# Generating clean fuel with individual gold atoms

A July 22, 2016 news item on Nanowerk highlights an international collaboration focused on producing clean fuel,

A combined experimental and theoretical study comprising researchers from the Chemistry Department and LCN [London Centre for Nanotechnology], along with groups in Argentina, China, Spain and Germany, has shed new light on the behaviour of individual gold atoms supported on defective thin cerium dioxide films – an important system for catalysis and the generation of clean hydrogen for fuel.

A July ??, 2016 LCN press release, which originated the news item, expands on the theme of catalysts, the research into individual gold atoms, and how all this could result in clean fuel,

Catalysis plays a vital role in our world; an estimated 80% of all chemical and materials are made via processes which involve catalysts, which are commonly a mixture of metals and oxides. The standard motif for these heterogeneous catalysts (where the catalysts are solid and the reactants are in the gas phase) is of a high surface area oxide support that is decorated with metal nanoparticles a few nanometres in diameter. Cerium dioxide (ceria, CeO2) is a widely used support material for many important industrial processes; metal nanoparticles supported on ceria have displayed high activities for applications including car catalytic converters, alcohol synthesis, and for hydrogen production. There are two key attributes of ceria which make it an excellent active support material: its oxygen storage and release ability, and its ability to stabilise small metal particles under reaction conditions. A recent system that has been the focus of much interest has been that of gold nanoparticles and single atoms with ceria, which has demonstrated high activity towards the water-gas-shift reaction, (CO + H2O —> CO2 + H2) a key stage in the generation of clean hydrogen for use in fuel cells.

The nature of the active sites of these catalysts and the role that defects play are still relatively poorly understood; in order to study them in a systematic fashion, the researchers prepared model systems which can be characterised on the atomic scale with a scanning tunnelling microscope.

Figure: STM images of CeO2-x(111) ultrathin films before and after the deposition of Au single atoms at 300 K. The bright lattice is from the oxygen atoms at the surface – vacancies appear as dark spots

These model systems comprised well-ordered, epitaxial ceria films less than 2 nm thick, prepared on a metal single crystal, upon which single atoms and small clusters of gold were evaporated onto under ultra-high-vacuum (essential to prevent contamination of the surfaces). Oxygen vacancy defects – missing oxygen atoms in the top layer of the ceria – are relatively common at the surface and appear as dark spots in the STM images. By mapping the surface before and after the deposition of gold, it is possible to analyse the binding of the metal atoms, in particular there does not appear to be any preference for binding in the vacancy sites at 300 K.

Publishing their results in Physical Review Letters, the researchers combined these experimental results with theoretical studies of the binding energies and diffusion rates across the surface. They showed that kinetic effects governed the behaviour of the gold atoms, prohibiting the expected occupation of the thermodynamically more stable oxygen vacancy sites. They also identified electron transfer between the gold atoms and the ceria, leading to a better understanding of the diffusion phenomena that occur at this scale, and demonstrated that the effect of individual surface defects may be more minor than is normally imagined.

Here’s a link to and a citation for the paper,

Diffusion Barriers Block Defect Occupation on Reduced CeO2(111) by P.G. Lustemberg, Y. Pan, B.-J. Shaw, D. Grinter, Chi Pang, G. Thornton, Rubén Pérez, M. V. Ganduglia-Pirovano, and N. Nilius. Phys. Rev. Lett. Vol. 116, Iss. 23 — 10 June 2016 2016DOI:http://dx.doi.org/10.1103/PhysRevLett.116.236101 Published 9 June 2016

This paper is behind a paywall.

# Gold nanoparticles and two different collective oscillations

An April 27, 2016 news item on phys.org describes research into gold nanoparticles and Surface Plasmon Resonance at Hokkaido University and the University of Tsukuba (Japan),

The research group of Professor Hiroaki Misawa of Research Institute for Electronic Science, Hokkaido University and Assistant Professor Atsushi Kubo of the Faculty of Pure and Applied Sciences, University of Tsukuba, have successfully observed the dephasing time of the two different types of collective motions of electrons generated on the surface of a gold nanoparticle for the first time in the world, by combining a laser that emits ultrashort light pulses with a photoemission electron microscope.

An April 26, 2016 Hokkaido University press release, which originated the news item, explains further,

When gold is reduced to the size in nanometer scale, its color is red instead of gold. When gold nanoparticles are exposed to light, the collective oscillations of electrons existing on the localized surface of the gold causes red light to be strongly absorbed and dispersed.

This phenomenon is called Surface Plasmon Resonance. The red color of stained glass is also a result of this phenomenon. Recently, gold nanoparticles have been widely used in various fields, such as application in pregnancy tests.

This collective oscillations of electrons on the surface of gold nanoparticles caused by light was considered to be a phenomenon that sustained only for an extremely short time, and difficult to measure due to this shortness.

Our research group developed a methodology to measure the dephasing time of the collective oscillations of electrons occurring on the surface of gold nanoparticles by combining a laser that emits ultrashort light pulses of a few femtoseconds (1 femtosecond: 1´10-15 seconds), and a photoemission electron microscope in high spatial resolution.

When measured by this technique, the different dephasing times of the two different collective oscillations, namely dipole and quadrupole surface plasmon modes, could be resolved and identified as 5 femtoseconds and 9 femtoseconds, respectively.

