Finding blood clots using Nanotechnology .. BEFORE …they wreak havoc.

Finding blood clots before they wreak havoc

Anne Trafton, MIT News Office
Simple urine test developed by MIT engineers uses nanotechnology to detect dangerous blood clotting.
Life-threatening blood clots can form in anyone who sits on a plane for a long time, is confined to bed while recovering from surgery, or takes certain medications.
There is no fast and easy way to diagnose these clots, which often remain undetected until they break free and cause a stroke or heart attack. However, new technology from MIT may soon change that: A team of engineers has developed a way to detect blood clots using a simple urine test.
The noninvasive diagnostic, described in a recent issue of the journal ACS Nano, relies on nanoparticles that detect the presence of thrombin, a key blood-clotting factor.
Such a system could be used to monitor patients who are at high risk for blood clots, says Sangeeta Bhatia, senior author of the paper and the John and Dorothy Wilson Professor of Biochemistry.
“Some patients are at more risk for clotting, but existing blood tests are not consistently able to detect the formation of new clots,” says Bhatia, who is also a senior associate member of the Broad Institute and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES).
Lead authors of the paper are Kevin Lin, a graduate student in chemical engineering, and Gabriel Kwong, a postdoc in IMES. Other authors are Andrew Warren, a graduate student in Health Sciences and Technology (HST), and former HST postdoc David Wood.
Sensing thrombin
Blood clotting is produced by a complex cascade of protein interactions, culminating in the formation of fibrin, a fibrous protein that seals wounds. The last step of this process — the conversion of fibrinogen to fibrin — is controlled by an enzyme called thrombin.
Current tests for blood clotting are very indirect, Bhatia says. One, known as the D-dimer test, looks for the presence of fibrin byproducts, which indicates that a clot is being broken down, but will not detect its initial formation.
Bhatia and her colleagues developed their new test based on a technology they first reported last year for early detection of colorectal cancer. “We realized the same exact technology would work for blood clots,” she says. “So we took the test we had developed before, which is an injectable nanoparticle, and made it a thrombin sensor.”
The system consists of iron oxide nanoparticles, which the Food and Drug Administration has approved for human use, coated with peptides (short proteins) that are specialized to interact with thrombin. After being injected into mice, the nanoparticles travel throughout the body. When the particles encounter thrombin, the thrombin cleaves the peptides at a specific location, releasing fragments that are then excreted in the animals’ urine.
Once the urine is collected, the protein fragments can be identified by treating the sample with antibodies specific to peptide tags included in the fragments. The researchers showed that the amount of these tags found in the urine is directly proportional to the level of blood clotting in the mice’s lungs.
In the previous version of the system, reported last December in Nature Biotechnology, the researchers used mass spectrometry to distinguish the fragments by their mass. However, testing samples with antibodies is much simpler and cheaper, the researchers say.
Rapid screening
Bhatia says she envisions two possible applications for this kind of test. One is to screen patients who come to the emergency room complaining of symptoms that might indicate a blood clot, allowing doctors to rapidly triage such patients and determine if more tests are needed.
“Right now they just don’t know how to efficiently define who to do the more extensive workup on. It’s one of those things that you can’t afford to miss, so patients can get an unnecessarily expensive workup,” Bhatia says.
Another application is monitoring patients who are at high risk for a clot — for example, people who have to spend a lot of time in bed recovering from surgery. Bhatia is working on a urine dipstick test, similar to a pregnancy test, that doctors could give patients when they go home after surgery.
“If a patient is at risk for thrombosis, you could send them home with a 10-pack of these sticks and say, ‘Pee on this every other day and call me if it turns blue,’” she says.
The technology could also be useful for predicting recurrence of clots, says Henri Spronk, an assistant professor of biochemistry at Maastricht University in the Netherlands.
“High levels of activation markers have been related to recurrent thrombosis, but they don’t have good sensitivity or specificity. Through application of the nanoparticles, if proven well-tolerated and nontoxic, alterations in the normal low levels of physiological thrombin generation might be easily detected,” says Spronk, who was not part of the research team.
Bhatia plans to launch a company to commercialize the technology, with funding from MIT’s Deshpande Center for Technological Innovation. Other applications for the nanoparticle system could include monitoring and diagnosing cancer. It could also be adapted to track liver, pulmonary, and kidney fibrosis, Bhatia says.
The research was funded by the Koch Institute Frontier Research Fund, the Kathy and Curt Marble Cancer Research Fund, the Mazumdar-Shaw International Oncology Fellows Program, the Burroughs Wellcome Fund, and the Deshpande Center.

