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Shape matters for light-activated nanocatalysts

Points matter when designing nanoparticles that drive important chemical reactions using the power of light.

Researchers at Rice University’s Laboratory for Nanophotonics (LANP) have long known that a nanoparticle’s shape affects how it interacts with light, and their latest study shows how shape affects a particle’s ability to use light to catalyze important chemical reactions.

In a comparative study, LANP graduate students Lin Yuan and Minhan Lou and their colleagues studied aluminum nanoparticles with identical optical properties but different shapes. The most rounded had 14 sides and 24 blunt points. Another was cube-shaped, with six sides and eight 90-degree corners. The third, which the team dubbed “octopod,” also had six sides, but each of its eight corners ended in a pointed tip.

All three varieties have the ability to capture energy from light and release it periodically in the form of super-energetic hot electrons that can speed up catalytic reactions. Yuan, a chemist in the research group of LANP director Naomi Halas, conducted experiments to see how well each of the particles performed as photocatalysts for hydrogen dissociation reaction. The tests showed octopods had a 10 times higher reaction rate than the 14-sided nanocrystals and five times higher than the nanocubes. Octopods also had a lower apparent activation energy, about 45% lower than nanocubes and 49% lower than nanocrystals.

“The experiments demonstrated that sharper corners increased efficiencies,” said Yuan, co-lead author of the study, which is published in the American Chemical Society journal ACS Nano. “For the octopods, the angle of the corners is about 60 degrees, compared to 90 degrees for the cubes and more rounded points on the nanocrystals. So the smaller the angle, the greater the increase in reaction efficiencies. But how small the angle can be is limited by chemical synthesis. These are single crystals that prefer certain structures. You cannot make infinitely more sharpness.”

Lou, a physicist and study co-lead author in the research group of LANP’s Peter Nordlander, verified the results of the catalytic experiments by developing a theoretical model of the hot electron energy transfer process between the light-activated aluminum nanoparticles and hydrogen molecules.

“We input the wavelength of light and particle shape,” Lou said. “Using these two aspects, we can accurately predict which shape will produce the best catalyst.”

The work is part of an ongoing green chemistry effort by LANP to develop commercially viable light-activated nanocatalysts that can insert energy into chemical reactions with surgical precision. LANP has previously demonstrated catalysts for ethylene and syngas production, the splitting of ammonia to produce hydrogen fuel and for breaking apart “forever chemicals.”

“This study shows that photocatalyst shape is another design element engineers can use to create photocatalysts with the higher reaction rates and lower activation barriers,” said Halas, Rice’s Stanley C. Moore Professor of Electrical and Computer Engineering, director of Rice’s Smalley-Curl Institute and a professor of chemistry, bioengineering, physics and astronomy, and materials science and nanoengineering.

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Going small for big solutions: Sub-nanoparticle catalysts made from coinage elements as effective catalysts

Due to their small size, nanoparticles find varied applications in fields ranging from medicine to electronics. Their small size allows them a high reactivity and semiconducting property not found in the bulk states. Sub-nanoparticles (SNPs) have an extremely small diameter of around 1 nm, making them even smaller than nanoparticles. Almost all atoms of SNPs are available and exposed for reactions, and therefore, SNPs are expected to have extraordinary functions beyond the properties of nanoparticles, particularly as catalysts for industrial reactions. However, preparation of SNPs requires fine control of the size and composition of each particle on a sub-nanometer scale, making the application of conventional production methods near impossible.

To overcome this, researchers at the Tokyo Institute of Technology led by Dr. Takamasa Tsukamoto and Prof. Kimihisa Yamamoto previously developed the atom hybridization method (AHM) which surpasses the previous trials of SNP synthesis. Using this technique, it is possible to precisely control and diversely design the size and composition of the SNPs using a “macromolecular template” called phenylazomethine dendrimer. This improves their catalytic activity than the NP catalysts.

Now, in their latest study published in Angewandte Chemie International Edition, the team has taken their research one step further and has investigated the chemical reactivity of alloy SNPs obtained through the AHM. “We created monometallic, bimetallic, and trimetallic SNPs (containing one, combination of two, and combination of three metals respectively), all composed of coinage metal elements (copper, silver, and gold), and tested each to see how good of a catalyst each of them is,” reports Dr Tsukamoto. 

