This artist’s rendering shows a synthetic polymer (purple) that activates STING proteins (yellow and green motifs) for cancer immunotherapy. Credit: Shenyang Zhiyan Science and Technology Co. Ltd.
ByUT SOUTHWESTERN MEDICAL CENTERFEBRUARY 8, 2021
New immunotherapy drug activates the body’s innate immune system to fight cancer.
A new nanoparticle-based drug can boost the body’s innate immune system and make it more effective at fighting off tumors, researchers at UT Southwestern have shown. Their study, published in Nature Biomedical Engineering, is the first to successfully target the immune molecule STING with nanoparticles about one millionth the size of a soccer ball that can switch on/off immune activity in response to their physiological environment.
“Activating STING by these nanoparticles is like exerting perpetual pressure on the accelerator to ramp up the natural innate immune response to a tumor,” says study leader Jinming Gao, Ph.D., a professor in UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center and a professor of otolaryngology – head and neck surgery, pharmacology, and cell biology.
For more than a decade, researchers and pharmaceutical companies have been racing to develop drugs that target STING, which stands for “stimulator of interferon genes.” The STING protein, discovered in 2008, helps mediate the body’s innate immune system — the collection of immune molecules that act as first responders when a foreign agent circulates in the body, including cancer DNA. Research has suggested that activating STING can make the innate immune system more powerful at fighting tumors or infections. However, results from earlier clinical trials involving first-generation compounds targeting STING for activation failed to demonstrate an impressive clinical effect.
“A major limitation of conventional small molecule drugs is that after injection into tumors, they are washed out from the tumor site by blood perfusion, which can reduce antitumor efficacy while causing systemic toxicities,” explains Gao.
Jinming Gao, Ph.D. Credit: UT Southwestern Medical Center
Gao and his colleagues at UTSW discovered another approach that is different from the earlier or first-generation STING agonist approaches that utilize synthetic cyclic dinucleotide to activate STING in the body. Gao and his team aimed to design a polymer — a manmade macromolecule that can self-assemble into nanoparticles — to effectively deliver cyclic GMP-AMP (cGAMP), a natural small molecule activator of STING, to the protein target. But one polymer they synthesized, PC7A, produced an unexpected and novel effect: It activated STING even without cGAMP. The group reported the initial results in 2017, not knowing at the time exactly how PC7A worked; the polymer didn’t resemble any other drugs that activated STING.
In the new paper, Gao’s team showed that PC7A binds to a different site on the STING molecule from known drugs. Moreover, its effect on the STING protein is different. While existing drugs activate the protein over the course of about six hours, PC7A forms polyvalent condensates with STING for over 48 hours, causing a more sustained effect on STING. This longer innate immune activation, they showed, leads to a more effective T cell response against multiple solid tumors. Mice survived longer and had slower tumor growth when they received a combination of PC7A and cGAMP, the researchers found.
The polymer also has other advantages. When circulating in the bloodstream, the polymers are present as small round nanoparticles that do not bind to STING. It’s only when those nanoparticles enter immune cells that they separate, attach to STING, and activate the immune response. That means that PC7A might be less likely to cause side effects throughout the body than other STING-targeting drugs, says Gao, although clinical trials will be needed to prove that.
Because PC7A binds to a different site of the STING molecule, the compound might work in patients for whom typical STING-targeting drugs do not. Up to 20 percent of people have inherited a slightly different gene for STING; the variant makes the STING protein resistant to several cyclic dinucleotide drugs. Gao and his team demonstrated that PC7A can still activate cells that express these STING variants.
“There’s been a lot of excitement about therapies that target STING and the potential role these compounds could play in expanding the benefits of immunotherapies for cancer patients,” says Gao. “We believe that our new nanotechnology approach offers a way to activate STING without some of the limitations we’ve seen with earlier STING agonist drugs in development.”
Reference: “Polycarbonate-based ultra-pH sensitive nanoparticles improve therapeutic window” by Xu Wang, Jonathan Wilhelm, Wei Li, Suxin Li, Zhaohui Wang, Gang Huang, Jian Wang, Houliang Tang, Sina Khorsandi, Zhichen Sun, Bret Evers and Jinming Gao, 17 November 2020, Nature Communications. DOI: 10.1038/s41467-020-19651-7
Other UTSW researchers who contributed to this study were Suxin Li, Min Luo, Zhaohui Wang, Qiang Feng, Jonathan Wilhelm, Xu Wang, Wei Li, Jian Wang, Agnieszka Cholka, Yang-xin Fu, Baran Sumer, and Hongtao Yu.
