"Lures" against clots and cancer

Heart disease, stroke, sepsis and cancer are the cause of the largest number of deaths in the world. They also have something in common: they are all badociated with activated platelets, the cells that circulate in our blood and normally help to form blood clots to stop bleeding and promote wound healing, but can also contribute to training. dangerous blood clots. tumors and other problems. Several antiplatelet drugs have been developed to fight platelet-related conditions, but their effects are not easily reversible and patients taking these drugs are at risk of uncontrolled bleeding in the event of an injury. In addition, if these patients have to undergo surgery, they must stop their treatment until one week before the intervention, which increases their risk of developing blood clots.

Now, a team of researchers at Harvard University's Wyss Institute and several partner institutions has developed a reversible, drug-free antiplatelet therapy that uses deactivated platelets that could reduce the risk of blood clots and potentially prevent them from forming blood clots. metastases of cancer. The research is reported in Translational medicine science.

"Reversibility and immediate onset of action are major strengths of our platelet lures. We believe that they are useful in hospital situations such as the prevention of clotting in high-risk patients just before surgery, or when they are administered with chemotherapy to prevent Anne-Laure Papa, Ph.D., first author, postdoctoral fellow at the Wyss Institute, in collaboration with founding director of the Institute, Donald Ingber, MD, Ph.D., when the research was done and is now an adjunct professor at George Washington University, Ingber is also a Judah Folkman Professor of Vascular Biology at Harvard Medical School and the Vascular Biology Program at the University of Washington. 39, Boston Children's Hospital, as well as professor of bioengineering at the Harvard School of Engineering and Applied Science.

Clot cancellation

The decoys are human platelets whose outer lipid membrane and viscera were removed in the laboratory by centrifugation and treatment with a detergent. Because they are essentially empty, lures are about a third of the size of normal platelets, but they retain the majority of the adhesive proteins on their surface. Lures can still use these surface molecules to bind to other naturally occurring cells in the blood, but they are unable to activate the clotting process.

When the lures were perfused into a channel mimicking microfluidic blood vessels and exposed to platelet stimulating chemicals, they did not exhibit normal coagulation behavior. And when researchers added lures to normal human blood (a decoy for five platelets) in the channel, they found that the ability of normal platelets to aggregate and bind to the cbad walls was reduced.

"Lures, unlike normal intact pads, are unable to bind to the vessel wall and probably hinder their ability to bind as well." One way to imagine is that decoys are fast-moving skaters. along the wall an ice rink and their high speed prevent other skaters from hanging on the wall, which prevents them from slowing down and clinging on it. "Dad explained.

Importantly, scientists were able to quickly reverse the inhibition of normal platelet activity by simply adding fresh platelets to the channels. The administration of intravenous platelets to patients is already a common procedure in hospitals. Thus, a patient with platelet callers who must quickly regain the ability to form blood clots as a result of an injury or surgery can be easily treated in no time. Lures could also be created from platelets taken from the same patient, providing a form of personalized cell therapy that would not trigger an immune response.

The researchers then tested their lures in rabbits and found that the same 1: 5 ratio of lures to normal blood platelets prevented them from developing blood clots after injury to the blood vessels. Platelet count and platelet size are similar in rabbits and humans; it is therefore likely that they have the same effect in human patients.

Counteract tumors

In addition to binding to each other and to the walls of blood vessels, platelets are known to bind to cancer cells, thereby protecting them from the body's immune system and helping them to form new metastatic tumors at remote sites. When the team perfused normal platelets and human bad cancer cells into their microfluidic channels, the cancer cells stuck to and began to invade the walls of the cbad, similar to their behavior during training. new tumors. Encouragingly, the addition of decoys to normal platelets almost completely prevented platelets from helping cancer cells to invade the cbad wall, suggesting that they could prevent the formation of new tumors.

To confirm this potential, the researchers injected mice with human platelets or a combination of platelets and lures, followed by cancerous bad cells. The team found that mice receiving platelets and lures developed metastatic tumors and many smaller and smaller tumors than those receiving normal platelets. Although they have not yet been tested in humans, it is possible that someday these lures will be infused to patients during chemotherapy to prevent the spread of existing tumors, or injected during surgical operations to prevent tumor cells released from forming new tumors elsewhere in the body. .

Dad's Lab continues to work on this technology to ensure that lures can last longer in the blood for increased efficiency and to determine if they can be loaded with medications to help administer treatments directly. on sites of clots and blood tumors, or even kill circulating tumor cells in the blood.

"In this study, we were able to create what actually constitutes a predominantly negative cell therapy to prevent platelet-mediated clotting and metastatic cascades," Ingber said. "This is another example of how seemingly unrelated diseases often have common contributing factors, such as inflammation, stress or, in this case, activated platelets, and we can develop new therapies for multiple disorders by targeting one of these key factors. "

This article has been republished from documents provided by the Wyss Institute of Harvard University. Note: Content may have changed for length and content. For more information, please contact the cited source.

Reference: Anne-Laure Papa, et al. Platelet lures inhibit thrombosis and prevent the formation of metastatic tumors in preclinical models. Translational medicine science. (2019) DOI: 10.1126 / scitranslmed.aau5898