Research using gold nanoparticles as optical antennae to harvest light for photovoltaic cell and an artificial photosynthesis system that can split water to obtain hydrogen is progressing. The successful measurement of the dephasing time of the collective oscillations of electrons is considered to be a useful guideline in developing these systems.

Here’s a link to and a citation for the paper,

Dissecting the Few-Femtosecond Dephasing Time of Dipole and Quadrupole Modes in Gold Nanoparticles Using Polarized Photoemission Electron Microscopy by Quan Sun†, Han Yu, Kosei Ueno, Atsushi Kubo, Yasutaka Matsuo, and Hiroaki Misawa. ACS Nano, 2016, 10 (3), pp 3835–3842 DOI: 10.1021/acsnano.6b00715Publication Date (Web): February 15, 2016

This paper appears to be open access.

# Black gold: ultralight, high density nanoporous gold

South Korean researchers have found a way to fabricate a new kind of gold nanoparticle according to a March 28, 2016 news item on ScienceDaily,

A new material is more solid and 30 percent lighter than standard gold, scientists report. In their study, the team investigated grain boundaries in nanocrystalline np-Au and found a way to overcome the weakening mechanisms of this material, thereby suggesting its usefulness.

A March 28, 2016 Ulsan National Institute of Science and Technology (UNIST) press release (also on EurekAlert) by Chorok Oh, which originated the news item, provides more information,

A team of Korean research team, led by Professor Ju-Young Kim (School of Materials Science and Engineering) of Ulsan National Institute of Science and Technology (UNIST), South Korea has recently announced that they have successfully developed a way to fabricate an ultralight, high-dense nanoporous gold (np-Au).

In a new paper, published in Nano Letters on March 22, the team reported that this newly developed material, which they have dubbed “Black Gold” is twice more solid and 30% lighter than standard gold.

According to Prof. Kim, “This particular nanoporous gold has a 100,000 times wider surface when compared to standard gold. Moreover, due to its chemically stablity, it is also harmless to humans.”

The surfaces of np-Au are rough and the metal loses its shine and eventually turns black when they are at sizes less than 100 nanometres (nm). This is the reason that they are called “Black Gold”.

In their study, the team investigated grain boundaries in nanocrystalline np-Au and found a way to overcome the weakening mechanisms of this material, thereby suggesting its usefulness.

The team used a ball milling technique to increase the flexural strength of the three gold-silver precursor alloys. Then, using free corrosion dealloying of silver from gold-silver alloys, they were able to achieve the nanoporous surface. According to the team, “The size of the pores can be controlled by the temperature and concentration of nitrate.” Moreover, they also note that this crack-free nanoporous gold samples are reported to exhibit excellent durability in three-point bending tests.

Prof. Kim’s team notes, “Ball-milled np-Au has a much greater density of two-dimensional defects than annealed and prestrained np-Au, where intergranular fracture is preferred.” They continue, “Therefore, the probable existence of grain boundary opening in the highest tensile region is attributed to the flexural strength of np-Au.”

They suggest that this newly developed technique can be also applied to many other metal, as the np-Au produced by this technique have shown increased strength and durability while still maintaining the good qualities of standard gold.

This means that this technique can be also used in other technologies, like catalytic-converting as observed by platinum, the automobile catalyst and palladium, the hydrogen sensor catalyst.

Here’s a link to and a citation for the paper,

Weakened Flexural Strength of Nanocrystalline Nanoporous Gold by Grain Refinement by Eun-Ji Gwak and Ju-Young Kim. Nano Lett., Article ASAP DOI: 10.1021/acs.nanolett.6b00062 Publication Date (Web): March 16, 2016

This paper is behind a paywall.

# Mass production of nanoparticles?

With all the years of nanotechnology and nanomaterials research it seems strange that mass production of nanoparticles is still very much in the early stages as a Feb. 24, 2016 news item on phys.org points out,

Nanoparticles – tiny particles 100,000 times smaller than the width of a strand of hair – can be found in everything from drug delivery formulations to pollution controls on cars to HD TV sets. With special properties derived from their tiny size and subsequently increased surface area, they’re critical to industry and scientific research.

They’re also expensive and tricky to make.

Now, researchers at USC [University of Southern California] have created a new way to manufacture nanoparticles that will transform the process from a painstaking, batch-by-batch drudgery into a large-scale, automated assembly line.

A Feb. 24, 2016 USC news release (also on EurekAlert) by Robert Perkins, which originated the news item, offers additional insight,

Consider, for example, gold nanoparticles. They have been shown to easily penetrate cell membranes without causing any damage — an unusual feat given that most penetrations of cell membranes by foreign objects can damage or kill the cell. Their ability to slip through the cell’s membrane makes gold nanoparticles ideal delivery devices for medications to healthy cells or fatal doses of radiation to cancer cells.