This research was supported by funds from the National Institutes of Health (U54 CA244719) and Mendelson-Young Endowment for Cancer Therapeutics.
Gao holds the Elaine Dewey Sammons Distinguished Chair in Cancer Research, in honor of Eugene P. Frenkel, M.D. at UTSW.
One of the most remarkable recent advances in biomedical research has been the development of highly targeted gene-editing methods such as CRISPR that can add, remove, or change a gene within a cell with great precision. The method is already being tested or used for the treatment of patients with sickle cell anemia and cancers such as multiple myeloma and liposarcoma, and today, its creators Emmanuelle Charpentier and Jennifer Doudna received the Nobel Prize in chemistry.
While gene editing is remarkably precise in finding and altering genes, there is still no way to target treatment to specific locations in the body. The treatments tested so far involve removing blood stem cells or immune system T cells from the body to modify them, and then infusing them back into a patient to repopulate the bloodstream or reconstitute an immune response—an expensive and time-consuming process.
Building on the accomplishments of Charpentier and Doudna, Tufts researchers have for the first time devised a way to directly deliver gene-editing packages efficiently across the blood brain barrier and into specific regions of the brain, into immune system cells, or to specific tissues and organs in mouse models. These applications could open up an entirely new line of strategy in the treatment of neurological conditions, as well as cancer, infectious disease, and autoimmune diseases.
A team of Tufts biomedical engineers, led by associate professor Qiaobing Xu, sought to find a way to package the gene editing “kit” so it could be injected to do its work inside the body on targeted cells, rather than in a lab.
They used lipid nanoparticles (LNPs)—tiny “bubbles” of lipid molecules that can envelop the editing enzymes and carry them to specific cells, tissues, or organs. Lipids are molecules that include a long carbon tail, which helps give them an “oily” consistency, and a hydrophilic head, which is attracted to a watery environment.
There is also typically a nitrogen, sulfur, or oxygen-based link between the head and tail. The lipids arrange themselves around the bubble nanoparticles with the heads facing outside and the tails facing inward toward the center.
Xu’s team was able to modify the surface of these LNPs so they can eventually “stick” to certain cell types, fuse with their membranes, and release the gene-editing enzymes into the cells to do their work.
Making a targeted LNP takes some chemical crafting.
By creating a mix of different heads, tails, and linkers, the researchers can screen— first in the lab—a wide variety of candidates for their ability to form LNPs that target specific cells. The best candidates can then be tested in mouse models, and further modified chemically to optimize targeting and delivery of the gene-editing enzymes to the same cells in the mouse.
“We created a method around tailoring the delivery package for a wide range of potential therapeutics, including gene editing,” said Xu. “The methods draw upon combinatorial chemistry used by the pharmaceutical industry for designing the drugs themselves, but instead we are applying the approach to designing the components of the delivery vehicle.”
In an ingenious bit of chemical modeling, Xu and his team used a neurotransmitter at the head of some lipids to assist the particles in crossing the blood-brain barrier, which would otherwise be impermeable to molecule assemblies as large as an LNP.
The ability to safely and efficiently deliver drugs across the barrier and into the brain has been a long-standing challenge in medicine. In a first, Xu’s lab delivered an entire complex of messenger RNAs and enzymes making up the CRISPR kit into targeted areas of the brain in a living animal.
Some slight modifications to the lipid linkers and tails helped create LNPs that could deliver into the brain the small molecule antifungal drug amphotericin B (for treatment of meningitis) and a DNA fragment that binds to and shuts down the gene producing the tau protein linked to Alzheimer’s disease.
More recently, Xu and his team have created LNPs to deliver gene-editing packages into T cells in mice. T cells can help in the production of antibodies, destroy infected cells before viruses can replicate and spread, and regulate and suppress other cells of the immune system.
The LNPs they created fuse with T cells in the spleen or liver—where they typically reside—to deliver the gene-editing contents, which can then alter the molecular make-up and behavior of the T cell. It’s a first step in the process of not just training the immune system, as one might do with a vaccine, but actually engineering it to fight disease better.