Unlike corresponding nanoparticles, the SNPs created were found to be stable and more effective. Moreover, SNPs showed a high catalytic performance even under the milder conditions, in direct contrast to conventional catalysts. Monometallic, bimetallic, and trimetallic SNPs demonstrated the formation of different products, and this hybridization or combination of metals seemed to show a higher turnover frequency (TOF). The trimetallic combination “Au4Ag8Cu16” showed the highest TOF because each metal element plays a unique role, and these effects work in concert to contribute to high reaction activity.

Furthermore, SNP selectively created hydroperoxide, which is a high-energy compound that cannot be normally obtained due to instability. Mild reactions without high temperature and pressure realized in SNP catalysts resulted in the stable formation of hydroperoxide by suppressing its decomposition.

When asked about the relevance of these findings, Prof Yamamoto states: “We demonstrate for the first time ever, that olefin hydroperoxygenation can been catalyzed under extremely mild conditions using metal particles in the quantum size range. The reactivity was significantly improved in the alloyed systems especially for the trimetallic combinations, which has not been studied previously.”

The team emphasized that because of the extreme miniaturization of the structures and the hybridization of different elements, the coinage metals acquired a high enough reactivity to catalyze the oxidation even under the mild condition. These findings will prove to be a pioneering key in the discovery of innovative sub-nanomaterials from a wide variety of elements and can solve energy crises and environmental problems in the years to come.

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Layer of nanoparticles could improve LED performance and lifetime

Adding a layer of nanoparticles to LED designs could help them produce more light for the same energy, and also increase their lifetime.

This is according to a team from Imperial College London and the Indian Institute of Technology (IIT) Guwahati who have found a new way to boost the amount of light LEDs produce. They report their innovation in the journal Light Science & Applications.

Making light-emitting diode (LED) light sources more efficient and longer-lasting will mean they use less energy, reducing the environmental impact of their electricity use. LEDs are used in a wide range of applications, from traffic lights and backlighting for electronic displays, smartphones, large outdoor screens, and general decorative lighting, to sensing, water purification, and decontamination of infected surfaces.

The team modelled the impact of placing a two-dimensional (single layer) of nanoparticles between the LED chip, which produces the light, and the transparent casing that protects the chip. Although the casing is necessary, it can cause unwanted reflections of the light emitted from the LED chip, meaning not all the light escapes.

They found that adding a layer of finely tuned nanoparticles could reduce these reflections, allowing up to 20 percent more light to be emitted. The reflections also increase the heat inside the device, degrading the LED chip faster, so reducing the reflections could also reduce the heat and increase the lifetime of LED chips.

Co-author Dr Debabrata Sikdar from IIT Guwahati, formerly a European Commission Marie Curie-Sklodowska Fellow at Imperial, commented: “While improvements to the casing have been suggested previously, most make the LED bulkier or more difficult to manufacture, diminishing the economic effect of the improvement.

“We think that our innovation, based on fundamental theory and the detailed, balanced optimization analysis we performed, could be introduced into existing manufacturing processes with little disruption or added bulk.”

Co-author Professor Sir John Pendry, from the Department of Physics at Imperial, said: “The simplicity of the proposed scheme and the clear physics underpinning it should make it robust and, hopefully, easily adaptable to the existing LED manufacturing process.

“It is obvious that with larger light extraction efficiency, LEDs will provide greater energy savings as well as longer lifetime of the devices. This will definitely have a global impact on the versatile LED-based applications and their multi-billion-dollar market worldwide.”

Co-author Professor Alexei Kornyshev, from the Department of Chemistry at Imperial, commented: “The predicted effect is a result of development of a systematic theory of various photonic effects related to nanoparticle arrays at interfaces, applied and experimentally tested in the context of earlier reported switchable mirror-windows, tuneable-colour mirrors, and optical filters.”

The next stage for the research will be manufacturing a prototype LED device with a nanoparticle layer, testing the best configurations predicted by the theory — including the size, shape, material and spacing of the nanoparticles, and how far the layer should be from the LED chip.

The authors believe that the principles used can work along with other existing schemes implemented for enhancing light extraction efficiency of LEDs. The same scheme could also apply to other optical devices where the transmission of light across interfaces is crucial, such as in solar cells.

