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What does a catalytic converter have to do with drugs?
A lot, it turns out. Catalytic converters in our cars convert toxic gas emissions into into acceptable ones. A key element is the metal palladium, which catalyses the oxidation of pollutants like carbon monoxide to carbon dioxide. In a recent article in Nature Communications, researchers at CSB have developed a medical version of nano-palladium to enable chemistry to take place inside cells in our body. The discovery allows the administration of harmless prodrugs, which then get specifically activated at sites of cancer.
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Macrophages, immune cells in our body, have a long to-do list. They defend us from bacteria, are essential in wound healing, keep the heart beating and perform other vital tasks. In a new twist, these cells are now shown to dramatically accumulate on the outside of cancer microvessels following radiation therapy. There, they elicit dynamic and focally localized bursts of capillary leaks. This in turn enhances drug delivery, especially of nanomaterials. These new insights have implications for the design of next-generation tumor targeted nanomaterials and clinical trials for adjuvant strategies.
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Pancreatic ductal adenocarcinoma is one of the deadliest types of tumors, in part because it is usually detected at a late stage. To facilitate the diagnosis of this tumor, researchers at CSB have developed a multiplexed nanoplasmonic assay to analyze extracellular vesicles in blood of patients. While some blood biomarkers have previously been proposed, none of them have proven sufficiently accurate in clinical practice. We have now identified a new five-marker signature that yielded the most accurate diagnosis in a large cohort of patient samples.
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Immunotherapy and especially immune checkpoint blockers (ICBs) are revolutionizing how we treat many cancers. Designed to activate the immune system, these drugs can be extraordinarily effective in some patients. But progress has been slowed by our limited understanding of why ICBs work well in some cancers and patients but not in others. Now, Mikael Pittet and colleagues have used molecular imaging to track ICBs in real time and at high resolution within tumors. Their study, published in Science Translational Medicine, uncovers a previously undiscovered mechanism of treatment resistance, which can be overcome with additional chemical modifications.
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Cardiac macrophages charging ahead
While we knew for a while that the healthy heart contains tissue resident macrophages, these cells’ organ specific functions were unknown. Triggered by a serendipitous finding of ECG abnormalities during a cardiac MRI scan of a mouse after macrophage ablation, a CSB team of investigators now describes previously unknown electrical properties of macrophages. When coupled to myocytes via gap junctions, macrophages depolarize in sync with conducting cells. In a sink-source relationship, electric current flows back and forth between macrophages and cardiomyocytes. Macrophages influence conduction through the atrioventricular node, the electrical connection between the heart’s chambers. When macrophages are manipulated, the flow of electricity slows down, and may even cease altogether. Such a condition requires pacemaker treatment in humans. These surprising findings, published in Cell, jolt the field of electrophysiology and may lead to new therapeutic opportunities for patients with cardiac arrhythmias. The collaborative effort was spearheaded by teams at MGH but also involved investigators at the BWH and in Freiburg, Germany.
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Tiny nanoparticles hunt for macrophages
Macrophages are white blood cells that can turn against us in atherosclerosis. Instead of cleaning up tissue as usual, they attack the arterial wall and destroy its architecture. The resulting stoppage of blood flow causes myocardial infarction and stroke. An entire field of research focuses on understanding these cells, and how to stop them from becoming turn coats. Until now, it was not even possible to detect them reliably in patients. In a recent Nature Communications report, a modified polyglucose nanoparticle (18F-Macroflor) was developed for imaging macrophages by PET. Macroflor enriches in cardiac and plaque macrophages, thereby increasing PET signal in murine infarcts and both mouse and rabbit atherosclerotic plaques. This work marks an important step towards a clinical tool to non-invasively monitor macrophage biology in patients. Such an imaging tool can then be used to spot danger spots in several diseases, and test new macrophage-targeted therapeutics while directly watching the cells.
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Iron gives blood its red color. The metal is essential to life, but it can be toxic because of its oxidative properties. Remarkably, we receive relatively little of our daily iron needs through diet. By far the majority of the iron we need is recycled. According to current thinking, as red blood cells age, large phagocytes residing in the spleen capture them, digest the cell structures, and recycle iron. A new paper from CSB published in Nature Medicine shows that most red blood cell disposal actually occurs in the liver, especially when demands for disposal increase (as they do in many physiologic and pathophysiologic situations). Moreover, specialized white blood cells consume old red blood cells in the circulation before migrating to the liver to shuttle iron for storage and new red blood cell production. The process buffers against dangerous fluctuations in iron availability, keeping the body in balance.
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Quintuple-target RNAi: hitting five targets is better than just one
Vascular endothelial cells express five adhesion molecules to recruit leukocytes from the blood stream: E- and P-selectin, ICAM-1 and -2, and VCAM-1. In atherosclerosis, activated endothelial cells express high levels of these signals, thus expanding the number of neutrophils and monocytes that migrate from blood into a growing plaque. After myocardial infarction, the adhesion molecule expression increases even further due to higher autonomic nervous activity. A collaborating team of groups at MIT and MGH now used a new class of nanoparticles with high avidity to endothelial cells to decrease endothelial cell adhesion molecule expression. The polymeric nanoparticles made of low-molecular-weight polyamines and lipids were loaded with 5 distinct siRNAs silencing the expression of all adhesion molecules. Multiple gene silencing was enabled by exquisite silencing efficiency after nanoparticle delivery. Hitting five targets at once, the therapy reduced recruitment of leukocytes to atherosclerotic plaques in mice, dampening vascular wall inflammation and making plaques smaller. Furthermore, RNAi decreased migration of leukocytes into infarcted myocardium, improving the recovery after ischemia. Such a strategy may help to prevent reinfarction and heart failure in high-risk patients with acute MI.
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Rapid and efficient diagnosis of bacterial infection is critical in combating infections, esp. in the hospital setting where drug resistance to antibiotics is on the rise. CSB investigators have developed a new device to shorten the diagnosis of bacterial infection to less than 2 hours. The “PAD” system (short for polarization diagnostics) is a combination of optical read-outs of genetic bacterial information and can ultimately performed in a physician’s office at low cost.
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Macrophages are mostly viewed as tumor-promoting cells. They can infiltrate solid tumors in high numbers, and their presence at the tumor site is often associated with decreased patient survival. However, much less is known about macrophages located outside the tumor stroma. Mikael Pittet and colleagues now show that a population of lymph node macrophages, called subcapsular sinus (SCS) macrophages, unexpectedly protects against melanoma. The study was published in Science on March 17, 2016.
