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In what fields would APM cause the most pronounced economic disruption and the collapse of global supply chains to more local chains?

The digital revolution had far-reaching effects on information industries. APM-based production promises to have similarly far-reaching effects, but transposed into the world of physical products. In thinking about implications for international trade and economic organization, three aspects should be kept in mind: a shift from scarce to common raw materials, a shift from long supply chains to more direct paths from raw materials to finished products, and a shift toward flexible, localized manufacturing based on production systems with capabilities that are comparable on-demand printing. This is enough to at least suggest the scope of the changes to expect from a mature form of APM-based production — which again is a clear prospect but emphatically not around the corner.
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-Posted by Stephanie C

(credit: Mary Leonard, University of Pennsylvania Biomedical Art & Design)

Research into using nanotechnology for improved drug delivery continues to advance as current nanoparticle technology is combined with increasingly more sophisticated biotechnology. One major problem with using nanoparticles for targeted drug delivery is that the patient’s immune system often clears the particle before they can be effective. A new approach uses a peptide derived from an important immune system molecule to fool the immune system. A commentary accompanying the publication (abstract) of the research in Science describes how short peptides from a human protein called CD47, which tells important immune system cells that cells or particles bearing the protein are human, not foreign, were used as a “passport” to get nanoparticles past the immune system. Additional details are supplied in a University of Pennsylvania news release “Penn Researchers Develop Protein ‘Passport’ That Helps Nanoparticles Get Past Immune System“:

… The research was conducted by professor Dennis Discher, graduate students Pia Rodriguez, Takamasa Harada, David Christian and Richard K. Tsai and postdoctoral fellow Diego Pantano … “From your body’s perspective,” Rodriguez said, “an arrowhead a thousand years ago and a pacemaker today are treated the same — as a foreign invader.

“We’d really like things like pacemakers, sutures and drug-delivery vehicles to not cause an inflammatory response from the innate immune system.”

The innate immune system attacks foreign bodies in a general way. Unlike the learned response of the adaptive immune system, which includes the targeted antibodies that are formed after a vaccination, the innate immune system tries to destroy everything it doesn’t recognize as being part of the body.

This response has many cellular components, including macrophages — literally “big eaters” — that find, engulf and destroy invaders. Proteins in blood serum work in tandem with macrophages; they adhere to objects in the blood stream and draw macrophages’ attention. If the macrophage determines these proteins are stuck to a foreign invader, they will eat it or signal other macrophages to form a barrier around it.

Drug-delivery nanoparticles naturally trigger this response, so researchers’ earlier attempts to circumvent it involved coating the particles with polymer “brushes.” These brushes stick out from the nanoparticle and attempt to physically block various blood serum proteins from sticking to its surface.

However, these brushes only slow down the macrophage-signaling proteins, so Discher and colleagues tried a different approach: Convincing the macrophages that the nanoparticles were part of the body and shouldn’t be cleared.

In 2008, Discher’s group showed that the human protein CD47, found on almost all mammalian cell membranes, binds to a macrophage receptor known as SIRPa in humans. Like a patrolling border guard inspecting a passport, if a macrophage’s SIRPa binds to a cell’s CD47, it tells the macrophage that the cell isn’t an invader and should be allowed to proceed on.

“There may be other molecules that help quell the macrophage response,” Discher said. “But human CD47 is clearly one that says, ‘Don’t eat me’.”

Since the publication of that study, other researchers determined the combined structure of CD47 and SIRPa together. Using this information, Discher’s group was able to computationally design the smallest sequence of amino acids that would act like CD47. This “minimal peptide” would have to fold and fit well enough into the receptor of SIRPa to serve as a valid passport.

After chemically synthesizing this minimal peptide, Discher’s team attached it to conventional nanoparticles that could be used in a variety of experiments.

“Now, anyone can make the peptide and put it on whatever they want,” Rodriguez said.