However, a single milligram of gold nanoparticles currently costs about $80 (depending on the size of the nanoparticles). That places the price of gold nanoparticles at$80,000 per gram while a gram of pure, raw gold goes for about $50. “It’s not the gold that’s making it expensive,” Malmstadt [Noah Malmstadt of the USC Viterbi School of Engineering] said. “We can make them, but it’s not like we can cheaply make a 50-gallon drum full of them.” A fluid situation At this time, the process of manufacturing a nanoparticle typically involves a technician in a chemistry lab mixing up a batch of chemicals by hand in traditional lab flasks and beakers. The new technique used by Brutchey [Richard Brutchey of the USC Dornsife College of Letters, Arts and Sciences] and Malmstadt instead relies on microfluidics — technology that manipulates tiny droplets of fluid in narrow channels. “In order to go large scale, we have to go small,” Brutchey said. Really small. The team 3-D printed tubes about 250 micrometers in diameter, which they believe to be the smallest, fully enclosed 3-D printed tubes anywhere. For reference, your average-sized speck of dust is 50 micrometers wide. They they built a parallel network of four of these tubes, side-by-side, and ran a combination of two nonmixing fluids (like oil and water) through them. As the two fluids fought to get out through the openings, they squeezed off tiny droplets. Each of these droplets acted as a micro-scale chemical reactor in which materials were mixed and nanoparticles were generated. Each microfluidic tube can create millions of identical droplets that perform the same reaction. This sort of system has been envisioned in the past, but it hasn’t been able to be scaled up because the parallel structure meant that if one tube got jammed, it would cause a ripple effect of changing pressures along its neighbors, knocking out the entire system. Think of it like losing a single Christmas light in one of the old-style strands — lose one and you lose them all. Brutchey and Malmstadt bypassed this problem by altering the geometry of the tubes themselves, shaping the junction between the tubes such that the particles come out a uniform size and the system is immune to pressure changes. Here’s a link to and a citation for the paper, Flow invariant droplet formation for stable parallel microreactors by Carson T. Riche, Emily J. Roberts, Malancha Gupta, Richard L. Brutchey & Noah Malmstadt. Nature Communications 7, Article number: 10780 doi:10.1038/ncomms10780 Published 23 February 2016 This is an open access paper. # A nanoparticle ‘printing press’ This research comes from Montréal, Canada via a Jan. 7, 2016 McGill University news release (also on EurekAlert*), Gold nanoparticles have unusual optical, electronic and chemical properties, which scientists are seeking to put to use in a range of new technologies, from nanoelectronics to cancer treatments. Some of the most interesting properties of nanoparticles emerge when they are brought close together – either in clusters of just a few particles or in crystals made up of millions of them. Yet particles that are just millionths of an inch in size are too small to be manipulated by conventional lab tools, so a major challenge has been finding ways to assemble these bits of gold while controlling the three-dimensional shape of their arrangement. One approach that researchers have developed has been to use tiny structures made from synthetic strands of DNA to help organize nanoparticles. Since DNA strands are programmed to pair with other strands in certain patterns, scientists have attached individual strands of DNA to gold particle surfaces to create a variety of assemblies. But these hybrid gold-DNA nanostructures are intricate and expensive to generate, limiting their potential for use in practical materials. The process is similar, in a sense, to producing books by hand. Enter the nanoparticle equivalent of the printing press. It’s efficient, re-usable and carries more information than previously possible. In results reported online in Nature Chemistry, researchers from McGill’s Department of Chemistry outline a procedure for making a DNA [deoxyribonucleic acid] structure with a specific pattern of strands coming out of it; at the end of each strand is a chemical “sticky patch.” When a gold nanoparticle is brought into contact to the DNA nanostructure, it sticks to the patches. The scientists then dissolve the assembly in distilled water, separating the DNA nanostructure into its component strands and leaving behind the DNA imprint on the gold nanoparticle. … The researchers have made an illustration of their concept available, Credit: Thomas Edwardson “These encoded gold nanoparticles are unprecedented in their information content,” says senior author Hanadi Sleiman, who holds the Canada Research Chair in DNA Nanoscience. “The DNA nanostructures, for their part, can be re-used, much like stamps in an old printing press.” The news release includes suggestions for possible future applications, From stained glass to optoelectronics Some of the properties of gold nanoparticles have been recognized for centuries. Medieval artisans added gold chloride to molten glass to create the ruby-red colour in stained-glass windows – the result, as chemists figured out much later, of the light-scattering properties of tiny gold particles. Now, the McGill researchers hope their new production technique will help pave the way for use of DNA-encoded nanoparticles in a range of cutting-edge technologies. First author Thomas Edwardson says the next step for the lab will be to investigate the properties of structures made from these new building blocks. “In much the same way that atoms combine to form complex molecules, patterned DNA gold particles can connect to neighbouring particles to form well-defined nanoparticle assemblies.” These could be put to use in areas including optoelectronic nanodevices and biomedical sciences, the researchers say. The patterns of DNA strands could, for example, be engineered to target specific proteins on cancer cells, and thus serve to detect cancer or to selectively destroy cancer cells. Here’s a link to and a citation for the paper, Transfer of molecular recognition information from DNA nanostructures to gold nanoparticles by Thomas G. W. Edwardson, Kai Lin Lau, Danny Bousmail, Christopher J. Serpell, & Hanadi F. Sleiman. Nature Chemistry (2016) doi:10.1038/nchem.2420 Published online 04 January 2016 This paper is behind a paywall. *’also on EurekAlert’ added on Jan. 8, 2016. # ‘Stained glass nanotechnology’ for color displays From a Dec. 4, 2015 news