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Study demonstrates X-ray fluorescence spectroscopy is a non-destructive way to date artwork
Ancient Japanese gold leaf artists were truly masters of their craft. An analysis of six ancient Namban paper screens show that these artifacts are gilded with gold leaf that was hand-beaten to the nanometer scale. Study leader Sofia Pessanha of the Atomic Physics Center of the University of Lisbon in Portugal believes that the X-ray fluorescence technique her team used in the analysis could also be used to date other artworks without causing any damage to them. The results are published in Springer’s journal Applied Physics A: Material Science and Processing.
Gold leaf refers to a very thin sheet made from a combination of gold and other metals. It has almost no weight and can only be handled by specially designed tools. Even though the ancient Egyptians were probably the first to gild artwork with it, the Japanese have long been credited as being able to produce the thinnest gold leaf in the world. In Japanese traditional painting, decorating with gold leaf is named Kin-haku, and the finest examples of this craft are the Namban folding screens, or byobu. These were made during the late Momoyama (around 1573 to 1603) and early Edo (around 1603 to 1868) periods.
Pessanha’s team examined six screens that are currently either part of a museum collection or in a private collection in Portugal. Four screens belong to the Momoyama period, and two others were decorated during the early Edo period. The researchers used various X-ray fluorescence spectroscopy techniques to test the thickness and characteristics of the gold layers. The method is completely non-invasive, no samples needed to be taken, and therefore the artwork was not damaged in any way. Also, the apparatus needed to perform these tests is portable and can be done outside of a laboratory.
The gilding was evaluated by taking the attenuation or weakening of the different characteristic lines of gold leaf layers into account. The methodology was tested to be suitable for high grade gold alloys with a maximum of 5 percent influence of silver, which is considered negligible.
The two screens from the early Edo period were initially thought to be of the same age. However, Pessanha’s team found that gold leaf on a screen kept at Museu Oriente in Lisbon was thinner, hence was made more recently. This is in line with the continued development of the gold beating techniques carried out in an effort to obtain ever thinner gold leaf.
“This simple comparison allowed establishing a timeline between the manufacture of two pieces attributed to the same period, proving that X-ray fluorescence techniques can be an important asset in the dating of artworks,” says Pessanha.
Reference: Pessanha, S. et al (2014). Comparison of gold leaf thickness in Namban folding screens using X-ray fluorescence, Applied Physics A: Material Science and Processing. DOI 10.1007/s00339-014-8531-z
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CORAL GABLES, Fla. (June 25, 2014) — With the continuing need for very small devices in therapeutic applications, there is a growing demand for the development of nanoparticles that can transport and deliver drugs to target cells in the human body.
Recently, researchers created nanoparticles that under the right conditions, self-assemble – trapping complementary guest molecules within their structure. Like tiny submarines, these versatile nanocarriers can navigate in the watery environment surrounding cells and transport their guest molecules through the membrane of living cells to sequentially deliver their cargo.
Although the transport of molecules inside cells with nanoparticles has been previously achieved using various methods, researchers have developed nanoparticles capable of delivering and exchanging complementary molecules. For practical applications, these nanocarriers are highly desirable, explains Francisco Raymo, professor of chemistry in the University of Miami College of Arts and Sciences and lead investigator of this project.
"The ability to deliver distinct species inside cells independently and force them to interact, exclusively in the intracellular environment, can evolve into a valuable strategy to activate drugs inside cells," Raymo says.
The new nanocarriers are15 nanometers in diameter. They are supramolecular constructs made up of building blocks called amphiphilic polymers. These nanocarriers hold the guest molecules within the confines of their water-insoluble interior and use their water-soluble exterior to travel through an aqueous environment. As a result, these nanovehicles are ideal for transferring molecules that would otherwise be insoluble in water, across a liquid environment.
IMAGE: The sequential transport of donors and acceptors across cell membranes with independent and dynamic nanocarriers enables energy transfer exclusively in the intracellular space with concomitant fluorescence activation.