Nanopolymers Open New Way to Detect Cancerous Tumors

201306047919620The drug which was synthesized in association with Control Laboratory of Food and Drug Department of Iran’s Ministry of Health, Hygiene, and Medical Education can be used in MRI as the contrast agents in addition to curing cancerous tumors.
The aim of this study was to evaluate the contrast optimization of silicon-based gadolinium oxide nanoparticles with nanocomposite coating, and to compare gadolinium nanoparticle with the common contrast agent in magnetic resonance imaging (Magnevist). In this study, the new emulsion made of gadolinium oxide nanoparticle and POSS-PCU nanocomposite was investigated. In comparison with Magnevist, gadolinium oxide nanoparticles can increase the signal of MRI by reducing relaxation time or by increasing the rate of relaxation.

They can also create high contrast optimization in MRI as positive contrast in comparison with iron oxide nanoparticles (negative contrast agent).
In line with targeting methods and through connecting to biocompatible materials, the new medicine has obtained other useful results in drug delivery in order to detect lymphatic glands of breast cancer and hepatic tumors.
Since the non-nanoic sample of this drug has acquired the confirmation of US Foodstuff and Medications Standard Organization, it has FDA certificate. The drug has passed the laboratorial and animal tests, and it is going to be tested on humans too.
Results of the research have been published in December 2010 in Biological Trace Element Research, vol. 137, issue 3. For more information about the details of the research, study the full article on pages 324-334 on the same journal.


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Nanoparticles Harness Powerful Radiation Therapy for Cancer

Posted: May 17th, 2013

Nanoparticle harnesses powerful radiation therapy for cancer

(Nanowerk News) Researchers at the University of Missouri have demonstrated the ability to create a multi-layered harness nanoparticle that can safely encapsulate powerful alpha-emitting radioisotopes and target tumors. The resulting nanoparticles not only offer the possibility of delivering tumor-killing alpha emitters to tumors, but also sparing healthy tissue from radiation damage. J. David Robinson and his colleagues published their findings in the journal PLoS One (“Gold Coated Lanthanide Phosphate Nanoparticles for Targeted Alpha Generator Radiotherapy”).Typically, when radiation treatment is recommended for cancer patients, doctors are able to deliver radiation from a source outside the body or they might inject one of several radiopharmaceuticals that emit low-energy radiation known as beta particles. For years, scientists have been studying how to use “alpha emitters,” which are radioactive elements that release high-energy alpha particles that would more effectively damage cancer cells and trigger cell death. The challenge to using alpha emitters is that the decay elements, the so-called daughters, are themselves highly toxic and difficult to contain in the vicinity of the tumor, thus causing significant damage to healthy tissues.”If you think of beta particles as slingshots or arrows, alpha particles would be similar to cannon balls,” said Dr. Robertson. He explains that recent work has shown that alpha particles can be effective in treating cancer in specific instances. “For example, a current study using radium-223 chloride, which emits alpha particles, has been fast-tracked by the U.S. Food and Drug Administration because it has been shown to be effective in treating bone cancer. However, it only works for bone cancer because the element, radium, is attracted to the bone and stays there. We believe we have found a solution that will allow us to target alpha particles to other cancer sites in the body in an effective manner.”In their studies, Dr. Robertson and colleagues from Oak Ridge National Laboratory and the School of Medicine at the University of Tennessee in Knoxville used the isotope actinium-225, an element that when it decays produces a high-energy alpha particle and radioactive daughter elements, which are also capable of emitting alpha particles. Efforts to contain the daughter elements using traditional molecular constraints proved fruitless because the emitted alpha particles broke the chemical bonds necessary to hold the daughter elements in place.The Missouri team solved this problem by sequestering actinium-225 in the core of a gold-coated magnetic nanoparticle. The magnetic layer, comprised of gadolinium phosphate, serves to increase retention of the daughter elements while simplifying particle purification and the gold coating provides a surface to which tumor-targeting molecules can be attached. In the experiments described in their current publication, the researchers used an antibody that targets a receptor found on the surface of lung tumors.”Holding these alpha emitters in place is a technical challenge that researchers have been trying to overcome for 15 years,” Dr. Robertson said. “With our nanoparticle design, we are able to keep more than 80 percent of the element inside the nanoparticle 24 hours after it is created.” While alpha particles are extremely powerful, they do not travel very far, so when the nanoparticles get close to the targeted cancer cells, the alpha particles are more selective at damaging cancer cells but not surrounding cells.