item on ScienceDaily, A new method for building “drawbridges” between metal nanoparticles may allow electronics makers to build full-color displays using light-scattering nanoparticles that are similar to the gold materials that medieval artisans used to create red stained-glass. “Wouldn’t it be interesting if we could create stained-glass windows that changed colors at the flip of a switch?” said Christy Landes, associate professor of chemistry at Rice and the lead researcher on a new study about the drawbridge method that appears this week in the open-access journal Science Advances. The research by Landes and other experts at Rice University’s Smalley-Curl Institute could allow engineers to use standard electrical switching techniques to construct color displays from pairs of nanoparticles that scatter different colors of light. For centuries, stained-glass makers have tapped the light-scattering properties of tiny gold nanoparticles to produce glass with rich red tones. Similar types of materials could increasingly find use in modern electronics as manufacturers work to make smaller, faster and more energy-efficient components that operate at optical frequencies. A Dec. 4, 2015 Rice University news release (also on EurekAlert), which originated the news item, describes the research in more detail, Though metal nanoparticles scatter bright light, researchers have found it difficult to coax them to produce dramatically different colors, Landes said. Rice’s new drawbridge method for color switching incorporates metal nanoparticles that absorb light energy and convert it into plasmons, waves of electrons that flow like a fluid across a particle’s surface. Each plasmon scatters and absorbs a characteristic frequency of light, and even minor changes in the wave-like sloshing of a plasmon shift that frequency. The greater the change in plasmonic frequency, the greater the difference between the colors observed. “Engineers hoping to make a display from optically active nanoparticles need to be able to switch the color,” Landes said. “That type of switching has proven very difficult to achieve with nanoparticles. People have achieved moderate success using various plasmon-coupling schemes in particle assemblies. What we’ve shown though is variation of the coupling mechanism itself, which can be used to produce huge color changes both rapidly and reversibly.” To demonstrate the method, Landes and study lead author Chad Byers, a graduate student in her lab, anchored pairs of gold nanoparticles to a glass surface covered with indium tin oxide (ITO), the same conductor that’s used in many smartphone screens. By sealing the particles in a chamber filled with a saltwater electrolyte and a silver electrode, Byers and Landes were able form a device with a complete circuit. They then showed they could apply a small voltage to the ITO to electroplate silver onto the surface of the gold particles. In that process, the particles were first coated with a thin layer of silver chloride. By later applying a negative voltage, the researchers caused a conductive silver “drawbridge” to form. Reversing the voltage caused the bridge to withdraw. “The great thing about these chemical bridges is that we can create and eliminate them simply by applying or reversing a voltage,” Landes said. “This is the first method yet demonstrated to produce dramatic, reversible color changes for devices built from light-activated nanoparticles.” This research has its roots in previous work (from the news release), Byers said his research into the plasmonic behavior of gold dimers began about two years ago. “We were pursuing the idea that we could make significant changes in optical properties of individual particles simply by altering charge density,” he said. “Theory predicts that colors can be changed just by adding or removing electrons, and we wanted to see if we could do that reversibly, simply by turning a voltage on or off.” The experiments worked. The color shift was observed and reversible, but the change in the color was minute. “It wasn’t going to get anybody excited about any sort of switchable display applications,” Landes said. But she and Byers also noticed that their results differed from the theoretical predictions. Landes said that was because the predictions were based upon using an inert electrode made of a metal like palladium that isn’t subject to oxidation. But silver is not inert. It reacts easily with oxygen in air or water to form a coat of unsightly silver oxide. This oxidizing layer can also form from silver chloride, and Landes said that is what was occurring when the silver counter electrode was used in Byers’ first experiments. The scientists decided to embrace imperfection (from the news release), “It was an imperfection that was throwing off our results, but rather than run away from it, we decided to use it to our advantage,” Landes said. Rice plasmonics pioneer and study co-author Naomi Halas, director of the Smalley-Curl Institute, said the new research shows how plasmonic components could be used to produce electronically switchable color-displays. “Gold nanoparticles are particularly attractive for display purposes,” said Halas, Rice’s Stanley C. Moore Professor of Electrical and Computer Engineering and professor of chemistry, bioengineering, physics and astronomy, and materials science and nanoengineering. “Depending upon their shape, they can produce a variety of specific colors. They are also extremely stable, and even though gold is expensive, very little is needed to produce an extremely bright color.” In designing, testing and analyzing the follow-up experiments on dimers, Landes and Byers engaged with a brain trust of Rice plasmonics experts that included Halas, physicist and engineer Peter Nordlander, chemist Stephan Link, materials scientist Emilie Ringe and their students, as well as Paul Mulvaney of the University of Melbourne in Australia. Together, the team confirmed the composition and spacing of the dimers and showed how metal drawbridges could be used to induce large color shifts based on voltage inputs. Nordlander and Hui Zhang, the two theorists in the group, examined the device’s “plasmonic coupling,” the interacting dance that plasmons engage in when they are in close contact. For instance, plasmonic dimers are known to act as light-activated capacitors, and prior research has shown that connecting dimers with nanowire bridges brings about a new state of resonance known as a “charge-transfer plasmon,” which has its own distinct optical signature. “The electrochemical bridging of the interparticle gap enables a fully reversible transition