"Once inside a living cell, the particles mix and exchange their cargo. This interaction enables the energy transfer between the internalized molecules," says Raymo, director of the UM laboratory for molecular photonics. "If the complementary energy donors and acceptors are loaded separately and sequentially, the transfer of energy between them occurs exclusively within the intracellular space," he says. "As the energy transfer takes place, the acceptors emit a fluorescent signal that can be observed with a microscope."
Essential to this mechanism are the noncovalent bonds that loosely hold the supramolecular constructs together. These weak bonds exist between molecules with complementary shapes and electronic properties. They are responsible for the ability of the supramolecules to assemble spontaneously in liquid environments. Under the right conditions, the reversibility of these weak noncovalent contacts allows the supramolecular constructs to exchange their components as well as their cargo.
The experiments were conducted with cell cultures. It is not yet known if the nanoparticles can actually travel through the bloodstream.
"That would be the dream, but we have no evidence that they can actually do so," Raymo says. "However, this is the direction we are heading."
The next phase of this investigation involves demonstrating that this method can be used to do chemical reactions inside cells, instead of energy transfers.
"The size of these nanoparticles, their dynamic character and the fact that the reactions take place under normal biological conditions (at ambient temperature and neutral environment) makes these nanoparticles an ideal vehicle for the controlled activation of therapeutics, directly inside the cells," Raymo says.
IMAGE: The sequential transport of donors and acceptors across cell membranes with independent and dynamic nanocarriers enables energy transfer exclusively in the intracellular space with concomitant fluorescence activation.
The current study is titled "Intracellular guest exchange between dynamic supramolecular hosts." It's published in the Journal of the American Chemical Society. Other authors are John F. Callan, co-corresponding author of the study, from the School of Pharmacy and Pharmaceutical Sciences at the University of Ulster; Subramani Swaminathan and Janet Cusido from the UM's Laboratory for Molecular Photonics, Department of Chemistry in the College of Arts and Sciences; and Colin Fowley and Bridgeen McCuaghan, School of Pharmacy and Pharmaceutical Sciences at the University of Ulster.
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This work focuses on the interactions between molecules and in particular on "amphiphilic" molecules, which contain two distinct parts to them. Household detergent is a good example of a product that relies on interacting amphiphilic molecules. Detergent molecules comprise two distinct parts: one that prefers to form bonds with water (hydrophilic) and the other that likes oily substances (hydrophobic). Detergents are used for cleaning because when they are added to dirty water, they orient and assemble around oily dirt, forming small clusters that allow grease and dirt to be more easily removed from the water.
The newly reported method takes the concept of amphiphilic assembly one step further, and applies it to a completely new set of hydrophobic molecules, intriguingly with no water-loving part to them. These new "hydrophobic amphiphiles" still have different 'parts', but the assembly process relies on more subtle interactions.
The research was carried out by an international team of researchers led by Dr Martin Hollamby (Keele University, UK) and Dr Takashi Nakanishi (National Institute for Materials Science, Japan). Together they showed used neutron scattering techniques at the Institut Laue-Langevin (ILL) to investigate the arrangement of these clusters and showed that hydrophobic amphiphiles can still assemble into extended structures in much the same way as conventional amphiphiles.
One example is a molecule shaped like a football but with a long tail. The amphiphile has been tailor made from 'bucky balls' - football-shaped molecules made up of 60 carbon atoms (C60) which are chemically modified by attaching a much longer 'tail' made up of chains of carbon atoms, as found in a regular soap. The new detergents resemble "molecular tadpoles". When dissolved in solvents that interact with the tails, these molecules assemble to form a core of C60 spheres and a shell of carbon chains.
"Changing the chemistry of the chains can even lead to gels made of bundled C60 wires that have a measureable (photo)conductivity" explains Dr Martin Hollamby. "By adding pristine C60 in place of the solvent, we instead prepare a sheet-like material with totally different properties".
Small-angle neutron scattering data obtained on beamline D11 at the ILL was crucially used to prove the internal structure of these clusters.