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Water molecules are gold for nanocatalysis

Nanocatalysts made of gold nanoparticles dispersed on metal oxides are very promising for the industrial, selective oxidation of compounds, including alcohols, into valuable chemicals. They show high catalytic activity, particularly in aqueous solution. A team of researchers from Ruhr-Universität Bochum (RUB) has been able to explain why: Water molecules play an active role in facilitating the oxygen dissociation needed for the oxidation reaction. The team of Professor Dominik Marx, Chair of Theoretical Chemistry, reports in the high-impact journal ACS Catalysis on 14 July 2020.

Rushing for gold

Most industrial oxidation processes involve the use of agents, such as chlorine or organic peroxides, that produce toxic or useless by-products. Instead, using molecular oxygen, O2, and splitting it to obtain the oxygen atoms needed to produce specific products would be a greener and more attractive solution. A promising medium for this approach is the gold/metal oxide (Au/TiO2) system, where the metal oxide titania (TiO2) supports nanoparticles of gold. These nanocatalysts can catalyse the selective oxidation of molecular hydrogen, carbon monoxide and especially alcohols, among others. A crucial step behind all reactions is the dissociation of O2, which comprises a usually high energy barrier. And a crucial unknown in the process is the role of water, since the reactions take place in aqueous solutions.

In a 2018 study, the RUB group of Dominik Marx, Chair of Theoretical Chemistry and Research Area coordinator in the Cluster of Excellence Ruhr Explores Solvation (Resolv), already hinted that water molecules actively participate in the oxidative reaction: They enable a stepwise charge-transfer process that leads to oxygen dissociation in the aqueous phase. Now, the same team reveals that solvation facilitates the activation of molecular oxygen (O2) at the gold/metal oxide (Au/TiO2) nanocatalyst: In fact, water molecules help to decrease the energy barrier for the O2 dissociation. The researchers quantified that the solvent curbs the energy costs by 25 per cent compared to the gas phase. “For the first time, it has been possible to gain insights into the quantitative impact of water on the critical O2 activation reaction for this nanocatalyst — and we also understood why,” says Dominik Marx.

Mind the water molecules

The RUB researchers applied computer simulations, the so-called ab initio molecular dynamics simulations, which explicitly included not only the catalyst but also as many as 80 surrounding water molecules. This was key to gain deep insights into the liquid-phase scenario, which contains water, in direct comparison to the gas phase conditions, where water is absent. “Previous computational work employed significant simplifications or approximations that didn’t account for the true complexity of such a difficult solvent, water,” adds Dr. Niklas Siemer who recently earned his PhD at RUB based on this research.

Scientists simulated the experimental conditions with high temperature and pressure to obtain the free energy profile of O2 in both liquid and gas phase. Finally, they could trace back the mechanistic reason for the solvation effect: Water molecules induce an increase of local electron charge towards oxygen that is anchored at the nanocatalyst perimeter; this in turn leads to the less energetic costs for the dissociation. In the end, say the researchers, it’s all about the unique properties of water: “We found that the polarizability of water and its ability to donate hydrogen bonds are behind oxygen activation,” says Dr. Munoz-Santiburcio. According to the authors, the new computational strategy will help to understand and improve direct oxidation catalysis in water and alcohols.

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New nanoparticle drug combination for atherosclerosis

Physicochemical cargo-switching nanoparticles (CSNP) designed by KAIST can help significantly reduce cholesterol and macrophage foam cells in arteries, which are the two main triggers for atherosclerotic plaque and inflammation.

The CSNP-based combination drug delivery therapy was proved to exert cholesterol-lowering, anti-inflammatory, and anti-proliferative functions of two common medications for treating and preventing atherosclerosis that are cyclodextrin and statin. Professor Ji-Ho Park and Dr. Heegon Kim from KAIST’s Department of Bio and Brain Engineering said their study has shown great potential for future applications with reduced side effects.

Atherosclerosis is a chronic inflammatory vascular disease that is characterized by the accumulation of cholesterol and cholesterol-loaded macrophage foam cells in the intima. When this atherosclerotic plaque clogs and narrows the artery walls, they restrict blood flow and cause various cardiovascular conditions such as heart attacks and strokes. Heart attacks and strokes are the world’s first and fifth causes of death respectively.

Oral statin administration has been used in clinics as a standard care for atherosclerosis, which is prescribed to lower blood cholesterol and inhibit its accumulation within the plaque. Although statins can effectively prevent the progression of plaque growth, they have only shown modest efficacy in eliminating the already-established plaque. Therefore, patients are required to take statin drugs for the rest of their lives and will always carry the risk of plaque ruptures that can trigger a blood clot.