The research team’s experiments used a mouse model to demonstrate better imaging of tumors and as well as improved efficacy of an anti-cancer drug-delivery particle.

As this minimal peptide might one day be attached to a wide range of drug-delivery vehicles, the researchers also attached antibodies of the type that could be used in targeting cancer cells or other kinds of diseased tissue. Beyond a proof of concept for therapeutics, these antibodies also served to attract the macrophages’ attention and ensure the minimal peptide’s passport was being checked and approved.

“We’re showing that the peptide actually does inhibit the macrophage’s response,” Discher said. “We force the interaction and then overwhelm it.”

The test of this minimal peptide’s efficacy was in mice that were genetically modified so their mac[r]ophages had SIRPa receptors similar to the human version. The researchers injected two kinds of nanoparticles — ones carrying the peptide passport and ones without — and then measured how fast the mice’s immune systems cleared them.

“We used different fluorescent dyes on the two kinds of nanoparticles, so we could take blood samples every 10 minutes and measure how many particles of each kind were left using flow cytometry,” Rodriguez said. “We injected the two particles in a 1-to-1 ratio and 20-30 minutes later, there were up to four times as many particles with the peptide left.”

Even giving therapeutic nanoparticles an additional half-hour before they are eaten by macrophages could be a major boon for treatments. Such nanoparticles might need to make a few trips through the macrophage-heavy spleen and liver to find their targets, but they shouldn’t stay in the body indefinitely. Other combinations of exterior proteins might be appropriate for more permanent devices, such as pacemaker leads, enabling them to hide from the immune system for longer periods of time.

While more research is necessary before such applications become a reality, reducing the peptide down to a sequence of only a few amino acids was a critical step. The relative simplicity of this passport molecule to be more easily synthesized makes it a more attractive component for future therapeutics. …

A very interesting feature of this work is the computational identification of a small structure, in this case a peptide, that can substitute for a crucial part of the function of a large biological system (phagocytic cells to recognize non-self). We should probably expect to see this strategy often as nanomedicine evolves from predominantly biotechnology toward more machine-like advanced nanotechnology.
—James Lewis, PhD

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I like to read a lot of journals and articles about different topics and then lie on the couch or take a walk and just let all the information settle. Then all of a sudden I can get an idea and connect some dots. Then it’s back to reading so I can fill in missing pieces.
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[I] found the names and professional emails of lots of professors in my area who were working on pancreatic cancer…. Week after week I’d receive endless rejections. The most helpful one was actually from a researcher who took the time to point out every flaw and reason why my project was impossible.
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One of my most world- expanding experiences came very quickly when I went to Singularity U in California. I met people who weren’t afraid of failure, but just used failure to say well that path didn’t work and moved on.

Stories like this are good reminders to value not only good ideas, but to value people who show propensity for innovation.
-Posted by Stephanie C

(Credit: Courtesy of UCLA Engineering)

One of the most promising near-term applications of current nanotechnology is in targeted drug delivery to treat cancer. Despite the fact that a number of approaches based on very different areas of nanoscience have shown promise in delivering a wide variety of agents in different animal models of cancer, a number of challenges remain, principally involving the stability of the nanoparticles in the circulatory system, getting them into cancer cells, releasing the cargo to kill the cells, and the fact that cancer cells often have defenses against anti-cancer drugs. A core-shell nanoparticle has been cleverly adapted to deliver a particularly effective agent to where it is needed. A hat tip to ScienceDaily for reprinting this UCLA news release “Tiny capsule effectively kills cancer cells“:

Devising a method for more precise and less invasive treatment of cancer tumors, a team led by researchers from the UCLA Henry Samueli School of Engineering and Applied Science has developed a degradable nanoscale shell to carry proteins to cancer cells and stunt the growth of tumors without damaging healthy cells.