"The light elements that makes up these 'molecular tadpoles' are easily located by neutrons" says Dr Isabelle Grillo, at the ILL. "Moreover, small angle neutron scattering which we use at the ILL allows to characterise the self-assembled systems from the nanometre scale to tenth of micrometres and is perfectly adapted to observe the coming together of the C60 footballs' into these beautiful core structures."
This flexibility is the remarkable thing about the new route towards self-organised structures. A great variety of different structures can be produced just by making small changes to the chemical structure and the additives (solvent or C¬60) used. This level of control over self-assembly in complex molecules such as C60 is unprecedented.
One area that could be significantly impacted by this new discovery is the field of 'molecular electronics'. These carbon-based electronics could provide a cheaper alternative to traditional silicon technology and allow for flexible handheld devices for many functions, including smartphones and tablets for watching TV.
Furthermore, the new molecular electronic components could lead to improved properties (e.g. higher efficiency, lower power consumption) simply by optimizing how the molecules interact with each other. In 2018 during the next World Cup in Russia you could be using football-shaped molecules to actually watch the football!
Excess Free Radicals in the body (called oxidative stress) triggers many diseases, but it's easy to prevent or in some cases reverse. To neutralize excess free radicals in the body, eat antioxidant foods daily, with high ORAC values (see ORAC table http://www.oracvalues.com/sort/orac-value ) and drink Hydrated Fullerene or C-60 water-the highest antioxidant in the world. For information contact me
The paths taken by a single cholinergic neuron as it branches through a thin section of the forebrain of a mouse
Nathans Lab, eLife
By studying laboratory mice, scientists at The Johns Hopkins University have succeeded in plotting the labyrinthine paths of some of the largest nerve cells in the mammalian brain: cholinergic neurons, the first cells to degenerate in people with Alzheimer’s disease.
“For us, this was like scaling Mount Everest,” says Jeremy Nathans, Ph.D., professor of molecular biology and genetics, neuroscience, and ophthalmology at the Johns Hopkins University School of Medicine. “This work reveals the amazing challenges that cholinergic neurons face every day. Each of these cells is like a city connected to its suburbs by a single, one-lane road, with all of the emergency services located only in the city. You can imagine how hard it would be in a crisis if all of the emergency vehicles had to get to the suburbs along that one road. We think something like this might be happening when cholinergic neurons trying to repair the damage done by Alzheimer’s disease.”
Each cholinergic neuron, Nathans explains, has roughly 1,000 branch points. If lined up end to end, one neuron’s branches would add up to approximately 15 times the length of the mouse brain. But all of the branches are connected by a single, extremely thin “pipeline” to one hub — the cell body — that provides for the needs of the branches. The challenge of moving material through this single pipeline could make it very difficult for cholinergic neurons to combat the challenges that come with a disorder like Alzheimer’s disease, he says. Now, by mapping the branches and pipelines, scientists will likely get a better fix on what happens when the neurons fail to meet the challenges.
Cholinergic neurons are among the largest neurons in the mammal brain. Named for their release of a chemical messenger called acetylcholine, they number only in the thousands in mouse brains, a tiny fraction of the 50 to 100 million total neurons. Their cell bodies are located at the base of the brain near its front end, but their branches extend throughout the cerebral cortex, the outermost, wrinkled layer of “grey matter” that is responsible for the mind’s most advanced intellectual functions. Therefore, although there are relatively few cholinergic neurons, they affect a very large part of the brain, Nathans says.
Due to the technical challenge of visualizing the complicated paths of hundreds of tiny branches from a single neuron tangled within millions of other neurons, the actual size and shape of individual cholinergic neurons — and the territory they cover — had been unknown until now, Nathans says. Using genetic engineering methods, the Nathans team programmed several cholinergic neurons per mouse to make a protein that could be seen with a colored chemical reaction. Critical to the success of the work was the ability to limit the number of cells making the protein — if all of the cholinergic neurons made the protein, it would have been impossible to distinguish individual branches.