between two plasmonic coupling regimes, one capacitive and the other conductive,” Nordlander said. “The shift between these regimes is evident from the dynamic evolution of the charge transfer plasmon.” Halas said the method provides plasmonic researchers with a valuable tool for precisely controlling the gaps between dimers and other multiparticle plasmonic configurations. “In an applied sense, gap control is important for the development of active plasmonic devices like switches and modulators, but it is also an important tool for basic scientists who are conducting curiosity-driven research in the emerging field of quantum plasmonics.” I’m glad the news release writer included the background work leading to this new research and to hint at the level of collaboration needed to achieve the scientists’ new understanding of color switching. Here’s a link to and a citation for the paper, From tunable core-shell nanoparticles to plasmonic drawbridges: Active control of nanoparticle optical properties by Chad P. Byers, Hui Zhang, Dayne F. Swearer, Mustafa Yorulmaz, Benjamin S. Hoener, Da Huang, Anneli Hoggard, Wei-Shun Chang, Paul Mulvaney, Emilie Ringe, Naomi J. Halas, Peter Nordlander, Stephan Link, and Christy F. Landes. Science Advances 04 Dec 2015: Vol. 1, no. 11, e1500988 DOI: 10.1126/sciadv.1500988 In case you missed it in the news release, this is an open access paper. # Combining gold and palladium for catalytic and plasmonic octopods Hopefully I did not the change meaning when I made the title for this piece more succinct. In any event, this research comes from the always prolific Rice University in Texas, US (from a Nov. 30, 2015 news item on Nanotechnology Now), Catalysts are substances that speed up chemical reactions and are essential to many industries, including petroleum, food processing and pharmaceuticals. Common catalysts include palladium and platinum, both found in cars’ catalytic converters. Plasmons are waves of electrons that oscillate in particles, usually metallic, when excited by light. Plasmonic metals like gold and silver can be used as sensors in biological applications and for chemical detection, among others. Plasmonic materials are not the best catalysts, and catalysts are typically very poor for plasmonics. But combining them in the right way shows promise for industrial and scientific applications, said Emilie Ringe, a Rice assistant professor of materials science and nanoengineering and of chemistry who led the study that appears in Scientific Reports. “Plasmonic particles are magnets for light,” said Ringe, who worked on the project with colleagues in the U.S., the United Kingdom and Germany. “They couple with light and create big electric fields that can drive chemical processes. By combining these electric fields with a catalytic surface, we could further push chemical reactions. That’s why we’re studying how palladium and gold can be incorporated together.” The researchers created eight-armed specks of gold and coated them with a gold-palladium alloy. The octopods proved to be efficient catalysts and sensors. A Nov. 30, 2015 Rice University news release (also on EurekAlert), which originated the news item, expands on the theme, “If you simply mix gold and palladium, you may end up with a bad plasmonic material and a pretty bad catalyst, because palladium does not attract light like gold does,” Ringe said. “But our particles have gold cores with palladium at the tips, so they retain their plasmonic properties and the surfaces are catalytic.” Just as important, Ringe said, the team established characterization techniques that will allow scientists to tune application-specific alloys that report on their catalytic activity in real time. The researchers analyzed octopods with a variety of instruments, including Rice’s new Titan Themis microscope, one of the most powerful electron microscopes in the nation. “We confirmed that even though we put palladium on a particle, it’s still capable of doing everything that a similar gold shape would do. That’s really a big deal,” she said. “If you shine a light on these nanoparticles, it creates strong electric fields. Those fields enhance the catalysis, but they also report on the catalysis and the molecules present at the surface of the particles,” Ringe said. The researchers used electron energy loss spectroscopy, cathodoluminescence and energy dispersive X-ray spectroscopy to make 3-D maps of the electric fields produced by exciting the plasmons. They found that strong fields were produced at the palladium-rich tips, where plasmons were the least likely to be excited. Ringe expects further research will produce multifunctional nanoparticles in a variety of shapes that can be greatly refined for applications. Her own Rice lab is working on a metal catalyst to turn inert petroleum derivatives into backbone molecules for novel drugs. Here’s a link to and a citation for the paper, Resonances of nanoparticles with poor plasmonic metal tips by Emilie Ringe, Christopher J. DeSantis, Sean M. Collins, Martial Duchamp, Rafal E. Dunin-Borkowski, Sara E. Skrabalak, & Paul A. Midgley. Scientific Reports 5, Article number: 17431 (2015) doi:10.1038/srep17431 Published online: 30 November 2015 This is an open access paper, # A view to controversies about nanoparticle drug delivery, sticky-flares, and a PNAS surprise Despite all the excitement and claims for nanoparticles as vehicles for drug delivery to ‘sick’ cells there is at least one substantive problem, the drug-laden nanoparticles don’t actually enter the interior of the cell. They are held in a kind of cellular ‘waiting room’. Leonid Schneider in a Nov. 20, 2015 posting on his For Better Science blog describes the process in more detail, A large body of scientific nanotechnology literature is dedicated to the biomedical aspect of nanoparticle delivery into cells and tissues. The functionalization of the nanoparticle surface is designed to insure their specificity at targeting only a certain type of cells, such as cancers cells. Other technological approaches aim at the cargo design, in order to ensure the targeted release of various biologically active agents: small pharmacological substances, peptides or entire enzymes, or nucleotides such as regulatory small RNAs or even genes. There is however a main limitation to this approach: though cells do readily take up nanoparticles through specific membrane-bound receptor interaction (endocytosis) or randomly (pinocytosis), these nanoparticles hardly ever truly reach the inside of the cell, namely its nucleocytoplasmic space. Solid nanoparticles are namely continuously surrounded by