in the journal Nature Materials describes a promising new way to ferry cancer drugs across the BBB and reach the sites of disease . While the researchers have not yet tried this new approach in people, they have some encouraging evidence from studies in mouse models of medulloblastoma, an aggressive brain cancer that’s diagnosed in hundreds of children each year.
The team, including Daniel Heller, Memorial Sloan Kettering Cancer Center, New York, NY, and Praveen Raju, Icahn School of Medicine at Mount Sinai, New York, NY, wanted to target a protein called P-selectin. The protein is found on blood vessel cells at sites of infection, injury, or inflammation, including cancers. The immune system uses such proteins to direct immune cells to the places where they are needed, allowing them to exit the bloodstream and enter other tissues.
Heller’s team thought they could take advantage of P-selectin and its molecular homing properties as a potential way to deliver cancer drugs to patients. But first they needed to package the drugs in particles tiny enough to stick to P-selectin like an immune cell.
That’s when they turned to a drug-delivery construct called a nanoparticle, which can have diameters a thousand times smaller than that of a human hair. But what’s pretty unique here is the nanoparticles are made from chains of sugar molecules called fucoidan, which are readily extracted from a type of brown seaweed that grows in Japan. It turns out that this unlikely ingredient has a special ability to attract P-selectin.
In the new study, the researchers decided to put their novel fucoidan nanoparticles to the test in the brain, while building on their previous animal work in the lungs . That work showed that when fucoidan nanoparticles bind to P-selectin, they trigger a process that shuttles them across blood vessel walls.
This natural mechanism should also allow nanoparticle-packaged substances in the bloodstream to pass through vessel walls in the BBB and into the surrounding brain tissue. The hope was it would do so without damaging the BBB, a critical step for improving the treatment of brain tumors.
In studies with mouse models of medulloblastoma, the team loaded the nanoparticles with a cancer drug called vismodegib. This drug is approved for certain skin cancers and has been tested for medulloblastoma. The trouble is that the drug on its own comes with significant side effects in children at doses needed to effectively treat this brain cancer.
The researchers found that the vismodegib-loaded nanoparticles circulating in the mice could indeed pass through the intact BBB and into the brain. They further found that the particles accumulated at the site of the medulloblastoma tumors, where P-selectin was most abundant, and not in other healthy parts of the brain. In the mice, the approach allowed the vismodegib treatment to work better against the cancer and at lower doses with fewer side effects.
This raised another possibility. Radiation is a standard therapy for children and adults with brain tumors. The researcher found that radiation boosts P-selectin levels specifically in tumors. The finding suggests that radiation targeting specific parts of the brain prior to nanoparticle treatment could make it even more effective. It also may help to further limit the amount of cancer-fighting drug that reaches healthy brain cells and other parts of the body.
The fucoidan nanoparticles could, in theory, deliver many different drugs to the brain. The researchers note their promise for treating brain tumors of all types, including those that spread to the brain from other parts of the body. While much more work is needed, these seaweed-based nanoparticles may also help in delivering drugs to a wide range of other brain conditions, such as multiple sclerosis, stroke, and focal epilepsy, in which seizures arise from a specific part of the brain. It’s a discovery that brings new meaning to the familiar adage that good things come in small packages.
 P-selectin-targeted nanocarriers induce active crossing of the blood-brain barrier via caveolin-1-dependent transcytosis. Tylawsky DE, Kiguchi H, Vaynshteyn J, Gerwin J, Shah J, Islam T, Boyer JA, Boué DR, Snuderl M, Greenblatt MB, Shamay Y, Raju GP, Heller DA. Nat Mater. 2023 Mar;22(3):391-399.
 P-selectin is a nanotherapeutic delivery target in the tumor microenvironment. Shamay Y, Elkabets M, Li H, Shah J, Brook S, Wang F, Adler K, Baut E, Scaltriti M, Jena PV, Gardner EE, Poirier JT, Rudin CM, Baselga J, Haimovitz-Friedman A, Heller DA. Sci Transl Med. 2016 Jun 29;8(345):345ra87.