Because microscopes cannot see through thick tissue, Nathans and his team preserved the mouse brains and then thinly sliced them to produce serial images. The branching path of each neuron was then painstakingly reconstructed from the serial images and analyzed. In adult mice, he says, the average length of the branches of a single cholinergic neuron, lined up end to end, is 31 cm (12 inches), varying from 11 to 49 cm (4 to 19 inches). The average length of a mouse brain is only 2 cm — a bit less than one inch. Although each cholinergic neuron, on average, contains approximately 1,000 branch points, they vary significantly in the extent of the territory that they cover.
The researchers used the same techniques to study the cholinergic neurons of mice with a rodent form of Alzheimer’s disease and found that the branches were fragmented. They also found clumps of material that may have been debris from the disintegrating branches.
Although the cholinergic neurons of human brains have not been individually traced, Nathans’ team was able to calculate that the average cholinergic neuron in the human brain has a total branch length of approximately 100 meters, a bit longer than a football field. “That is a really long pipeline, especially if one considers that the pipes have diameters of only 30 thousandths of a millimeter, far narrower than a human hair,” says Nathans.
He adds, “Although our study only defined a few simple, physical properties of these neurons, such as size and shape, it has equipped us to form and test better hypotheses about what goes wrong with them during disease.”
Other authors of the report include Hao Wu and John Williams of the Johns Hopkins University School of Medicine.
This work was supported by grants from the Human Frontier Science Program, the Howard Hughes Medical Institute and the Brain Science Institute of The Johns Hopkins University.
New Synthesis Method of Nickel-Carbon Heterofullerenes Presented
Heterofullerene molecula. Image courtesy of the authors of the research
Scientists from several British, Spanish and Russian research centers (MIPT, Institute for Spectroscopy RAS, Kurchatov Institute and Kintech Lab Ltd) have come up with a method of synthesizing a new type of nickel-carbon compound. The article titled Formation of nickel-carbon heterofullerenes under electron irradiation has been published by Dalton Transactions and is available as a pre-print at arxiv.org. The first author of the article is Alexander Sinitsa, an MIPT student, and the leading author is Andrey Popov (Institute for Spectroscopy RAS, 1989 MIPT graduate).
Heterofullerenes are hollow molecules with a nearly-spherical shape, which, unlike the typical fullerenes, contain atoms of elements other than carbon. Such compounds were synthesized quite a while ago, in 1991, but till now no heterofullerenes containing nickel, or any other transition metal, have been obtained. Yet, as the authors point out in their article, transition metals are now being studied as catalysts in the synthesis of carbon nanotubes and graphene.
“I’d like to emphasize that the majority of calculations have been performed by a student. Hopefully, students regularly visit the MIPT site and get inspired by their colleagues’ successes. If you are especially interested in the role of MIPT graduates in research, then I can tell you that Irina Lebedeva graduated from the Institute in 2008, and Andrey Knizhnik, perhaps in 1999, but I’m not exactly sure about the year. I’d also like to point out that Elena Bichoutskaia (a Saint Petersburg State University Faculty of Physics graduate) is a member of the Russian diaspora abroad, which is typical of international cooperation of Russian scientists,” Andrey Popov told the MIPT Press Service.
The synthesis of nickel heterofullerenes is supposed to be carried out under electron irradiation, which is used in high-resolution transmission electron microscopy (HRTEM) in order to obtain detailed snapshots showing, if needed, separate atoms. A number of previous experiments conducted by various research groups demonstrated that electronic irradiation can also be applied to synthesize a variety of nanostructures, e.g., one-layer carbon fullerene-filled nanotubes were transformed into two-layer ones.
Using the latest data obtained from the HRTEM images and the results of computer modelling by methods of molecular dynamics, the scientists have shown the potential possibility to transform graphene flakes with nickel cluster into nickel-carbon heterofullerene.
The scientists, though, are not sure about the practical application of such heterofullerenes. According to Andrey Popov, “these new-type molecules can reveal some interesting electronic, magnetic, and optic features, or it may be possible to combine them with some organic functional complexes of interest to biologists and physicians. They can also be used to create 3D organic-metallic structures to store hydrogen”.