Xu’s approach to editing T cell genomes is much more targeted, efficient, and likely to be safer than methods tried so far using viruses to modify their genome.
“By targeting T cells, we can tap into a branch of the immune system that has tremendous versatility in fighting off infections, protecting against cancer, and modulating inflammation and autoimmunity,” said Xu.
Xu and his team explored further the mechanism by which LNPs might find their way to their targets in the body. In experiments aimed at cells in the lungs, they found that the nanoparticles picked up specific proteins in the bloodstream after injection.
The proteins, now incorporated into the surface of the LNPs, became the main component that helped the LNPs to latch on to their target. This information could help improve the design of future delivery particles.
While these results have been demonstrated in mice, Xu cautioned that more studies and clinical trials will be needed to determine the efficacy and safety of the delivery method in humans.
The authors acknowledge the support received from the National Science Foundation through the Engineering Research Center for Nanotechnology-Enabled Water Treatment (EEC1449500) and via Grant CBET 1437630. The authors also acknowledge funding from the National Science Foundation Graduate Research Fellowship Program under grant no. DGE-1752134, awarded to C.J.P. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation.
ABSTRACT
Transmembrane protein channels, including ion channels and aquaporins that are responsible for fast and selective transport of water, have inspired membrane scientists to exploit and mimic their performance in membrane technologies. These biomimetic membranes comprise discrete nanochannels aligned within amphiphilic matrices on a robust support. While biological components have been used directly, extensive work has also been conducted to produce stable synthetic mimics of protein channels and lipid bilayers.
However, the experimental performance of biomimetic membranes remains far below that of biological membranes. In this review, we critically assess the status and potential of biomimetic desalination membranes. We first review channel chemistries and their transport behavior, identifying key characteristics to optimize water permeability and salt rejection.
We compare various channel types within an industrial context, considering transport performance, processability, and stability. Through a re-examination of previous vesicular stopped-flow studies, we demonstrate that incorrect permeability equations result in an overestimation of the water permeability of nanochannels. We find in particular that the most optimized aquaporin-bearing bilayer had a pure water permeability of 2.1 L m–2 h–1 bar–1, which is comparable to that of current state-of-the-art polymeric desalination membranes.
Through a quantitative assessment of biomimetic membrane formats, we analytically show that formats incorporating intact vesicles offer minimal benefit, whereas planar biomimetic selective layers could allow for dramatically improved salt rejections. We then show that the persistence of nanoscale defects explains observed subpar performance. We conclude with a discussion on optimal strategies for minimizing these defects, which could enable breakthrough performance.
Biomimetic Desalination Membranes
As stressors like population growth, industrialization, and climate change threaten to deplete and contaminate our freshwater resources, larger bodies of saline water could provide a vast supply of water for drinking, agricultural, and industrial use.(1) However, desalination of these waters requires more energy and financial resources than traditional freshwater purification methods.(2) Currently, the state-of-the-art technology for desalination is reverse osmosis (RO) using thin-film-composite (TFC) polyamide membranes.(3,4) Fully aromatic TFC-RO membranes are readily produced at industrial scale through interfacial polymerization, whereby a rapid reaction occurs at the interface of immiscible organic and aqueous phases to form a highly cross-linked polyamide selective layer on a porous support(5) (Figure 1). With the advent of the TFC-RO membrane and energy recovery devices, seawater desalination energy requirements for the RO stage have drastically reduced from ∼15 kWh m–3 using the original cellulose acetate membranes of the 1970s down to only ∼2 kWh m–3, only ∼25% above the practical minimum energy.(2)
Figure 1. Transition in desalination research from focusing on dense polymers that reject salt by a solution-diffusion mechanism to considering sub-nanometer channels capable of molecularly sieving ions. In the solution-diffusion panel (left), common reactants for TFC-RO membranes are represented, which rapidly react at an organic–aqueous interface during interfacial polymerization to form a cross-linked, fully aromatic polyamide selective layer with characteristic ridge-valley morphology. Salt rejection determined by a solution-diffusion mechanism results from the higher partitioning and/or diffusion rates of water over ions. In the ion sieving panel (right), common molecular sieves that have been considered for desalination are shown, with ideal water pathways illustrated. In pores similar in size to water, single-file water transport is induced. Nanotubes and nanochannels can be synthetic (e.g., carbon nanotubes) or biological (e.g., aquaporins). To produce nanoporous sheets, sub-nanometer pores where only a few atoms are vacant have been etched in single-layer graphene using chemical oxidation, electron beam irradiation, doping, and ion bombardment.(12) For 2D laminates, the water pathway is through interlayer spaces between sheets. Studies so far have primarily considered graphene oxide nanosheets for 2D laminates.(13,14) The molecular sieving mechanism for ion rejection is by size exclusion, where highly uniform pores exclude larger solutes and ideally transport only molecules similar in size to water.