To address these issues, Professor Park and Dr. Kim exploited another antiatherogenic agent called cyclodextrin. In their paper published in the Journal of Controlled Release on March 10, Professor Park and Dr. Kim reported that the polymeric formulation of cyclodextrin with a diameter of approximately 10 nanometers(nm) can accumulate within the atherosclerotic plaque 14 times more and effectively reduce the plaque even at lower doses, compared to cyclodextrin in a non-polymer structure.

Moreover, although cyclodextrin is known to have a cytotoxic effect on hair cells in the cochlea, which can lead to hearing loss, cyclodextrin polymers developed by Professor Park’s research group exhibited a varying biodistribution profile and did not have this side effect.

In the follow-up study reported in ACS Nano on April 28, the researchers exploited both cyclodextrin and statin and form the cyclodextrin-statin self-assembly drug complex, based on previous findings that each drug can exert local anti-atherosclerosis effect within the plaque. The complex formation processes were optimized to obtain homogeneous and stable nanoparticles with a diameter of about 100 nm for systematic injection.

The therapeutic synergy of cyclodextrin and statin could reportedly enhance plaque-targeted drug delivery and anti-inflammation. Cyclodextrin led to the regression of cholesterol in the established plaque, and the statins were shown to inhibit the proliferation of macrophage foam cells. The study suggested that combination therapy is required to resolve the complex inflammatory cholesterol-rich microenvironment within the plaque.

Professor Park said, “While nanomedicine has been mainly developed for the treatment of cancers, our studies show that nanomedicine can also play a significant role in treating and preventing atherosclerosis, which causes various cardiovascular diseases that are the leading causes of death worldwide.”

This work was supported by KAIST and the National Research Foundation (NRF) of Korea.

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Nanomaterial gives robots chameleon skin

A new film made of gold nanoparticles changes color in response to any type of movement. Its unprecedented qualities could allow robots to mimic chameleons and octopi — among other futuristic applications.

Unlike other materials that try to emulate nature’s color changers, this one can respond to any type of movement, like bending or twisting. Robots coated in it could enter spaces that might be dangerous or impossible for humans, and offer information just based on the way they look.

For example, a camouflaged robot could enter tough-to-access underwater crevices. If the robot changes color, biologists could learn about the pressures facing animals that live in these environments.

Although some other color-changing materials can also respond to motion, this one can be printed and programmed to display different, complex patterns that are difficult to replicate. The UC Riverside scientists who created this nanomaterial documented their process in a Nature Communications paper published this past week.

Nanomaterials are simply materials that have been reduced to an extremely small scale — tens of nanometers in width and length, or, about the size of a virus. When materials like silver or gold become smaller, their colors will change depending on their size, shape, and the direction they face.

“In our case, we reduced gold to nano-sized rods. We knew that if we could make the rods point in a particular direction, we could control their color,” said chemistry professor Yadong Yin. “Facing one way, they might appear red. Move them 45 degrees, and they change to green.”

The problem facing the research team was how to take millions of gold nanorods floating in a liquid solution and get them all to point in the same direction to display a uniform color.

Their solution was to fuse smaller magnetic nanorods onto the larger gold ones. The two different-sized rods were encapsulated in a polymer shield, so that they would remain side by side. That way, the orientation of both rods could be controlled by magnets.

“Just like if you hold a magnet over a pile of needles, they all point in the same direction. That’s how we control the color,” Yin said.

Once the nanorods are dried into a thin film, their orientation is fixed in place and they no longer respond to magnets. “But, if the film is flexible, you can bend and rotate it, and will still see different colors as the orientation changes,” Yin said.

Other materials, like butterfly wings, are shiny and colorful at certain angles, and can also change color when viewed at other angles. However, those materials rely on precisely ordered microstructures, which are difficult and expensive to make for large areas. But this new film can be made to coat the surface of any sized object just as easily as applying spray paint on a house.

Though futuristic robots are an ultimate application of this film, it can be used in many other ways. UC Riverside chemist Zhiwei Li, the first author on this paper, explained that the film can be incorporated into checks or cash as an authentication feature. Under normal lighting, the film is gray, but when you put on sunglasses and look at it through polarized lenses, elaborate patterns can be seen. In addition, the color contrast of the film may change dramatically if you twist the film.

The applications, in fact, are only limited by the imagination. “Artists could use this technology to create fascinating paintings that are wildly different depending on the angle from which they are viewed,” Li said. “It would be wonderful to see how the science in our work could be combined with the beauty of art.”