Medulloblastoma Diagnosis and Treatment (National Cancer Institute/NIH)
Brain Basics: Know Your Brain (National Institute of Neurological Disorders and Stroke/NIH)
The Daniel Heller Lab (Memorial Sloan Kettering Cancer Center, New York, NY)
Praveen Raju (Mount Sinai, New York, NY)
NIH Support: National Cancer Institute; National Institute of Neurological Disorders and Stroke
An Inflammatory View of Early Alzheimer’s Disease
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Detecting the earliest signs of Alzheimer’s disease (AD) in middle-aged people and tracking its progression over time in research studies continue to be challenging. But it is easier to do in shorter-lived mammalian models of AD, especially when paired with cutting-edge imaging tools that look across different regions of the brain. These tools can help basic researchers detect telltale early changes that might point the way to better prevention or treatment strategies in humans.
That’s the case in this technicolor snapshot showing early patterns of inflammation in the brain of a relatively young mouse bred to develop a condition similar to AD. You can see abnormally high levels of inflammation throughout the front part of the brain (orange, green) as well as in its middle part—the septum that divides the brain’s two sides. This level of inflammation suggests that the brain has been injured.
What’s striking is that no inflammation is detectable in parts of the brain rich in cholinergic neurons (pink), a distinct type of nerve cell that helps to control memory, movement, and attention. Though these neurons still remain healthy, researchers would like to know if the inflammation also will destroy them as AD progresses.
This colorful image comes from medical student Sakar Budhathoki, who earlier worked in the NIH labs of Lorna Role and David Talmage, National Institute of Neurological Disorders and Stroke (NINDS). Budhathoki, teaming with postdoctoral scientist Mala Ananth, used a specially designed wide-field scanner that sweeps across brain tissue to light up fluorescent markers and capture the image. It’s one of the scanning approaches pioneered in the Role and Talmage labs [1,2].
The two NIH labs are exploring possible links between abnormal inflammation and damage to the brain’s cholinergic signaling system. In fact, medications that target cholinergic function remain the first line of treatment for people with AD and other dementias. And yet, researchers still haven’t adequately determined when, why, and how the loss of these cholinergic neurons relates to AD.
It’s a rich area of basic research that offers hope for greater understanding of AD in the future. It’s also the source of some fascinating images like this one, which was part of the 2022 Show Us Your BRAIN! Photo and Video Contest, supported by NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative.
 NeuRegenerate: A framework for visualizing neurodegeneration. Boorboor S, Mathew S, Ananth M, Talmage D, Role LW, Kaufman AE. IEEE Trans Vis Comput Graph. 2021;Nov 10;PP.
 NeuroConstruct: 3D reconstruction and visualization of neurites in optical microscopy brain images. Ghahremani P, Boorboor S, Mirhosseini P, Gudisagar C, Ananth M, Talmage D, Role LW, Kaufman AE. IEEE Trans Vis Comput Graph. 2022 Dec;28(12):4951-4965.
Alzheimer’s Disease & Related Dementias (National Institute on Aging/NIH)
Role Lab (National Institute of Neurological Disorders and Stroke/NIH)
Talmage Lab (NINDS)
The Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)
Show Us Your BRAINs! Photo and Video Contest (BRAIN Initiative)
NIH Support: National Institute of Neurological Disorders and Stroke
Can Autoimmune Antibodies Explain Blood Clots in COVID-19?
Posted on by Dr. Francis Collins
For people with severe COVID-19, one of the most troubling complications is abnormal blood clotting that puts them at risk of having a debilitating stroke or heart attack. A new study suggests that SARS-CoV-2, the coronavirus that causes COVID-19, doesn’t act alone in causing blood clots. The virus seems to unleash mysterious antibodies that mistakenly attack the body’s own cells to cause clots.
The NIH-supported study, published in Science Translational Medicine, uncovered at least one of these autoimmune antiphospholipid (aPL) antibodies in about half of blood samples taken from 172 patients hospitalized with COVID-19. Those with higher levels of the destructive autoantibodies also had other signs of trouble. They included greater numbers of sticky, clot-promoting platelets and NETs, webs of DNA and protein that immune cells called neutrophils spew to ensnare viruses during uncontrolled infections, but which can lead to inflammation and clotting. These observations, coupled with the results of lab and mouse studies, suggest that treatments to control those autoantibodies may hold promise for preventing the cascade of events that produce clots in people with COVID-19.