Reduced Operational Costs, Improved Reliability and Efficiency and Enhanced Product Water Quality
Despite the substantial reduction in energy consumption and overall cost, seawater RO still has room for improvement. While current water permeabilities enable near-optimal performance, increased water-solute selectivity would allow for reduced operational costs, improved reliability and efficiency, and enhanced product water quality.(4) For example, TFC-RO membranes inadequately retain chloride and some small neutral solutes, such as boron in seawater desalination and trace organic contaminants in wastewater reuse, necessitating extra purification steps which increase the cost of desalination.(4)Transport through the polyamide layer is well described by the solution-diffusion model, in which permeants (i.e., water and solutes) partition into the dense polyamide layer and diffuse through it (Figure 1).(6)
The resultant permselectivity of the membrane is attributed to differences in abilities and rates of species to dissolve into and diffuse through the polyamide membrane material.(7) Although intrinsic water permeability can far exceed salt permeability during solution diffusion, as it does for polyamide, historical data suggest that it will be difficult to significantly advance performance with polymeric systems. Commercial desalination and water purification membranes typically exhibit a permeability–selectivity trade-off, similar to the Robeson plot for polymeric gas separations.(8−11)
Furthermore, despite many decades of extensive research, no polymeric material has yet surpassed the desalination performance (i.e., water permeability, water-salt selectivity, and cost-effectiveness) of fully aromatic polyamide.
To overcome the limitations of the solution-diffusion-based polyamide membranes, research focus has shifted toward the development of desalination membranes that remove solutes via molecular sieving. In this mechanism of ion rejection, highly uniform, rigid pores that are smaller than the diameter of hydrated salt ions transport water and nearly completely reject ions by size exclusion (Figure 1). Recent formats of molecular sieves considered for desalination include nanotubes and nanochannels, two-dimensional (2D) laminates, and nanoporous sheets (Figure 1).(14)
However, these top-down efforts have failed so far to achieve adequate salt rejection due to the persistence of defects coupled with the daunting challenges of tuning interlayer spacing or pore size.(12,13,15)
Biomimetic membranes, or composites comprising an amphiphilic matrix with discrete, aligned nanochannels on a robust support, may provide a platform for industrial-scale molecular sieves that overcome the limitations of solution-diffusion-based polyamide membranes.