In a new study, published online Feb. 1 in the peer-reviewed journal Nano Today [abstract], a group led by Yi Tang, a professor of chemical and biomolecular engineering and a member of the California NanoSystems Institute at UCLA, reports developing tiny shells composed of a water-soluble polymer that safely deliver a protein complex to the nucleus of cancer cells to induce their death. The shells, which at about 100 nanometers are roughly half the size of the smallest bacterium, degrade harmlessly in non-cancerous cells.

The process does not present the risk of genetic mutation posed by gene therapies for cancer, or the risk to healthy cells caused by chemotherapy, which does not effectively discriminate between healthy and cancerous cells, Tang said.

“This approach is potentially a new way to treat cancer,” said Tang. “It is a difficult problem to deliver the protein if we don’t use this vehicle. This is a unique way to treat cancer cells and leave healthy cells untouched.”

The cell-destroying material, apoptin, is a protein complex derived from an anemia virus in birds. This protein cargo accumulates in the nucleus of cancer cells and signals to the cell to undergo programmed self-destruction.

The polymer shells are developed under mild physiological conditions so as not to alter the chemical structure of the proteins or cause them to clump, preserving their effectiveness on the cancer cells.

Tests done on human breast cancer cell lines in laboratory mice showed significant reduction in tumor growth.

“Delivering a large protein complex such as apoptin to the innermost compartment of tumor cells was a challenge, but the reversible polymer encapsulation strategy was very effective in protecting and escorting the cargo in its functional form,” said Muxun Zhao, lead author of the research and a graduate student in chemical and biomolecular engineering at UCLA.

Tang’s group continues to research ways of more precisely targeting tumors, prolonging the circulation time of the capsules and delivering other highly sought-after proteins to cancer cells.

There is nothing very interesting here from the standpoint of the eventual development of atomically precise manufacturing, but this work presents an excellent case for making the most of the current tools of nanotechnology and employing a deep knowledge of biotechnology and using imaging technology to see what happens inside of cells to develop a promising solution to a set of difficult and important problems.
—James Lewis, PhD

Christine Peterson

Foresight Co-Founder and Past President Christine Peterson is interviewed on the Singularity Weblog in a 47-minute tour that covers nanotechnology, the founding of the Foresight Institute, her work on personal life extension through Health Activator, open source, and the Technological Singularity. “Christine Peterson on Singularity 1 on 1: Join Us to Push the Future in a Positive Direction“:

During my Singularity 1 on 1 interview with Christine Peterson we discuss a variety of topics such as: how she got interested in nanotechnology and the definition thereof; how, together with Eric Drexler, she started the Foresight Institute for Nanotechnology; her interest in life extension; Dr. Drexler’s seminal book Engines of Creation; cryonics and chemical brain preservation; 23andMe and other high- and low-tech tips for improved longevity; whether we should fear nanotechnology or not; the 3 most exciting promises of nanotech; women in technology; coining the term “open source” and using Apple computers; the technological singularity and her take on it…

Hear Christine discuss some challenges while presenting an essentially optimistic message—a wonderful future is coming from science and technology over the next few decades—a future that encourages everyone to get involved.
—James Lewis, PhD

Harmless bacteria could be re-engineered into microscopic factories that could, in addition to more immediate applications, perhaps provide components for more general molecular manufacturing systems. (credit Imperial College, London)

Synthetic biology and molecular manufacturing/productive nanosystems have in common the effort to rationally engineer systems to make and assemble parts for complex molecular machine systems. The effort in synthetic biology to design complex biological systems in a hierarchical architecture from well-characterized molecular parts is accelerating. A hat tip to ScienceDaily for reprinting this Imperial College news release “Discovery in synthetic biology a step closer to new industrial revolution“:

Scientists report that they have developed a method that cuts down the time it takes to make new ‘parts’ for microscopic biological factories from 2 days to only 6 hours.

The scientists, from Imperial College London, say their research brings them another step closer to a new kind of industrial revolution, where parts for these biological factories could be mass-produced. These factories have a wealth of applications including better drug delivery treatments for patients, enhancements in the way that minerals are mined from deep underground and advances in the production of biofuels.