the very same membrane barrier they first interacted with when entering the cell. These outer-cell membrane compartments mature into endosomal and then lysosomal vesicles, where their cargo is subjected to low pH and enzymatic digestion. The nanoparticles, though seemingly inside the cell, remain actually outside. … What follows is a stellar piece featuring counterclaims about and including Schneider’s own journalistic research into scientific claims that the problem of gaining entry to a cell’s true interior has been addressed by technologies developed in two different labs. Having featured one of the technologies here in a July 24, 2015 posting titled: Sticky-flares nanotechnology to track and observe RNA (ribonucleic acid) regulation and having been contacted a couple of times by one of the scientists, Raphaël Lévy from the University of Liverpool (UK), challenging the claims made (Lévy’s responses can be found in the comments section of the July 2015 posting), I thought a followup of sorts was in order. Scientific debates (then and now) Scientific debates and controversies are part and parcel of the scientific process and what most outsiders, such as myself, don’t realize is how fraught it is. For a good example from the past, there’s Leviathan and the Air-Pump: Hobbes, Boyle, and the Experimental Life (from its Wikipedia entry), Note: Links have been removed), Leviathan and the Air-Pump: Hobbes, Boyle, and the Experimental Life (published 1985) is a book by Steven Shapin and Simon Schaffer. It examines the debate between Robert Boyle and Thomas Hobbes over Boyle’s air-pump experiments in the 1660s. The style seems more genteel than what a contemporary Canadian or US audience is accustomed to but Hobbes and Boyle (and proponents of both sides) engaged in bruising communication. There was a lot at stake then and now. It’s not just the power, prestige, and money, as powerfully motivating as they are, it’s the research itself. Scientists work for years to achieve breakthroughs or to add more to our common store of knowledge. It’s painstaking and if you work at something for a long time, you tend to be invested in it. Saying you’ve wasted ten years of your life looking at the problem the wrong way or have misunderstood your data is not easy. As for the current debate, Schneider’s description gives no indication that there is rancour between any of the parties but it does provide a fascinating view of two scientists challenging one of the US’s nanomedicine rockstars, Chad Mirkin. The following excerpt follows the latest technical breakthroughs to the interior portion of the cell through three phases of the naming conventions (Nano-Flares, also known by its trade name, SmartFlares, which is a precursor technology to Sticky-Flares), Note: Links have been removed, The next family of allegedly nucleocytoplasmic nanoparticles which Lévy turned his attention to, was that of the so called “spherical nucleic acids”, developed in the lab of Chad Mirkin, multiple professor and director of the International Institute for Nanotechnology at the Northwestern University, USA. These so called “Nano-Flares” are gold nanoparticles, functionalized with fluorophore-coupled oligonucleotides matching the messenger RNA (mRNA) of interest (Prigodich et al., ACS Nano 3:2147-2152, 2009; Seferos et al., J Am. Chem.Soc. 129:15477-15479, 2007). The mRNA detection method is such that the fluorescence is initially quenched by the gold nanoparticle proximity. Yet when the oligonucleotide is displaced by the specific binding of the mRNA molecules present inside the cell, the fluorescence becomes detectable and serves thus as quantitative read-out for the intracellular mRNA abundance. Exactly this is where concerns arise. To find and bind mRNA, spherical nucleic acids must leave the endosomal compartments. Is there any evidence that Nano-Flares ever achieve this and reach intact the nucleocytoplasmatic space, where their target mRNA is? Lévy’s lab has focused its research on the commercially available analogue of the Nano-Flares, based on the patent to Mirkin and Northwestern University and sold by Merck Millipore under the trade name of SmartFlares. These were described by Mirkin as “a powerful and prolific tool in biology and medical diagnostics, with ∼ 1,600 unique forms commercially available today”. The work, led by Lévy’s postdoctoral scientist David Mason, now available in post-publication process at ScienceOpen and on Figshare, found no experimental evidence for SmartFlares to be ever found outside the endosomal membrane vesicles. On the contrary, the analysis by several complementary approaches, i.e., electron, fluorescence and photothermal microscopy, revealed that the probes are retained exclusively within the endosomal compartments. In fact, even Merck Millipore was apparently well aware of this problem when the product was developed for the market. As I learned, Merck performed a number of assays to address the specificity issue. Multiple hundred-fold induction of mRNA by biological cell stimulation (confirmed by quantitative RT-PCR) led to no significant changes in the corresponding SmartFlare signal. Similarly, biological gene downregulation or experimental siRNA knock-down had no effect on the corresponding SmartFlare fluorescence. Cell lines confirmed as negative for a certain biomarker proved highly positive in a SmartFlare assay. Live cell imaging showed the SmartFlare signal to be almost entirely mitochondrial, inconsistent with reported patterns of the respective mRNA distributions. Elsewhere however, cyanine dye-labelled oligonucleotides were found to unspecifically localise to mitochondria (Orio et al., J. RNAi Gene Silencing 9:479-485, 2013), which might account to the often observed punctate Smart Flare signal. More recently, Mirkin lab has developed a novel version of spherical nucleic acids, named Sticky-Flares (Briley et al., PNAS 112:9591-9595, 2015), which has also been patented for commercial use. The claim is that “the Sticky-flare is capable of entering live cells without the need for transfection agents and recognizing target RNA transcripts in a sequence-specific manner”. To confirm this, Lévy used the same approach as for the striped nanoparticles [not excerpted here]: he approached Mirkin by email and in person, requesting the original microscopy data from this publication. As Mirkin appeared reluctant, Lévy invoked the rules for data sharing by the journal PNAS, the funder NSF as well as the Northwestern University. After finally receiving Mirkin’s thin-optical microscopy data by air mail, Lévy and Mason re-analyzed it and determined the absence