After over 3.5 billion years of evolution,(16,17) the cell membranes of modern organisms can perform an array of highly complicated functions, which rely on a system of complex transmembrane proteins aligned within the amphiphilic lipid bilayer. In this system, water and only select ions pass through channel pores and pumps, depending on the energy and nutrient needs of the cell.(18,19) In pioneering work, Preston et al. determined that an integral membrane protein formed a biological channel that selectively transports water in and out of many types of cells. This protein was the CHannel-forming Integral Protein of 28 kDa (CHIP28),(20,21) later called the aquaporin. For these discoveries, Peter Agre and Roderick MacKinnon shared the 2003 Nobel Prize in Chemistry. Through additional biophysical studies, ion channels also showed impressive selectivity, inspiring the design of synthetic ion channels.(22−25)
Eventually, researchers realized the potential implications of these channels for industrial-scale water purification, especially aquaporin in the use of desalination, and attempted to produce biomimetic membranes, or materials that mimic the structure and performance of biological membranes.(26−35)
While much of the work has focused on water-solute separations, the biomimetic membrane format also presents opportunities to develop membranes with tunable selectivity based on a chosen channel type.However, translating biological mechanisms into industrial-scale technology necessitates scale-up by orders of magnitude—from the microscopic size of a cell membrane to tens of square meters.(36) For industrial relevance, the synthesis of a biomimetic membrane would need to be cost-effective and simple. Simultaneously, such a membrane would need to be mechanically stable under RO pressures exceeding 70 bar and chemically stable during repeated membrane cleaning and usage.(37) Notably, even at the lab scale, sufficiently high-salt rejection has not yet been achieved for biomimetic desalination membranes after over a decade of research.(37,38)
Therefore, channels, selective layer formats, synthesis strategies, and support layer types must be carefully considered to attain the capabilities of this technology. While certain aspects of biomimetic desalination membranes have been reviewed recently,(37−42) a critical analysis of their performance and their potential application in water-treatment processes remains necessary.In this critical review, we examine efforts toward biomimetic desalination membranes for water purification in order to identify the best strategies to realize their full potential for both desalination and solute–solute selectivity. We first examine molecular transport, contrasting solution-diffusion with molecular sieving and assessing transport through the mixed matrix of biomimetic selective layers. We next identify the key characteristics of the aquaporin that explain its ultraselectivity and fast water transport, comparing this biological channel to several synthetic channels and placing each in industrial context. Using corrected analysis of reported permeability measurements, we then show that the water permeabilities of many channels have been overestimated. Subsequently, we predict best-case-scenario outcomes for common biomimetic formats, including membranes with intact vesicles and membranes with planar biomimetic layers. For the more promising planar format, the biggest challenge is the presence of nanoscale defects. Through mathematical models, we estimate the defect density for several reported biomimetic membranes. We then discuss synthesis pathways that could limit both the presence of defects and the effect of defects on transport performance.
We conclude with a discussion on the practicality of biomimetic desalination membranes and how to best exploit the strengths of discrete nanochannels as molecular sieves in other applications beyond desalination.
Figure 2. Channel types for biomimetic membranes, including biological as well as bioinspired and bioderived. (a) Single channel water permeability versus pore interior diameter. The pore interior diameter here is defined as the inner diameter of the most constricted region. For PAH[4], the pore diameter shown refers to the average width of dynamic voids that formed in channel clusters.
Channel permeabilities from stopped-flow data and simulations were adjusted to 25 °C and corrected for any previous errors in permeability calculation (see SI, Section S1 for details). (b) (left) Overhead view of AqpZ tetramer and (right) side view of single AqpZ channel with characteristic hourglass shape. (c) GramA dimer as it exists in biological and vesicular environments. In organic solvents, the monomers can intertwine to form a parallel or antiparallel helix. AqpZ and GramA diagrams were drawn using PyMOL(69) with protein sequences from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB-PDB, https://www.rcsb.org/), PDB-ID codes 1RC2(70) and 1NRM.(71) (d) Dependence of water diffusivity through pores on the number of interior hydrogen-bond points.
Data extracted from ref (56). (e) Cyclic peptide nanotubes. (left) Hydrogen-bonding pattern of pore-forming, stacked cyclic peptides. A polyglycine structure is shown for simplicity; side residues would typically be present. (right) Modified cyclic peptide with interior peptide-mimicking functional groups. The analogous unmodified cyclic peptide is radially symmetrical with a fourth primary amine side chain (cyclo[(d-Ala-Lys)4]).(72) (f) Single-walled carbon nanotube porins (wide and narrow) with armchair pattern. Number of carbons approximate those of wCNTP and nCNTP. (g) (left) PAP[5] and (right) PAH[4] nanochannels with peptide appendages that form interarm hydrogen bonds. (h) (left) Aquafoldamer subunits with “sticky” ends. Differences in end groups that comprise Aqf1 and Aqf2 subunits are illustrated. (right) Weak hydrogen-bonding pattern of pore-forming, stacked aquafoldamers. Six subunits are needed to cross a DOPC membrane. (i) Pure water permeability versus total channel areal coverage in a DOPC bilayer. Single channel permeabilities from (a) were divided by channel cross-sectional area and converted into channel water permeability (A) coefficients using eq 3. Overall biomimetic layer A coefficients were calculated for various densities of channels within a DOPC bilayer using eq 7. DOPC bilayer hydraulic permeability was taken as 0.15 L m–2 h–1 bar–1.(73) The shaded region indicates the water permeability of current commercial TFC-RO membranes, an adequate range for desalination performance. Permeabilities are listed in Table S1.