Professor Paul Freemont, Co- Director of the Centre for Synthetic Biology and Innovation at Imperial College London and principal co-investigator of the study, which is published today in the journal Nucleic Acids Research [abstract, free full text PDF], says:

“Before the industrial revolution most items were made by hand, which meant that they were slower to manufacture, more expensive to produce and limited in number. We are at a similar juncture in synthetic biology, having to test and build each part from scratch, which is a long and slow process. We demonstrate in our study a new method that could help to rapidly scale up the production and testing of biological parts.”

Parts made up of DNA are re-engineered by scientists and put into cells to make biological factories. However, a major bottleneck in synthetic biology is the lack of parts from which to build new types of factories. To build parts using the current time-consuming method, scientists have to re-engineer DNA in a cell and observe how it works. If it functions according to their specifications, then the scientists store the part specifications in a catalogue.

Now, scientists from Imperial College London have devised a much quicker method that does away with the need for them to re-engineer a cell every time they want to make a new part. The team say their work could lead to vast new libraries of off-the-shelf components that could be used to build more sophisticated biological factories.

James Chappell, co-author of the study from the Centre for Synthetic Biology and Innovation at Imperial College London, says:

“One of the major goals in synthetic biology is to find a way to industrialise our processes so that we can mass produce these biological factories much in the same way that industries such as car manufacturers mass produce vehicles in a factory line. This could unlock the potential of this field of science and enable us to develop much more sophisticated devices that could be used to improve many facets of society. Excitingly, our research takes us one step closer to this reality, providing a rapid way of developing new parts.”

When a cell is re-engineered, the re-programmed DNA in the cell encodes a message that is conveyed by molecules called messenger ribonucleic acid (mRNA) to the cell’s production factories called ribosomes. The ribosomes translate the genetic information into a command that instructs the cell to perform functions. For example, scientists can already re-engineer a cell into an infection detector factory, which produces a protein that detects chemical signals from human pathogenic bacteria and changes colour to indicate their presence.

In the study, the Imperial researchers demonstrate for the first time that the same method can be achieved in a test tube outside of a cell. This involves extracting from cells the machinery that produces mRNA and proteins and providing the energy and building blocks to help them survive in test tubes. The team then add their re-programmed DNA to the solution and observe how it functions.

The advantage of this method is that scientists can develop litres of this cell-like environment so that multiple re-programmed DNA can be tested simultaneously, which speeds up the production process of parts.

The next stage of the research is to expand the types of parts and devices that can be developed using this method. They also are aiming to develop a method using robots to speed up and make the whole process automated.

Professor Richard Kitney, co- Director of the Centre for Synthetic Biology and Innovation at Imperial College London says: “Synthetic biology is seen by the British Government as having the potential to create new industries and jobs for the benefit of the UK economy. This work is part of a wider, major research programme within the Centre to develop technology that can be used across a range of industrial applications.”

The hope driving this research is that biological parts will transform industrial sectors like drug delivery and biofuels production into molecular manufacturing processes. Whether synthetic biology can eventually be made to contribute parts for nanofactories to implement more general molecular manufacturing using stronger, more rigid parts, remains to be seen.
—James Lewis, PhD

Shanta Dhar, right, an assistant professor of chemistry in the UGA Franklin College of Arts and Sciences, and doctoral student Sean Marrache have fabricated nanoparticles that boost the effectiveness of drugs by delivering them to the mitochondria of cells (credit: University of Georgia).

Targeted drug delivery is one of the most important contributions of current and near-term nanotechnology to medicine. New research shows that specifically targeting one component of the cell makes nanoparticle-mediated drug delivery much more effective for a variety of applications. A hat tip to KurzweilAI.net for reprinting this University of Georgia news release “UGA researchers boost efficacy of drugs by using nanoparticles to target ‘powerhouse of cells’“:

Nanoparticles have shown great promise in the targeted delivery of drugs to cells, but researchers at the University of Georgia have refined the drug delivery process further by using nanoparticles to deliver drugs to a specific organelle within cells.