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Nanosponges could intercept coronavirus infection

Nanoparticles cloaked in human lung cell membranes and human immune cell membranes can attract and neutralize the SARS-CoV-2 virus in cell culture, causing the virus to lose its ability to hijack host cells and reproduce.

The first data describing this new direction for fighting COVID-19 were published on June 17 in the journal Nano Letters. The “nanosponges” were developed by engineers at the University of California San Diego and tested by researchers at Boston University.

The UC San Diego researchers call their nano-scale particles “nanosponges” because they soak up harmful pathogens and toxins.

In lab experiments, both the lung cell and immune cell types of nanosponges caused the SARS-CoV-2 virus to lose nearly 90% of its “viral infectivity” in a dose-dependent manner. Viral infectivity is a measure of the ability of the virus to enter the host cell and exploit its resources to replicate and produce additional infectious viral particles.

Instead of targeting the virus itself, these nanosponges are designed to protect the healthy cells the virus invades.

“Traditionally, drug developers for infectious diseases dive deep on the details of the pathogen in order to find druggable targets. Our approach is different. We only need to know what the target cells are. And then we aim to protect the targets by creating biomimetic decoys,” said Liangfang Zhang, a nanoengineering professor at the UC San Diego Jacobs School of Engineering.

His lab first created this biomimetic nanosponge platform more than a decade ago and has been developing it for a wide range of applications ever since. When the novel coronavirus appeared, the idea of using the nanosponge platform to fight it came to Zhang “almost immediately,” he said.

In addition to the encouraging data on neutralizing the virus in cell culture, the researchers note that nanosponges cloaked with fragments of the outer membranes of macrophages could have an added benefit: soaking up inflammatory cytokine proteins, which are implicated in some of the most dangerous aspects of COVID-19 and are driven by immune response to the infection.

Making and testing COVID-19 nanosponges

Each COVID-19 nanosponge — a thousand times smaller than the width of a human hair — consists of a polymer core coated in cell membranes extracted from either lung epithelial type II cells or macrophage cells. The membranes cover the sponges with all the same protein receptors as the cells they impersonate — and this inherently includes whatever receptors SARS-CoV-2 uses to enter cells in the body.

The researchers prepared several different concentrations of nanosponges in solution to test against the novel coronavirus. To test the ability of the nanosponges to block SARS-CoV-2 infectivity, the UC San Diego researchers turned to a team at Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL) to perform independent tests. In this BSL-4 lab — the highest biosafety level for a research facility — the researchers, led by Anthony Griffiths, associate professor of microbiology at Boston University School of Medicine, tested the ability of various concentrations of each nanosponge type to reduce the infectivity of live SARS-CoV-2 virus — the same strains that are being tested in other COVID-19 therapeutic and vaccine research.

At a concentration of 5 milligrams per milliliter, the lung cell membrane-cloaked sponges inhibited 93% of the viral infectivity of SARS-CoV-2. The macrophage-cloaked sponges inhibited 88% of the viral infectivity of SARS-CoV-2. Viral infectivity is a measure of the ability of the virus to enter the host cell and exploit its resources to replicate and produce additional infectious viral particles.

“From the perspective of an immunologist and virologist, the nanosponge platform was immediately appealing as a potential antiviral because of its ability to work against viruses of any kind. This means that as opposed to a drug or antibody that might very specifically block SARS-CoV-2 infection or replication, these cell membrane nanosponges might function in a more holistic manner in treating a broad spectrum of viral infectious diseases. I was optimistically skeptical initially that it would work, and then thrilled once I saw the results and it sunk in what this could mean for therapeutic development as a whole,” said Anna Honko, a co-first author on the paper and a Research Associate Professor, Microbiology at Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL).

In the next few months, the UC San Diego researchers and collaborators will evaluate the nanosponges’ efficacy in animal models. The UC San Diego team has already shown short-term safety in the respiratory tracts and lungs of mice. If and when these COVID-19 nanosponges will be tested in humans depends on a variety of factors, but the researchers are moving as fast as possible.

“Another interesting aspect of our approach is that even as SARS-CoV-2 mutates, as long as the virus can still invade the cells we are mimicking, our nanosponge approach should still work. I’m not sure this can be said for some of the vaccines and therapeutics that are currently being developed,” said Zhang.