** Read the Complete Paper and Conclusions from AZ Nano by Following the Link Below
Cassandra J. Porter: Department of Chemical and Environmental Engineering, Yale University, New Haven, Connecticut
Jay R. Werber: Department of Chemical and Environmental Engineering, Yale University, New Haven, Connecticut and Department of Chemistry, University of Minnesota, Minneapolis, Minnesota
Mingjiang Zhong: Department of Chemical and Environmental Engineering, Yale University, New Haven, Connecticut
Corey J. Wilson: School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
Menachem Elimelech: Department of Chemical and Environmental Engineering, Yale University, New Haven, Connecticut
The development of bimetallic nanoparticles (i.e., tiny particles composed of two different metals that exhibit several new and improved properties) represents a novel area of research with a wide range of potential applications.
Now, a research team in the University of Maryland (UMD)’s Department of Materials Science and Engineering (MSE) has developed a new method for mixing metals generally known to be immiscible, or unmixable, at the nanoscale to create a new range of bimetallic materials.
Such a library will be useful for studying the role of these bimetallic particles in various reaction scenarios such as the transformation of carbon dioxide to fuel and chemicals.
The study, led by MSE Professor Liangbing Hu, waspublished inScience Advanceson April 24, 2020.Chunpeng Yang, an MSE Research Associate, served as first author on the study.
“With this method, we can quickly develop different bimetallics using various elements, but with the same structure and morphology,” said Hu. “Then we can use them to screen catalytic materials for a reaction; such materials will not be limited by synthesizing difficulties.”
The complex nature of nanostructured bimetallic particles makes mixing such particles difficult, for a variety of reasons—including the chemical makeup of the metals, particle size, and how metals arrange themselves at the nanoscale—using conventional methods.
This newnon-equilibrium synthesismethod exposes copper-based mixes to a thermal shock of approximately 1300 ̊ Celsius for .02 seconds and then rapidly cools them to room temperature. The goal of using such a short interval of thermal heat is to quickly trap, or ‘freeze,’ the high-temperature metal atoms at room temperature while maintaining their mixing state.
In doing so, the research team was able to prepare a collection of homogeneous copper-based alloys. Typically, copper only mixes with a few other metals, such as zinc and palladium—but by using this new method, the team broadened the miscible range to include copper with nickel, iron, and silver, as well.
“Using a scanning electron microscope (SEM) and transmission electron microscope (TEM), we were able to confirm the morphology – how the materials formed – and size of the resulting Cu-Ag [copper-silver] bimetallic nanoparticles,” Yang said.
This method will enable scientists to create more diverse nanoparticle systems, structures, and materials having applications in catalysis, biological applications, optical applications, and magnetic materials.
As a model system for rapid catalyst development, the team investigated copper-based alloys as catalysts for carbon monoxide reduction reactions, in collaboration withFeng Jiao, a professor in the Department of Chemical and Biomolecular Engineering at the University of Delaware.
The electro-catalysis of carbon monoxide reduction (COR) is an attractive platform, allowing scientists to use greenhouse gas and renewable electrical energy to produce fuels and chemicals.
“Copper is, thus far, the most promising monometallic electrocatalyst that drives carbon monoxide reduction to value-added chemicals,” said Jiao. “The ability to rapidly synthesize a wide variety of copper-based bimetallic nanoalloys with a uniform structure enables us to conduct fundamental studies on the structure-property relationship in COR and other catalyst systems.”
This non-equilibrium synthetic strategy can be extended to other bimetallic or metal oxide systems, too. Utilizing artificial intelligence-based machine learning, the method will make rapid catalyst screening and rational design possible.
For patients with malignant brain tumors, the prognosis remains dismal. With the most aggressive treatments available, patients are usually only expected to live about 14 months after a diagnosis
This is because, chemotherapy, the most common form of treatment for cancer, is uniquely challenging for braintumor patients. The delicate organ in our skulls is protected by a network of vessels and tissue called the blood-brain barrier that keeps most foreign substances out. Furthermore, chemotherapy drugs can cause significant damage to the rest of the body if they are not able to target the tumor in a pharmacologically significant dose.