In their work, the researchers developed and applied an authentic algorithm for modelling electron-nanostructure interactions. This allows taking into account both fast (just tens of picoseconds) and slow (lasting for full seconds) processes. The fast processes are associated with electron collisions, and the slow ones relate to molecular relaxation.
MIPT Press Service expresses gratitude to Andrey Popov for the invaluable help in preparing the material.
A surface catalyst with a built-in sensor: that's what chemist Hui Wang and co-workers built by bridging a size gap on the nano-scale. Their silver nanoparticles combine plasmon resonance with catalytic activity, making SERS and other analytical data available in real time on a surface catalyst.
Surface catalysts are notoriously difficult to study mechanistically, but scientists at the University of South Carolina and Rice University have shown how to get real-time reaction information from Ag nanocatalysts that have long frustrated attempts to describe their kinetic behavior in detail.
The key to the team's success was bridging a size gap that had represented a wide chasm to researchers in the past. To be effective as nanocatalysts, noble metals such as Au, Pt, Pd and Ag typically must be nanoparticles smaller than 5 nm, says Hui Wang, an assistant professor of chemistry and biochemistry at South Carolina who led the team in collaboration with Peter Nordlander of Rice University.
Unfortunately, 5 nm is below the size threshold at which plasmon resonance can be effectively harnessed. Plasmon resonance is a phenomenon giving rise to a dramatic enhancement of impinging electromagnetic signals, which is the basis of analytical techniques such as surface enhanced Raman spectroscopy (SERS).
The ability to utilize the analytical power of plasmon resonance in a nanomaterial requires larger nanoparticles, "at least tens of nanometers in diameter," says Wang. The incompatibility of the two size regimes had long precluded the use of a range of spectral techniques based on plasmon resonance—SERS is just one—on noble metal nanocatalysts under 5 nm.
But as they just reported in Nano Letters, Wang and his team managed to combine the best of both size worlds.
Starting with cuboidal nanoparticles about 50 nm wide and 120 nm long, they chemically etched flat surfaces in a way that generated curved surfaces, creating nanoparticles that successfully catalyzed a model surface hydrogenation reaction. According to the team, the catalysis is the result of replacing low-energy atoms on the flat surface with exposed atoms after etching.
"If you have a flat surface, the coordination number of every single surface atom is either eight or nine," says Wang of their nanoparticles, which had a surface of pure Ag before etching. "But if you have some atomic steps on a surface, the coordination number will decrease. These exposed atoms are more active."
The stepped surface of the etched nanomaterial thus mimics the environment of a sub-5-nm nanoparticle: more exposed, active surface atoms can participate in catalysis.
And the catalysis is on a nanoparticle with plasmonic activity, which the researchers showed can be "tuned" by varying the shape and size of the nanoparticles. The team demonstrated the ability to convert cuboids (something like a short rod but with square rather than round sides) into what they termed "nanorice" and "nanodumbbells" through two different kinds of chemical etching. The two shapes had distinct plasmonic properties that could be varied by stopping the etching at different stages to create different sizes and shapes of nanoscale rice and dumbbells.
That plasmonic activity can be harnessed for SERS and other analytical techniques to study catalytic reactions in great detail as they occur.
"Raman spectroscopy is extremely powerful, with information about molecular fingerprints—you can see the structures, you can tell how the molecules are oriented on the surface," Wang says. "If you want to use GC, HPLC, or mass spec, you have to damage a sample, but here you can actually monitor the reaction in real time.
"And there is much more information with this approach. For example, we identified the intermediate along the reaction pathway. With those other approaches, it's really hard to do that."
Oxidative stress (free radicals) are a contributing factor in all diseases
A recent US Patent application (May 22, 2104) for Fullerenes or Carbon 60 claims that oxidative stress from free radicals (or Reactive Oxygen Species (ROS)) is a contributing factor in all diseases. WOW I've never seen such a wide ranging claim-Walter Derzko, Toronto.