By targeting mitochondria, often called “the powerhouse of cells,” the researchers increased the effectiveness of mitochondria-acting therapeutics used to treat cancer, Alzheimer’s disease and obesity in studies conducted with cultured cells.

“The mitochondrion is a complex organelle that is very difficult to reach, but these nanoparticles are engineered so that they do the right job in the right place,” said senior author Shanta Dhar, an assistant professor of chemistry in the UGA Franklin College of Arts and Sciences.

Dhar and her co-author, doctoral student Sean Marrache, used a biodegradable, FDA-approved polymer to fabricate their nanoparticles and then used the particles to encapsulate and test drugs that treat a variety of conditions. Their results were published this week in early edition of the journal Proceedings of the National Academy of Sciences [abstract].

To test the effectiveness of their drug targeting system against cancer, they encapsulated the drug lonidamine, which works by inhibiting energy production in the mitochondria, and, separately, a form of the antioxidant vitamin E. They then treated cultured cancer cells and found that mitochondrial targeting increased the effectiveness of the drugs by more than 100 times when compared to the drugs alone and by five times when compared to the delivery of drugs with nanoparticles that target the outside of cells.

Similarly, the compound curcumin has shown promise in inhibiting formation of the amyloid plaques that are a hallmark of Alzheimer’s disease, but it quickly degrades in the presence of light and is broken down rapidly by the body. By encapsulating curcumin in the mitochondria-targeting nanoparticles, however, the researchers were able to restore the ability of brain cells in culture to survive despite the presence of a compound that encourages plaque formation. Nearly 100 percent of the cells treated with the mitochondria-targeting nanoparticles survived in the presence of the plaque-inducing compound, compared to 67 percent of cells treated with free curcumin and 70 percent of cells treated with nanoparticles that target the outside of cells.

Finally, the researchers encapsulated the obesity drug 2,4-DNP—which works by making energy production in the mitochondria less efficient—in their nanoparticles and found that it reduced the production of fat by cultured cells known as preadipocytes by 67 percent compared to cells treated with the drug alone and by 61 percent of cells treated with nanoparticles that target the outside of cells.

“A lot of diseases are associated with dysfunctional mitochondria, but many of the drugs that act on the mitochondria can’t get there,” Marrache said. “Rather than try to alter the drugs, which can reduce their effectiveness, we encapsulate them in these nanoparticles and precisely deliver them to the mitochondria.”

Dhar said that getting drugs to the mitochondria is no simple feat. Upon entering cells, nanoparticles enter a sorting center known as the endosome. The first thing Dhar and Marrache had to demonstrate was that the nanoparticles escape from the endosome and don’t end up in the cells’ disposal center, the lysosome.

The mitochondria itself is protected by two membranes separated by an interstitial space. The outer membrane only permits molecules of a certain size to pass through, while the inner membrane only permits molecules of a given range of charges to pass. The researchers constructed a library of nanoparticles and tested them until they identified the optimum size range—64 to 80 nanometers, or approximately 1,000 times finer than the width of a human hair—and an optimum surface charge, plus 34 millivolts.

Dhar notes the components they used to create the nanoparticles are FDA approved and that their methods are highly reproducible and therefore have the potential to be translated into clinical settings. The researchers are currently testing their targeted delivery system in rodents and say that preliminary results are promising.

“Mitochondrial dysfunctions cause many disorders in humans,” Dhar said, ” so there are several potential applications for this delivery system.”