Our blood vessels normally strike a balance between producing clotting and anti-clotting factors. This balance keeps us ready to seal up vessels after injury, but otherwise to keep our blood flowing at just the right consistency so that neutrophils and platelets don’t stick and form clots at the wrong time. But previous studies have suggested that SARS-CoV-2 can tip the balance toward promoting clot formation, raising questions about which factors also get activated to further drive this dangerous imbalance.
To learn more, a team of physician-scientists, led by Yogendra Kanthi, a newly recruited Lasker Scholar at NIH’s National Heart, Lung, and Blood Institute and his University of Michigan colleague Jason S. Knight, looked to various types of aPL autoantibodies. These autoantibodies are a major focus in the Knight Lab’s studies of an acquired autoimmune clotting condition called antiphospholipid syndrome. In people with this syndrome, aPL autoantibodies attack phospholipids on the surface of cells including those that line blood vessels, leading to increased clotting. This syndrome is more common in people with other autoimmune or rheumatic conditions, such as lupus.
It’s also known that viral infections, including COVID-19, produce a transient increase in aPL antibodies. The researchers wondered whether those usually short-lived aPL antibodies in COVID-19 could trigger a condition similar to antiphospholipid syndrome.
The researchers showed that’s exactly the case. In lab studies, neutrophils from healthy people released twice as many NETs when cultured with autoantibodies from patients with COVID-19. That’s remarkably similar to what had been seen previously in such studies of the autoantibodies from patients with established antiphospholipid syndrome. Importantly, their studies in the lab further suggest that the drug dipyridamole, used for decades to prevent blood clots, may help to block that antibody-triggered release of NETs in COVID-19.
The researchers also used mouse models to confirm that autoantibodies from patients with COVID-19 actually led to blood clots. Again, those findings closely mirror what happens in mouse studies testing the effects of antibodies from patients with the most severe forms of antiphospholipid syndrome.
While more study is needed, the findings suggest that treatments directed at autoantibodies to limit the formation of NETs might improve outcomes for people severely ill with COVID-19. The researchers note that further study is needed to determine what triggers autoantibodies in the first place and how long they last in those who’ve recovered from COVID-19.
The researchers have already begun enrolling patients into a modest scale clinical trial to test the anti-clotting drug dipyridamole in patients who are hospitalized with COVID-19, to find out if it can protect against dangerous blood clots. These observations may also influence the design of the ACTIV-4 trial, which is testing various antithrombotic agents in outpatients, inpatients, and convalescent patients. Kanthi and Knight suggest it may also prove useful to test infected patients for aPL antibodies to help identify and improve treatment for those who may be at especially high risk for developing clots. The hope is this line of inquiry ultimately will lead to new approaches for avoiding this very troubling complication in patients with severe COVID-19.
 Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19. Zuo Y, Estes SK, Ali RA, Gandhi AA, Yalavarthi S, Shi H, Sule G, Gockman K, Madison JA, Zuo M, Yadav V, Wang J, Woodard W, Lezak SP, Lugogo NL, Smith SA, Morrissey JH, Kanthi Y, Knight JS. Sci Transl Med. 2020 Nov 2:eabd3876.
Coronavirus (COVID-19) (NIH)
Antiphospholipid Antibody Syndrome (National Heart Lung and Blood Institute/NIH)
Kanthi Lab (National Heart, Lung, and Blood Institute, Bethesda, MD)
Knight Lab (University of Michigan)
NIH Support: National Heart, Lung, and Blood Institute
See the Human Cardiovascular System in a Whole New Way
Posted on by Dr. Francis Collins
Watch this brief video and you might guess you’re seeing an animated line drawing, gradually revealing a delicate take on a familiar system: the internal structures of the human body. But this movie doesn’t capture the work of a talented sketch artist. It was created using the first 3D, full-body imaging device using positron emission tomography (PET).