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Future medicine: Stem cells can leverage silica nanoparticles to track where they actually go

QDOTS imagesCAKXSY1K 8Giving patients stem cells packaged with silica nanoparticles could help  doctors determine the effectiveness of the treatments by revealing where the  cells go after they’ve left the injection needle.

Researchers from Stanford University report in a paper  published on Wednesday in the journal Science Translational Medicine  that silica nanoparticles taken up by stem cells make the cells visible on  ultrasound imaging. While other imaging techniques such as MRI can show where  stem cells are located in the body, that method is not as fast, affordable, or  widely available as an ultrasound scanner, and more importantly, it does not  offer a real-time view of injection, say experts.

Stem cells have significant medical promise because they can be turned into  other types of living cell. As well as helping doctors adjust therapeutic  dosages in patients, the new technique could help scientists perfect stem cell  treatments, says senior author Sanjiv  Gambhir. “For the most part, researchers shoot blindly—they don’t quite know  where the cells are going when they are injected, they don’t know if they home  in to the right target tissue, they don’t know if they survive, and they don’t  know if they leak into other tissue types,” says Gambhir.

This, in part, could be slowing advances in stem cell treatments. “If stem  cells are going to be used as a legitimate medical treatment for the repair of  damaged or diseased tissue, then we will need to know precisely where they are  going so the treatments can be optimized,” says Lara  Bogart, a physicist at the University of Liverpool. Bogart is developing  magnetic nanoparticles for tracking stem cells using MRI.To get a better view of where cells are going during and after injection,  Gambhir and colleagues used nanoparticles made of silica, a material that  reflects sound waves, so it can be detected in an ultrasound scan. The  nanoparticles were incubated with mesenchymal stem cells, which can develop into  cell types including bone cells, fat cells, and heart cells. The cells ingested  the nanoparticles, which did not change the cells’ growth rate or ability to  develop into different cell types. Inside the cells, the nanoparticles clumped  together, which made them more visible in an ultrasound.

The researchers then injected the nanoparticle-laden stem cells into the  hearts of mice and tracked their movements. Many research groups are testing  stem cells as a treatment after a heart attack or for other heart conditions in  both lab animals (see “A  Step Toward Healing Broken Hearts with Stem Cells” and “Injecting  Stem Cells into the Heart Could Stop Chronic Chest Pain”) as well as in  patients in clinical trials. A fast and real-time imaging tool could help  because researchers and doctors need to be sure that the cells reach the most  beneficial spots in a sickly heart.

“It’s very important to know where you inject the cells because you don’t  want to put them in areas damaged by the heart attack; that tissue is dead and a  very hostile environment,” says Jeff Bulte, a cell engineer at the Johns Hopkins  University School of Medicine who was not involved in the study. “On the other  hand, you want to place them as close to the site of damage as possible,” he  says.

The silica nanoparticles can also be detected in MRI machines because they  contain a strongly magnetic heavy metal known as gadolinium that shows up in the  scans. And they can be detected optically (through microscopes) because they  carry a fluorescent dye. “This gives us three complementary ways to image the  same particle,” says Bogart. Depending on the part of the body receiving the  transplant, the type of scanner available and the amount of time since  injection, a researcher may choose one method over another.

The mice used in the study were healthy, but the team plans to test the  tracking method in mice or other lab animals that have heart damage. The team  will also use the nanoparticles in different cell types and do more toxicity  studies prior to filing for FDA approval to test the nanoparticles in humans. “It will be about a three-year process to do first-in-man studies,” says  Gambhir.

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