Re: Fullerene and its use to maintain good health and to prolong the expected lifespan of mammals
...This is from a US patent application of fullerenes... or Carbon--60 partially dissolved in olive oil.
However, Ukrainian-produced hydrated fullerenes (C-60 HyFN's) from Kharkiv are much superior. (see US patent application http://www.freepatentsonline.com/y2014/0079746.html They don’t need an olive oil carrier, which takes two months to dissolve. They are water-soluble. Ukrainian scientists were the only ones who discovered how to make them water-soluble, without increasing its toxicity, like most functionalized fullerene derivatives, which are toxic. Pristine Carbon-60 is a natural product found in abundance in nature, safe and the highest antioxidant in the world and it scavenges/neutralizes excess free radicals in your body. It was approved by the Ukrainian Ministry of Health in 2010 as a “dietary supplement” after 18 years of clinical and preclinical studies—Walter Derzko.
Hydrated Fullerenes or Carbon-60, the highest anti-oxidant in the world is better than traditional botanical anti-oxidants such as blueberry extract or green tea extract, because it does not get immediately metabolized by gut bacteria, before it gets a chance to act as an anti-oxidant. That’s why we see differing ORAC test values for traditional botanical anti-oxidants under in vivo and in vitro conditions. Hydrated Fullerenes do not get metabolized by gut bacteria.
KEY QUOTE: WOW “all diseases caused by free radicals” I’ve never seen any scientist make this wide reaching claim, directly.--Walter Derzko
“Considerable evidence supports the view that oxidative damage involving free radicals occurs in most, if not all, human diseases. Oxidative stress is now recognized as an important contributor to the development of many human diseases including liver fibrosis, ischemia-reperfusion, atherosclerosis, neurodegenerative disease and age-related cancer as well as to process of ageing. Thus antioxidants and systems that can protect against oxidative stress are needed to maintain health. A large body of scientific evidence supports that oxidative stress is directly responsible for aging.”
From the Patent Application (Fullerene and its use to maintain good health and to prolong the expected lifespan of mammals) has a good description of oxidative stress and free radicals:
“2. Description of Related Art Free radicals, such as oxygen radicals and other reactive oxygen/nitrogen/chlorine species (hydroxyl, nitric oxide radicals), are constantly formed in vivo. Some of these molecules are physiologically useful, but they can also result in pathological oxidative stress to cells and tissues. Endogenous defences include both antioxidants and repairing systems. However, excess production of free radicals, their production in inappropriate relative amounts or deficiencies in endogenous defences can have deleterious effects. Free radicals can cause oxidative damage to lipids, DNA, bio molecules, rises in the concentration of intracellular calcium, as well as activation of proteases, nucleases and protein kinases. Considerable evidence supports the view that oxidative damage involving free radicals occurs in most, if not all, human diseases. Oxidative stress is now recognized as an important contributor to the development of many human diseases including liver fibrosis, ischemia-reperfusion, atherosclerosis, neurodegenerative disease and age-related cancer as well as to process of ageing. Thus antioxidants and systems that can protect against oxidative stress are needed to maintain health. A large body of scientific evidence supports that oxidative stress is directly responsible for aging (Aging Cell. 2009, 8(3):258-69) and an array of neuropathology conditions (Nutrition 2010, 26:595-603. Neurochem Res. 2007, 32:757-73). The free radical theory of aging proposes that the organism is unable to repair all of them and that, with time, unrepaired damages accumulate and put the organism at risk: in other words, free radicals provoke aging and death (FEBS Letters 2009, 498: 183-186. J. Neurochem. 2009, 108:1251-65). Antioxidants are the substances able to react with free radicals and to protect the body from the damage caused by these molecules (Ital J Biochem. 2006, 55:263-282). In particular, consumption in excess of some foods which are rich sources of antioxidants is considered to promote good health and longevity. It is now believed that the maintenance of redox balance within the body can forestall aging and promote good health and longevity..