These challenges have plagued scientists for years, but a team of researchers for Yale School of Medicine and Beijing Normal University just published a breakthrough study detailing a new method that offers a promise at treatment. The solution? Nanoparticles.
Nanoparticles, particles that are smaller than wavelengths of visible light and can only be seen under a special microscope, have the potential to pass through the blood-brain barrier. They can also carry drugs to targeted areas of the body, reducing the side effects on the rest of the body. But previous nanoparticles were very complex and not very efficient in penetrating in the brain.
This most recent paper, published in Nature Biomedical Engineering on March 30, 2020, describes a small carbon nanoparticle engineered by the two labs that could both deliver chemotherapy drugs across the blood-brain barrier and mark tumor cells with fluorescence in mice. What’s more, this nanoparticle is incredibly simple—made up of only one single compound.
“The major problems we’ve solved is to improve the delivery efficiency and specificity of nanoparticles,” says Jiangbing Zhou, Ph.D., associate Professor of Neurosurgery and of Biomedical Engineering at Yale School of Medicine. “We created nanoparticles like building a missile. There’s usually a GPS on every missile to guide it into a specific location and we’re able to guide particles to penetrate the brain and find tumors.”
The GPS-like targeting occurs because the nanoparticles engineered to be recognized by a molecule called LAT1, which is present in the blood-brain barrier as well as many tumors, but not in most other normal organs. As a result, chemotherapy drugs can be loaded on the dots and target tumors while barely affecting the rest of the body. The nanoparticles gain entry to the brain because they’ve been engineered to look like amino acids, which are allowed past the blood-brain barrier as nutrients.
The nanoparticles have wider implications than drug delivery. They can be stimulated to emit a fluorescence, which helps surgeons locate tumor to remove with greater accuracy.
Still, there’s a long road ahead before this research can be applied in a clinical setting, says Dr. Zhou. “It takes a long time before the technology can be translated into clinical applications,” he says. “But this finding suggests a new direction for developing nanoparticles for drug delivery to the brain by targeting LAT1 molecules.”
More information: Shuhua Li et al. Targeted tumour theranostics in mice via carbon quantum dots structurally mimicking large amino acids, Nature Biomedical Engineering (2020). DOI: 10.1038/s41551-020-0540-y
MIT engineers have developed magnetic nanoparticles (shown in white squares) that can stimulate the adrenal gland to produce stress hormones such as adrenaline and cortisol. Credit: Massachusetts Institute of Technology
Abnormal levels of stress hormones such as adrenaline and cortisol are linked to a variety of mental health disorders, including depression and posttraumatic stress disorder (PTSD). MIT researchers have now devised a way to remotely control the release of these hormones from the adrenal gland, using magnetic nanoparticles.
This approach could help scientists to learn more about how hormone release influences mental health, and could eventually offer a new way to treat hormone-linked disorders, the researchers say.
“We’re looking how can we study and eventually treat stress disorders by modulating peripheral organ function, rather than doing something highly invasive in the central nervous system,” says Polina Anikeeva, an MIT professor of materials science and engineering and of brain and cognitive sciences.
To achieve control over hormone release, Dekel Rosenfeld, an MIT-Technion postdoc in Anikeeva’s group, has developed specialized magnetic nanoparticles that can be injected into the adrenal gland. When exposed to a weak magnetic field, the particles heat up slightly, activating heat-responsive channels that trigger hormone release. This technique can be used to stimulate an organ deep in the body with minimal invasiveness.
Anikeeva and Alik Widge, an assistant professor of psychiatry at the University of Minnesota and a former research fellow at MIT’s Picower Institute for Learning and Memory, are the senior authors of the study. Rosenfeld is the lead author of the paper, which appears today in Science Advances.
Controlling hormones
Anikeeva’s lab has previously devised several novel magnetic nanomaterials, including particles that can release drugs at precise times in specific locations in the body.
In the new study, the research team wanted to explore the idea of treating disorders of the brain by manipulating organs that are outside the central nervous system but influence it through hormone release. One well-known example is the hypothalamic-pituitary-adrenal (HPA) axis, which regulates stress response in mammals. Hormones secreted by the adrenal gland, including cortisol and adrenaline, play important roles in depression, stress, and anxiety.