Subject to the usual caveat that these nanoparticles are still in an early stage of testing, having been tested only in cell culture, it is remarkable that such effective targeting to reach the matrix of the mitochondria was achieved by the relatively crude strategy of optimizing only particle size and surface charge through engineering polymer composition. So success was achieved through clever application of biological knowledge more than through sophisticated atomically precise construction. It will be fascinating to watch the evolution of this technology as ever more sophisticated construction leads to increasing effectiveness. While we are waiting, this targeting of drug delivery to mitochondria is likely to be especially helpful because so many pathologies seem rooted in imperfections and consequences of the symbiosis that led to eukaryotic cells, and all complex life on Earth, nearly two billion years ago.
—James Lewis, PhD

Predicted structure of the cyclic nonamer proposed by the theorists, shown to match the actual folded structure with remarkable accuracy (credit: Lawrence Berkeley National Laboratory).

Peptoids are chemical cousins of proteins that present opportunities for molecular engineering comparable to but different from those presented by biomolecular systems (reviewed by Drexler here). Progress toward rational design of peptoids has been reported by a team of scientists at New York University, Lawrence Berkeley National Laboratory, Simprota Corporation, Stony Brook University, and Temple University. A hat tip to KurzweilAI.net for describing this news release from Lawrence Berkeley National Laboratory “Form, Function and Folding: In collaboration with Berkeley Lab, a team of scientists move toward rational design of artificial proteins“:

In the world of proteins, form defines function. Based on interactions between their constituent amino acids, proteins form specific conformations, folding and twisting into distinct, chemically directed shapes. The resulting structure dictates the proteins’ actions; thus accurate modeling of structure is vital to understanding functionality.

Peptoids, the synthetic cousins of proteins, follow similar design rules. Less vulnerable to chemical or metabolic breakdown than proteins, peptoids are promising for diagnostics, pharmaceuticals, and as a platform to build bioinspired nanomaterials, as scientists can build and manipulate peptoids with great precision. But to design peptoids for a specific function, scientists need to first untangle the complex relationship between a peptoid’s composition and its function-defining folded structure.

Past efforts to predict protein structure have met with limited success, but now a scientific team led by Glenn Butterfoss, and Barney Yoo, research scientists at New York University, in collaboration with investigators from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab), Stony Brook University and Temple University have demonstrated that a computer modeling approach similar to one used to predict protein structures can accurately predict peptoid conformation as well.

The authors describe this accomplishment in a new paper in the Proceedings of the National Academy of Sciences (PNAS) titled, “De novo structure prediction and experimental characterization of folded peptoid oligomers,” [abstract] coauthored by Jonathan Jaworski, Ilya Chorny, Ken Dill, Ronald Zuckermann, Richard Bonneau, Kent Kirshenbaum, and Vincent Voelz.

“Natural selection has engineered protein sequences that can self-assemble into molecular machines with specific functions. Why can’t we do the same with biologically inspired synthetic materials?” Voelz, Principal Investigator with Temple University, explains. …

Together, they proposed a ‘blind structure prediction’ challenge. This self-assessment technique, responsible for the enormous progress in the world of protein structure modeling, allows scientists to test the fidelity of their computational models by predicting the three-dimensional structure of a known molecule and then comparing their proposed structure to the X-ray crystallography results.

An analogous, combined experimental-computational method was employed by the peptoid team in an effort to advance the computational design of peptoid structure. X-ray crystal structures for three peptoid molecules, two small and linear and one larger and cyclical, were simultaneously determined, but not disclosed to the theoretical modelers. The experimentalists then used a combination of two simulation techniques, Replica Exchange Molecular Dynamics (REMD) simulation and Quantum Mechanical refinement (QM). REMD can efficiently predict the preferred general conformations, and the QM calculations further refine the conformational prediction. In combination, these two calculations accurately define the physical structures of molecules.

The proposed structural predictions of the peptoid molecules did exceedingly well at calculating the actual folded conformations. The first two blind predictions were calculated for two linear, small N-alkyl and N-aryl peptoid trimers. Of these, the N-aryl peptoid trimer was the best blind prediction, matching the crystal described conformation to within 0.2 Å. The N-alkyl trimer prediction matched less well with the crystal results because of its increased flexibility.