of any evidence for endosomal escape, while all Sticky-Flare particles appeared to be localized exclusively inside vesicular membrane compartments, i.e., endosomes (Mason & Levy, bioRxiv 2015). I encourage you to read Schneider’s Nov. 20, 2015 posting in its entirety as these excerpts can’t do justice to it. The PNAS surprise PNAS (Proceedings of the National Academy of Science) published one of Mirkin’s papers on ‘Sticky-flares’ and is where scientists, Raphaël Lévy and David Mason, submitted a letter outlining their concerns with the ‘Sticky-flares’ research. Here’s the response as reproduced in Lévy’s Nov. 16, 2015 posting on his Rapha-Z-Lab blog Dear Dr. Levy, I regret to inform you that the PNAS Editorial Board has declined to publish your Letter to the Editor. After careful consideration, the Board has decided that your letter does not contribute significantly to the discussion of this paper. Thank you for submitting your comments to PNAS. Sincerely yours, Inder Verma Editor-in-Chief Judge for yourself, Lévy’s and Mason’s letter can be found here (pdf) and here. Conclusions My primary interest in this story is in the view it provides of the scientific process and the importance of and difficulty associated with the debates. I can’t venture an opinion about the research or the counterarguments other than to say that Lévy’s and Mason’s thoughtful challenge bears more examination than PNAS is inclined to accord. If their conclusions or Chad Mirkin’s are wrong, let that be determined in an open process. I’ll leave the very last comment to Schneider who is both writer and cartoonist, from his Nov. 20, 2015 posting, # Attomolar cancer detection: measuring microRNAs in blood The latest research does not lead to a magical disease detector where nanoscale sensors swim through the body continuously monitoring our health and alerting us should something untoward occur (see this Oct. 28, 2014 article on RT.com for more about Google X’s development plans for it and this Nov. 11, 2015 news item on Nanowerk for a measured response from a researcher in the field). Now onto some real research, a Nov. 17, 2015 news item on ScienceDaily announces an ultrasensitive (attoscale) sensor employing gold nanoparticles for detecting cancer, A simple, ultrasensitive microRNA sensor developed and tested by researchers from the schools of science and medicine at Indiana University-Purdue University Indianapolis and the Indiana University Melvin and Bren Simon Cancer Center holds promise for the design of new diagnostic strategies and, potentially, for the prognosis and treatment of pancreatic and other cancers. A Nov. 17, 2015 Indiana University-Purdue University Indianapolis news release on EurekAlert, which originated the news item, provides more detail about research that seems to have focused largely on pancreatic cancer detection (Note: Links have been removed), In a study published in the Nov. [2015] issue of ACS Nano, a peer-reviewed journal of the American Chemical Society focusing on nanoscience and nanotechnology research, the IUPUI researchers describe their design of the novel, low-cost, nanotechnology-enabled reusable sensor. They also report on the promising results of tests of the sensor’s ability to identify pancreatic cancer or indicate the existence of a benign condition by quantifying changes in levels of microRNA signatures linked to pancreatic cancer. MicroRNAs are small molecules of RNA that regulate how larger RNA molecules lead to protein expression. As such, microRNAs are very important in biology and disease states. “We used the fundamental concepts of nanotechnology to design the sensor to detect and quantify biomolecules at very low concentrations,” said Rajesh Sardar, Ph.D., who developed the sensor. “We have designed an ultrasensitive technique so that we can see minute changes in microRNA concentrations in a patient’s blood and confirm the presence of pancreatic cancer.” Sardar is an assistant professor of chemistry and chemical biology in the School of Science at IUPUI and leads an interdisciplinary research program focusing on the intersection of analytical chemistry and the nanoscience of metallic nanoparticles. “If we can establish that there is cancer in the pancreas because the sensor detects high levels of microRNA-10b or one of the other microRNAs associated with that specific cancer, we may be able to treat it sooner,” said Murray Korc, M.D., the Myles Brand Professor of Cancer Research at the IU School of Medicine and a researcher at the IU Simon Cancer Center. Korc, worked with Sardar to improve the sensor’s capabilities and led the testing of the sensor and its clinical uses as well as advancing the understanding of pancreatic cancer biology. “That’s especially significant for pancreatic cancer, because for many patients it is symptom-free for years or even a decade or more, by which time it has spread to other organs, when surgical removal is no longer possible and therapeutic options are limited,” said Korc. “For example, diagnosis of pancreatic cancer at an early stage of the disease followed by surgical removal is associated with a 40 percent five-year survival. Diagnosis of metastatic pancreatic cancer, by contrast, is associated with life expectancy that is often only a year or less. “The beauty of the sensor designed by Dr. Sardar is its ability to accurately detect mild increases in microRNA levels, which could allow for early cancer diagnosis,” Korc added. Over the past decade, studies have shown that microRNAs play important roles in cancer and other diseases, such as diabetes and cardiovascular disorders. The new IUPUI nanotechnology-based sensor can detect changes in any of these microRNAs. The sensor is a small glass chip that contains triangular-shaped gold nanoparticles called ‘nanoprisms.’ After dipping it in a sample of blood or another body fluid, the scientist measures the change in the nanoprism’s optical property to determine the levels of specific microRNAs. For anyone concerned about the cost associated with creating sensors based on gold, about patents, or about current techniques for monitoring microRNAs, there’s more from the news release (Note: A link has been removed), “Using gold nanoprisms may sound expensive, but it isn’t because these particles are so very tiny,” Sardar said. “It’s a rather cheap technique because it uses nanotechnology and needs very little gold.$250 worth of gold makes 4,000 sensors. Four thousand sensors allow you to do at least 4,000 tests. The low cost makes this technique ideal for use anywhere, including in low-resource environments in this country and around the world.”