The researchers also expect these nanosponges would work against any new coronavirus or even other respiratory viruses, including whatever virus might trigger the next respiratory pandemic.

Mimicking lung epithelial cells and immune cells

Since the novel coronavirus often infects lung epithelial cells as the first step in COVID-19 infection, Zhang and his colleagues reasoned that it would make sense to cloak a nanoparticle in fragments of the outer membranes of lung epithelial cells to see if the virus could be tricked into latching on it instead of a lung cell.

Macrophages, which are white blood cells that play a major role in inflammation, also are very active in the lung during the course of a COVID-19 illness, so Zhang and colleagues created a second sponge cloaked in macrophage membrane.

The research team plans to study whether the macrophage sponges also have the ability to quiet cytokine storms in COVID-19 patients.

“We will see if the macrophage nanosponges can neutralize the excessive amount of these cytokines as well as neutralize the virus,” said Zhang.

Using macrophage cell fragments as cloaks builds on years of work to develop therapies for sepsis using macrophage nanosponges.

In a paper published in 2017 in Proceedings of the National Academy of Sciences, Zhang and a team of researchers at UC San Diego showed that macrophage nanosponges can safely neutralize both endotoxins and pro-inflammatory cytokines in the bloodstream of mice. A San Diego biotechnology company co-founded by Zhang called Cellics Therapeutics is working to translate this macrophage nanosponge work into the clinic.

A potential COVID-19 therapeutic The COVID-19 nanosponge platform has significant testing ahead of it before scientists know whether it would be a safe and effective therapy against the virus in humans, Zhang cautioned. But if the sponges reach the clinical trial stage, there are multiple potential ways of delivering the therapy that include direct delivery into the lung for intubated patients, via an inhaler like for asthmatic patients, or intravenously, especially to treat the complication of cytokine storm.

A therapeutic dose of nanosponges might flood the lung with a trillion or more tiny nanosponges that could draw the virus away from healthy cells. Once the virus binds with a sponge, “it loses its viability and is not infective anymore, and will be taken up by our own immune cells and digested,” said Zhang.

“I see potential for a preventive treatment, for a therapeutic that could be given early because once the nanosponges get in the lung, they can stay in the lung for some time,” Zhang said. “If a virus comes, it could be blocked if there are nanosponges waiting for it.”

Growing momentum for nanosponges

Zhang’s lab at UC San Diego created the first membrane-cloaked nanoparticles over a decade ago. The first of these nanosponges were cloaked with fragments of red blood cell membranes. These nanosponges are being developed to treat bacterial pneumonia and have undergone all stages of pre-clinical testing by Cellics Therapeutics, the San Diego startup cofounded by Zhang. The company is currently in the process of submitting the investigational new drug (IND) application to the FDA for their lead candidate: red blood cell nanosponges for the treatment of methicillin-resistant staphylococcus aureus (MRSA) pneumonia. The company estimates the first patients in a clinical trial will be dosed next year.

The UC San Diego researchers have also shown that nanosponges can deliver drugs to a wound site; sop up bacterial toxins that trigger sepsis; and intercept HIV before it can infect human T cells.

The basic construction for each of these nanosponges is the same: a biodegradable, FDA-approved polymer core is coated in a specific type of cell membrane, so that it might be disguised as a red blood cell, or an immune T cell or a platelet cell. The cloaking keeps the immune system from spotting and attacking the particles as dangerous invaders.

“I think of the cell membrane fragments as the active ingredients. This is a different way of looking at drug development,” said Zhang. “For COVID-19, I hope other teams come up with safe and effective therapies and vaccines as soon as possible. At the same time, we are working and planning as if the world is counting on us.”

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Experiments in mice and human cells shed light on best way to deliver nanoparticle therapy for cancer

Researchers in the cancer nanomedicine community debate whether use of tiny structures, called nanoparticles, can best deliver drug therapy to tumors passively — allowing the nanoparticles to diffuse into tumors and become held in place, or actively — adding a targeted anti-cancer molecule to bind to specific cancer cell receptors and, in theory, keep the nanoparticle in the tumor longer. Now, new research on human and mouse tumors in mice by investigators at the Johns Hopkins Kimmel Cancer Center suggests the question is even more complicated.

Laboratory studies testing both methods in six models of breast cancer; five human cancer cell lines and one mouse cancer in mice with three variants of the immune system found that nanoparticles coated with trastuzumab, a drug that targets human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells, were better retained in the tumors than plain nanoparticles, even in tumors that did not express the pro-growth HER2 protein. However, immune cells of the host exposed to nanoparticles induced an anti-cancer immune response by activating T cells that invaded and slowed tumor growth.