Researchers at Washington University School of Medicine in St. Louis have demonstrated a new approach to treating muscular dystrophy. Mice with a form of this muscle-weakening disease showed improved strength and heart function when treated with nanoparticles loaded with rapamycin, an immunosuppressive drug recently found to improve recycling of cellular waste.
The study appears online in The FASEB Journal.
The investigators, including first author Kristin P. Bibee, MD, PhD, looked at a mouse model of Duchenne muscular dystrophy, the most severe inherited form of the disease. Duchenne exclusively affects boys who have to rely on wheelchairs by age 12 and die from heart or respiratory failure in their 20s.
The faulty gene that causes the disease prevents the body from producing dystrophin, a protein crucial for maintaining muscle cell integrity and function. The new study demonstrated that mice with muscular dystrophy, in addition to missing dystrophin, also can’t recycle cellular waste, a process known as autophagy, or self-eating.
“Autophagy plays a major role in disposing of cellular debris,” said senior author Samuel A. Wickline, MD, the James R. Hornsby Family Professor of Medicine. “If it doesn’t happen, you might say the cell chokes on its own refuse. In muscular dystrophy, defective autophagy is not necessarily a primary source of muscle weakness, but it clearly becomes a problem over time. If you solve that, you can help the situation by maintaining more normal cellular function.”
Though it’s not clear how the missing dystrophin protein might be responsible for the muscle cells’ poor housekeeping, the study showed that boosting autophagy improved skeletal muscle strength and heart function in these mice.
“Some investigators are looking for ways to replace dystrophin,” said co-author Conrad C. Weihl, MD, PhD, associate professor of neurology. “But here we are focusing on the defect in autophagy. What is exciting about our approach is that there are existing drugs that activate autophagy. And by repackaging the drug on nanoparticles, we can target it specifically to muscles and correct the defect in the cells’ ability to recycle waste.”
When treated with rapamycin nanoparticles, the mice showed a 30 percent increase in grip strength and a significant improvement in cardiac function, based on an increase in the volume of blood the heart pumped.
“An important aspect of our study is that we are treating both skeletal muscle and heart muscle with the same drug,” Wickline said. “The heart is a difficult organ to treat in muscular dystrophy. But even in older animals, this regimen works well to recover heart function, and it is effective over a short period of time and after only a few doses.”
“Death from Duchenne in many people is due to heart dysfunction,” said Weihl, who also treats patients with neuromuscular disorders at Barnes-Jewish Hospital. “So even improving cardiac function by 10 percent in late-stage disease could be very important.”
The nanoparticle used in the study consists of an inert core made of perfluorocarbon, originally designed as a blood substitute. The particles are about 200 nanometers in diameter—500 times smaller than the thickness of a human hair. The surface of the nanoparticle is coated with rapamycin, which suppresses the immune system. The drug typically is used to help prevent organ rejection in transplant patients. It is known for its anti-inflammatory properties and, more recently, for its role in activating autophagy.
When injected into the bloodstream, according to Wickline, the nanoparticles accumulate in areas of inflammation, where damaged tissues have leaky blood vessels and are undergoing cell death and repair.
“The nanoparticles tend to penetrate and be retained in areas of inflammation,” Wickline said. “Then they release the rapamycin over a period of time, so the drug itself can permeate the muscle tissue.”
Compared with oral delivery, the nanoparticle approach also allowed the researchers to give the mice smaller doses of the drug.
“We showed that oral doses of rapamycin, even at 10 times the dose we used in the nanoparticles, were ineffective,” Weihl said. “This is important because rapamycin suppresses the immune system, and directly targeting it to muscle in smaller doses would reduce unwanted side effects.”
Current treatment for Duchenne involves corticosteroids such as prednisone, which has been shown to extend the time patients are able to walk. But steroids also cause weight gain, brittle bones, high blood pressure and other long-term side effects.