Indiana University Research and Technology Corporation has filed a patent application on Sardar’s and Korc’s groundbreaking nanotechnology-enabled sensor. The researchers’ ultimate goal is to design ultrasensitive and extremely selective low-cost point-of-care diagnostics enabling individual therapeutic approaches to diseases.

Currently, polymerase chain reaction technology is used to determine microRNA signatures, which requires extraction of the microRNA from blood or other biological fluid and reverse transcription or amplification of the microRNA. PCR provides relative values. By contrast, the process developed at IUPUI is simpler, quantitative, more sensitive and highly specific even when two different microRNAs vary in a single position. The study demonstrated that the IUPUI nanotechnology-enabled sensor is as good as if not better than the most advanced PCR in detection and quantification of microRNA.

Here’s a link to and a citation for the paper,

Label-Free Nanoplasmonic-Based Short Noncoding RNA Sensing at Attomolar Concentrations Allows for Quantitative and Highly Specific Assay of MicroRNA-10b in Biological Fluids and Circulating Exosomes by Gayatri K. Joshi, Samantha Deitz-McElyea, Thakshila Liyanage, Katie Lawrence, Sonali Mali, Rajesh Sardar*, and Murray Korc. ACS Nano, Article ASAP DOI: 10.1021/acsnano.5b04527 Publication Date (Web): October 7, 2015

This is an open access paper.

The researchers have provided this illustration of gold nanoprisms,

Caption: Indiana University-Purdue University Indianapolis researchers have developed a novel, low-cost, nanotechnology-enabled reusable sensor for which a patent application has been filed. Credit: Department of Chemistry and Chemical Biology, School of Science, Indiana University-Purdue University Indianapolis

# Nano-alchemy: silver nanoparticles that look like and act like gold

This work on ‘nano-alchemy’ comes out of the King Abduhllah University of Science and Technology (KAUST) according to a Sept. 22, 2015 article by Lisa Zynga for phys.org (Note: A link has been removed),

In an act of “nano-alchemy,” scientists have synthesized a silver (Ag) nanocluster that is virtually identical to a gold (Au) nanocluster. On the outside, the silver nanocluster has a golden yellow color, and on the inside, its chemical structure and properties also closely mimic those of its gold counterpart. The work shows that it may be possible to create silver nanoparticles that look and behave like gold despite underlying differences between the two elements, and could lead to creating similar analogues between other pairs of elements.

“In some aspects, this is very similar to alchemy, but we call it ‘nano-alchemy,'” Bakr [Osman Bakr, Associate Professor of Materials Science and Engineering at King Abdullah University of Science and Technology (KAUST) in Saudi Arabia] told Phys.org. “When we first encountered the optical spectrum of the silver nanocluster, we thought that we may have inadvertently switched the chemical reagents for silver with gold, and ended up with gold nanoparticles instead. But repeated synthesis and measurements proved that the clusters were indeed silver and yet show properties akin to gold. It was really surprising to us as scientists to find not only similarities in the color and optical properties, but also the X-ray structure.”

In their study, the researchers performed tests demonstrating that the silver and gold nanoclusters have very similar optical properties. Typically, silver nanoclusters are brown or red in color, but this one looks just like gold because it emits light at almost the same wavelength (around 675 nm) as gold. The golden color can be explained by the fact that both nanoclusters have virtually identical crystal structures.

The question naturally arises: why are these silver and gold nanoclusters so similar, when individual atoms of silver and gold are very different, in terms of their optical and structural properties? As Bakr explained, the answer may have to do with the fact that, although larger in size, the nanoclusters behave like “superatoms” in the sense that their electrons orbit the entire nanocluster as if it were a single giant atom. These superatomic orbitals in the silver and gold nanoclusters are very similar, and, in general, an atom’s electron configuration contributes significantly to its properties.

Here’s one of the images used to illustrate Zynga’s article and the paper published by the American Chemical Society,

(Left) Optical properties of the silver and gold nanoclusters, with the inset showing photographs of the actual color of the synthesized nanoclusters. The graph shows the absorption (solid lines) and normalized emission (dotted lines) spectra. (Right) Various representations of the X-ray structure of the silver nanocluster. Credit: Joshi, et al. ©2015 American Chemical Society

I encourage you to read Zynga’s article in its entirety. For the more technically inclined, here’s a link to and a citation for the researchers’ paper,

[Ag25(SR)18]: The “Golden” Silver Nanoparticle by Chakra P. Joshi, Megalamane S. Bootharaju, Mohammad J. Alhilaly, and Osman M. Bakr.J. Am. Chem. Soc., 2015, 137 (36), pp 11578–11581 DOI: 10.1021/jacs.5b07088 Publication Date (Web): August 31, 2015