A description of the work will be published March 25 in Science Advances.

“It’s been known for a long time that nanoparticles, when injected into the bloodstream, are picked up by scavengerlike macrophages and other immune system cells,” explains senior study author Robert Ivkov, Ph.D., M.Sc., associate professor of radiation oncology and molecular radiation sciences at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. “Many researchers in the field have been focused on trying to reduce interactions with immune cells, because they have been trying to increase the circulation time of the nanoparticles and their retention in tumor cells. But our study demonstrates that the immune cells in the tumor collect and react to the particles in such a way to stimulate an anti-cancer response. This may hold potential for advancing beyond drug delivery toward developing cancer immunotherapies.”

The investigators conducted a few in vitro experiments in their study. First, they applied some plain starch-coated iron oxide nanoparticles and others coated with trastuzumab to five human breast cancer cell lines, finding that the amount of binding between the trastuzumab-coated nanoparticles and cells depended on how much the cancer cells expressed the oncogene HER2. In people, HER2-positive breast cancers are among the most resistant to standard chemotherapy. Trastuzumab, sold under the name Herceptin, targets the HER2-positive tumor cells and triggers the immune system as well.

Responses were surprisingly different in animal models, the researchers report. In separate experiments, the team used the nanoparticles in two immune-deficient strains of mice engrafted with cells from five human breast cancer cell lines — two that were HER2 negative and three that were HER2 positive. When they studied the animals’ tumors 24 hours later, they noticed that nanoparticles coated with trastuzumab were found in a concentration two to five times greater than the plain nanoparticles in all types of tumors, regardless of whether they expressed the HER2 protein. They also found that the amount of trastuzumab-coated nanoparticles was even greater (tenfold) in mice that had a fully functional immune system and were bearing mouse-derived tumors.

This led the researchers to suspect that the host animals’ immune systems were interacting strongly with the nanoparticles and playing a role in determining retention of the particles in the tumor, whether or not a drug was added.

More experiments, the team reports, revealed that tumor-associated immune cells were responsible for collecting the nanoparticles, and that mice bred with an intact immune system retained more of the trastuzumab-coated nanoparticles than mice bred without a fully functioning immune system.

In addition, inflammatory immune cells in the tumors’ immediate surroundings, or microenvironment, seized more of the coated nanoparticles than the plain ones. Finally, in a series of 30-day experiments, the researchers found that exposure to nanoparticles inhibited tumor growth three to five times more than controls, and increased CD8-positive cancer-killing T cells in the tumors. Surprisingly, Ivkov notes, the anti-cancer immune activating response was equally effective with exposure to either plain or trastuzumab-coated nanoparticles. Mice with defective T cells did not show tumor growth inhibition. The investigators say this demonstrated that systemic exposure to nanoparticles can cause a systemic host immune response that leads to anti-cancer immune stimulation, and does not require nanoparticles to be inside the tumors.

“Overall, our work suggests that complex interdependencies exist between the host and tumor immune responses to nanoparticle exposure,” Ivkov says. “These results offer intriguing possibilities for exploring nanoparticle ‘targeting’ of the tumor immune microenvironment. They also demonstrate exciting new potential to develop nanoparticles as platforms for cancer immune therapies.”

The investigators say they also plan to study whether the same types of immune responses can be generated for noncancer conditions, such as infectious diseases.

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X-ray microscopy at BESSY II: Nanoparticles can change cells

Today, nanoparticles are not only in cosmetic products, but everywhere, in the air, in water, in the soil and in food. Because they are so tiny, they easily enter into the cells in our body. This is also of interest for medical applications: Nanoparticles coated with active ingredients could be specifically introduced into cells, for example to destroy cancer cells. However, there is still much to be learned about how nanoparticles are distributed in the cells, what they do there, and how these effects depend on their size and coating.

New insights have come from a study at BESSY II, where Prof. Gerd Schneider’s team can take X-ray microscopy images with soft, intensive X-rays. Researchers from the X-ray microscopy group led by HZB biophysicist Dr. James McNally investigated cells with differently coated nanoparticles. The nanoparticles were exactly the same size, but were coated with different active ingredients.