Although it’s not clear why steroid treatment helps maintain skeletal muscle strength, Weihl said the study suggests prednisone also may promote autophagy, raising the possibility of combination therapy, in which both steroid treatment and rapamycin nanoparticles could be given simultaneously, each at lower doses.
This work was supported by the National Institutes of Health (NIH) grants R01 AR056223, HL073646, HL112518, HL113392, NS073457ß, K02 AG042095, the Muscular Dystrophy Association, and the American Heart Association.
Bibee KP, Cheng YJ, Ching JK, Marsh JN, Li AJ, Keeling RM, Connolly AM, Golumbek PT, Myerson JW, Hu G, Chen J, Shannon WD, Lanza GM, Weihl CC, Wickline SA. Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function. The FASEB Journal. Online Feb. 5, 2013.
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.
Freiburg researchers find purely chemical way to target therapeutic nano-containers to cells
Immunofluorescence image shows nanoparticles targeted to endothelial cells. The red particles turn orange when overlapping with the green caveolin in the lipid rafts of the cells. Source: Julia Voigt / Prasad Shastri
Scientists have discovered that a polymer can provide a key to get into tumors: Prof. Prasad Shastri, Director of the Institute of Macromolecular Chemistry and core member of the cluster of excellence BIOSS Centre for Biological Signalling Studies at the University of Freiburg, and graduate students Julia Voigt and Jon Christensen have developed a new paradigm to home nanoparticles, containers that measure a few 100 nanometers in size, to endothelial cells. Using just charged polymers with the right affinity for cell lipids the team has developed nanoparticles that can recognize specific cell types simply by their chemical properties. “This is a remarkable discovery, as it allows for the first time to target a specific cell type purely through biophysical principles, and without using the traditional ligand-receptor approach” says Prof. Shastri who led the study that was selected as cover article of the Proceedings of the National Academy of Sciences. Until now researchers placed molecules on nanoparticles that can latch onto proteins on cell surface - called receptors.
These receptors act as an address or a biological postal code. However in tumors these addresses can change rapidly with time. To solve this lack of precision Shastri and team developed particles that are delivered to endothelial cells using a biophysical approach. “This delivery approach does not require a biological postal code for targeting of nanoparticles and is an important step forward in developing nanoparticle based systems for treating cancers” says Julia Voigt the lead author of the paper.
Cancers are very hungry tissues and they need constant nourishment. This is provided through their own supply of blood vessels. “By going after endothelial cells that make up these blood vessels, we can starve the tumor or kill it with one payload” says Jon Christensen who is a co-author on this study and works on tumor metastasis.
Nanoparticles are used to deliver therapeutics in treating cancers. These very small pills, cornerstones of nanomedicine, get injected into the body and reach the tumor cells via the bloodstream. When they find the targeted cells, they need to be eaten so that the drug can act within the cell. This mechanism is called receptor-mediated endocytosis. Shastri and his team looked to develop a new approach that targets a transport process that is dominant in endothelial cells. It turns out that a structure called caveolae is found in large amounts on endothelial cells. Caveolae are “lipid rafts” on the cell membrane and are one of the doors into the endothelial cells. Prof. Shastri and his team discovered that by decorating nano-pills made of lipids with negatively charged polymers, nanoparticles can preferentially enter through this door. “How exactly these charged polymers enable the nanoparticles to unlock this door we are not sure yet, but we feel confident that with further studies this method could usher in a new approach to delivery of drugs in general” says Shastri. This project was funded by Nano@matrix supported by INTERREG and the cluster of excellence BIOSS Centre for Biological Signalling Studies.
Original Publication: Julia Voigt, Jon Christensen, V. Prasad Shastri: Differential uptake of nanoparticles by endothelial cells through polyelectrolytes with affinity for caveolae .PNAS Online Early Edition 2014.
Contact: Prof. Dr. V. Prasad Shastri Institute for Macromolecular Chemistry / BIOSS Centre for Biological Signalling Studies University of Freiburg Phone: 0761/203-6268 E-Mail: firstname.lastname@example.org
Click here for a printable version (pdf) of the press release.