The device is called an EXPLORER (EXtreme Performance LOng axial REsearch scanneR) total-body PET scanner. By pairing this scanner with an advanced method for reconstructing images from vast quantities of data, the researchers can make movies.
For this movie in particular, the researchers injected small amounts of a short-lived radioactive tracer—an essential component of all PET scans—into the lower leg of a study volunteer. They then sat back as the scanner captured images of the tracer moving up the leg and into the body, where it enters the heart. The tracer moves through the heart’s right ventricle to the lungs, back through the left ventricle, and up to the brain. Keep watching, and, near the 30-second mark, you will see in closer focus a haunting capture of the beating heart.
This groundbreaking scanner was developed and tested by Jinyi Qi, Simon Cherry, Ramsey Badawi, and their colleagues at the University of California, Davis . As the NIH-funded researchers reported recently in Proceedings of the National Academy of Sciences, their new scanner can capture dynamic changes in the body that take place in a tenth of a second . That’s faster than the blink of an eye!
This movie is composed of frames captured at 0.1-second intervals. It highlights a feature that makes this scanner so unique: its ability to visualize the whole body at once. Other medical imaging methods, including MRI, CT, and traditional PET scans, can be used to capture beautiful images of the heart or the brain, for example. But they can’t show what’s happening in the heart and brain at the same time.
The ability to capture the dynamics of radioactive tracers in multiple organs at once opens a new window into human biology. For example, the EXPLORER system makes it possible to measure inflammation that occurs in many parts of the body after a heart attack, as well as to study interactions between the brain and gut in Parkinson’s disease and other disorders.
EXPLORER also offers other advantages. It’s extra sensitive, which enables it to capture images other scanners would miss—and with a lower dose of radiation. It’s also much faster than a regular PET scanner, making it especially useful for imaging wiggly kids. And it expands the realm of research possibilities for PET imaging studies. For instance, researchers might repeatedly image a person with arthritis over time to observe changes that may be related to treatments or exercise.
Currently, the UC Davis team is working with colleagues at the University of California, San Francisco to use EXPLORER to enhance our understanding of HIV infection. Their preliminary findings show that the scanner makes it easier to capture where the human immunodeficiency virus (HIV), the cause of AIDS, is lurking in the body by picking up on signals too weak to be seen on traditional PET scans.
While the research potential for this scanner is clearly vast, it also holds promise for clinical use. In fact, a commercial version of the scanner, called uEXPLORER, has been approved by the FDA and is in use at UC Davis . The researchers have found that its improved sensitivity makes it much easier to detect cancers in patients who are obese and, therefore, harder to image well using traditional PET scanners.
As soon as the COVID-19 outbreak subsides enough to allow clinical research to resume, the researchers say they’ll begin recruiting patients with cancer into a clinical study designed to compare traditional PET and EXPLORER scans directly.
As these researchers, and other researchers around the world, begin to put this new scanner to use, we can look forward to seeing many more remarkable movies like this one. Imagine what they will reveal!
 First human imaging studies with the EXPLORER total-body PET scanner. Badawi RD, Shi H, Hu P, Chen S, Xu T, Price PM, Ding Y, Spencer BA, Nardo L, Liu W, Bao J, Jones T, Li H, Cherry SR. J Nucl Med. 2019 Mar;60(3):299-303.
 Subsecond total-body imaging using ultrasensitive positron emission tomography. Zhang X, Cherry SR, Xie Z, Shi H, Badawi RD, Qi J. Proc Natl Acad Sci U S A. 2020 Feb 4;117(5):2265-2267.
 “United Imaging Healthcare uEXPLORER Total-body Scanner Cleared by FDA, Available in U.S. Early 2019.” Cision PR Newswire. January 22, 2019.
Positron Emission Tomography (PET) (NIH Clinical Center)
EXPLORER Total-Body PET Scanner (University of California, Davis)
Cherry Lab (UC Davis)
Badawi Lab (UC Davis Medical Center, Sacramento)
NIH Support: National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering; Common Fund