The greater challenge facing the group was structural prediction of the larger, cyclic peptoid nonamer. Six different possible conformations were considered for the final, submitted prediction and the top pick proved to agree best with the crystallography results to an accuracy of 1.0 Å.

This success suggests that reliable structure prediction for complex three-dimensional folds is within reach, an enormous step forward on the path to reliable and efficient computational peptoid design. …

Their success at computational modeling could easily accelerate progress along this path to advanced molecular nanotechnology to determine the potential advantages of such structures. The main caveat is that the largest structure they have worked with so far is made from only nine subunits, so that it will be important to determine how well their computational method works with larger and more varied structures.
—James Lewis, PhD

The shear-activated nanotherapeutic breaks apart and releases its drug when it encounters regions of vascular narrowing (credit: Wyss Institute).

A novel nanoparticle that aggregates under normal blood flow but breaks apart under high shear stress encountered in regions of vascular narrowing was found to improve survival in mice with occluded blood vessels with 1/50th of the normal dose of a standard clot-busting drug. A hat tip to KurzweilAI for describing this news release “Harvard’s Wyss Institute Develops Novel Nanotherapeutic that Delivers Clot-Busting Drugs Directly to Obstructed Blood Vessels“:

Researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University have developed a novel biomimetic strategy that delivers life-saving nanotherapeutics directly to obstructed blood vessels, dissolving blood clots before they cause serious damage or even death. This new approach enables thrombus dissolution while using only a fraction of the drug dose normally required, thereby minimizing bleeding side effects that currently limit widespread use of clot-busting drugs.

The research findings, which were published online today in the journal Science [abstract], have significant implications for treating major causes of death, such as heart attack, stroke and pulmonary embolism, that are caused by acute vascular blockage by blood thrombi.

The inspiration for the targeted vascular nanotherapeutic approach came from the way in which normal blood platelets rapidly adhere to the lining of narrowed vessels, contributing to the development of atherosclerotic plaques. When vessels narrow, high shear stresses provide a physical cue for circulating platelets to stick to the vessel wall selectively in these regions. The vascular nanotherapeutic is similarly about the size of a platelet, but it is an aggregate of biodegradable nanoparticles that have been coated with the clot-busting drug, tissue plasminogen activator (tPA). Much like when a wet ball of sand breaks up into individual grains when it is sheared between two hands, the aggregates selectively dissociate and release tPA-coated nanoparticles that bind to clots and degrade them when they sense high shear stress in regions of vascular narrowing, such as caused by blood clot formation.

Disruption of normal blood flow to the heart, lung, and brain due to thrombosis is one of the leading causes of death and long-term adult disability in the developing world. Today, patients with pulmonary embolism, strokes, heart attacks and other types of acute thrombosis leading to near-complete vascular occlusion, are most frequently treated in an acute care hospital setting using systemic dosages of powerful clot-dissolving drugs. Because these drugs can cause severe and often fatal bleeding as they circulate freely throughout the body, the size of the dosage given to any patient is limited because efficacy must be balanced against risk.

The new shear-activated nanotherapeutic has the potential to overcome these efficacy limitations. By targeting and concentrating drug at the precise site of the blood vessel obstruction, the Wyss team has been able to achieve improved survival in mice with occluded lung vessels with less than 1/50th of the normal therapeutic dose, which should translate into fewer side effects and greater safety. This raises the possibility that, in the future, an emergency technician might be able immediately administer this nanotherapeutic to anyone suspected of having a life-threatening blood clot in a vital organ before the patient even reached the hospital.

This work is yet another instance in which near-term nanotechnology is providing opportunities to make current therapeutic approaches (biotech clot busting drugs, like tissue plasminogen activator) more effective and much safer to use so that they can be used more widely, supplied quickly in emergency situations, and, we can hope, help many more people.
—James Lewis, PhD