“X-ray microscopy offers significantly better resolution than light microscopy, and a much better overview than electron microscopy,” emphasizes Schneider. For the first time, the team obtained complete, three-dimensional, high-resolution images of the nanoparticle-treated cells with the organelles contained therein: including lipid droplets, mitochondria, multivesicular bodies and endosomes. Lipid droplets act as energy stores in the cell, while mitochondria metabolize this energy.

The analysis of the images showed: The nanoparticles accumulate preferentially in a subset of the cell organelles and also change the number of certain organelles at the expense of other organelles. The changes in organelle numbers were similar regardless of the nanoparticle coating, suggesting that many different kinds of nanoparticle coatings may induce a similar effect. To evaluate how general this effect is, further studies with other nanoparticle coatings and with other cell types must be performed.

“X-ray microscopy allows us to see the cell as a whole, so we were able to observe this behavior for the first time,” explains McNally. “We found that the absorption of such nanoparticles increases the number of mitochondria and endosomes, while other organelles, namely lipid droplets and multivesicular bodies, decrease,” says Burcu Kepsutlu, who carried out the experiments for her doctorate.”When we go on a starvation diet or run a marathon, we see similar changes in the cell — namely an increase in mitochondria and a decrease in lipid droplets,” says McNally. “Apparently it takes energy for the cell to absorb the nanoparticles, and the cell feels like it has just run a marathon.”

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Newly developed nanoparticles help fight lung cancer in animal model

Scientists have reported a new approach to treating lung cancer with inhaled nanoparticles developed at Wake Forest School of Medicine, part of Wake Forest Baptist Health.

In this proof of concept study, Dawen Zhao, M.D., Ph.D., associate professor of biomedical engineering at Wake Forest School of Medicine, used a mouse model to determine if metastatic lung tumors responded to an inhalable nanoparticle-immunotherapy system combined with the radiation therapy that is commonly used to treat lung cancer.

The study is published in the current issue of Nature Communications.

Lung cancer is the second most common cancer and the leading cause of cancer death among both men and women. More people die of lung cancer than of colon, breast and prostate cancers combined. Although immunotherapy is promising, it currently works in less than 20% of patients with lung cancer.

Significant clinical evidence suggests that at the time of diagnosis most patients’ tumors are poorly infiltrated by immune cells. This “cold” immune environment in tumors prevents the body’s immune system from recognizing and eliminating the tumor cells.

Overcoming this immunosuppressive tumor environment to attack the cancer efficiently is currently an area of great interest in the scientific community, Zhao said.

Previous approaches have involved direct injection of immunomodulators into tumors to boost their immune response. However, this approach is generally limited to surface and easily-accessed tumors, and can become less effective if repeated injections are needed to sustain immune response.

“The goal of our research was to develop a novel means to convert cold tumors to hot, immune-responsive tumors,” Zhao said. “We wanted it to be non-invasive without needle injection, able to access multiple lung tumors at a time, and be safe for repeated use. We were hoping that this new approach would boost the body’s immune system to more effectively fight lung cancer.”

The nanoparticle-immunotherapy system that Zhao and his team developed delivered immunostimulants via inhalation to a mouse model of metastatic lung cancer. The immunostimulant-loaded nanoparticle which, when deposited in the lung air sacs, were taken up by one specific type of immune cells, called antigen-presenting cells (APC).

The immunostimulant, cGAMP, in the nanoparticle was then released inside the cell, where stimulation of a particular immune pathway (STING) activated the APC cell, which is a critical step to induce systemic immune response.

The team also showed that combining the nanoparticle inhalation with radiation applied to a portion of one lung led to regression of tumors in both lungs and prolonged survival of the mice. In addition, the team reported that it completely eliminated lung tumors in some of the mice.

Through mechanistic studies the team then confirmed that the inhalation system converted those initially cold tumors in both lungs to hot tumors favorable for robust anti-cancer immunity.

Zhao’s inhalable immunotherapy presents several key advantages to previous methods, especially the ability to access deep-seated lung tumors because the nanoparticulate-carrying aerosol was designed to reach all parts of the lung, and the feasibility of repeated treatment by using a non-irritating aerosol formulation.

The treatment was shown to be well tolerated and safe without causing adverse immune-related distress in the mice.

The Wake Forest School of Medicine researchers have filed a provisional patent application for the inhalable nanoparticle-immunotherapy system.

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Materials provided by Wake Forest Baptist Medical Center. Note: Content may be edited for style and length.

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