“Some disorders that we consider neurological may be treatable from the periphery, if we can learn to modulate those local circuits rather than going back to the global circuits in the central nervous system,” says Anikeeva, who is a member of MIT’s Research Laboratory of Electronics and McGovern Institute for Brain Research.
As a target to stimulate hormone release, the researchers decided on ion channels that control the flow of calcium into adrenal cells. Those ion channels can be activated by a variety of stimuli, including heat. When calcium flows through the open channels into adrenal cells, the cells begin pumping out hormones. “If we want to modulate the release of those hormones, we need to be able to essentially modulate the influx of calcium into adrenal cells,” Rosenfeld says.
Unlike previous research in Anikeeva’s group, in this study magnetothermal stimulation was applied to modulate the function of cells without artificially introducing any genes.
To stimulate these heat-sensitive channels, which naturally occur in adrenal cells, the researchers designed nanoparticles made of magnetite, a type of iron oxide that forms tiny magnetic crystals about 1/5000 the thickness of a human hair. In rats, they found these particles could be injected directly into the adrenal glands and remain there for at least six months. When the rats were exposed to a weak magnetic field—about 50 millitesla, 100 times weaker than the fields used for magnetic resonance imaging (MRI)—the particles heated up by about 6 degrees Celsius, enough to trigger the calcium channels to open without damaging any surrounding tissue.
The heat-sensitive channel that they targeted, known as TRPV1, is found in many sensory neurons throughout the body, including pain receptors. TRPV1 channels can be activated by capsaicin, the organic compound that gives chili peppers their heat, as well as by temperature. They are found across mammalian species, and belong to a family of many other channels that are also sensitive to heat.
This stimulation triggered a hormone rush—doubling cortisol production and boosting noradrenaline by about 25 percent. That led to a measurable increase in the animals’ heart rates.
Treating stress and pain
The researchers now plan to use this approach to study how hormone release affects PTSD and other disorders, and they say that eventually it could be adapted for treating such disorders. This method would offer a much less invasive alternative to potential treatments that involve implanting a medical device to electrically stimulate hormone release, which is not feasible in organs such as the adrenal glands that are soft and highly vascularized, the researchers say.
Another area where this strategy could hold promise is in the treatment of pain, because heat-sensitive ion channels are often found in pain receptors.
“Being able to modulate pain receptors with this technique potentially will allow us to study pain, control pain, and have some clinical applications in the future, which hopefully may offer an alternative to medications or implants for chronic pain,” Anikeeva says. With further investigation of the existence of TRPV1 in other organs, the technique can potentially be extended to other peripheral organs such as the digestive system and the pancreas.
Nanoparticles have the ability to make their way easily into cells. For the first time, high-resolution 3D microscopy images from BESSY II offer new insights about their distribution and function.
Nanoparticles easily penetrate cells. How they are distributed there and what they do is shown for the first time by high-resolution 3D microscopy images on BESSY II. For example, certain nanoparticles accumulate preferentially in certain organelles of the cell. This can increase the energy turnover in the cell. “The cell looks like a marathon, obviously it takes energy to absorb such nanoparticles,” says lead author James McNally.
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 penetrate 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, a lot has hardly been researched: for example, how nanoparticles are distributed in the cells, what they do there and how this effect depends on their size and coating.
Overview of the entire cell
A study at BESSY II has now brought new insights, where Prof. Gerd Schneider’s team can carry out X-ray microscopy images with soft, intensive X-rays. A group around the HZB biophysicist Dr. James McNally has used X-ray microscopy to examine cells with differently coated nanoparticles. The nanoparticles were exactly the same size, but coated with different active ingredients. “X-ray microscopy offers significantly better resolutions than light microscopy and a much better overview than electron microscopy,” emphasizes Schneider.
The cell looks like it has just run a marathon, apparently, the cell requires energy to absorb such nanoparticles. – Dr James McNally, Study Lead Author and Biophysicist, Helmholtz-Zentrum Berlin
Energy storage is decreasing
“X-ray microscopy allows us to see the cell as a whole, so we were able to observe this peculiarity for the first time,” explains McNally. “We found that the uptake of 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 it feels like after a marathon.”
Accumulation in organelles
For the first time, they received complete, three-dimensional, high-resolution images of the cells with the organelles contained therein, including lipid droplets, multivesicular bodies, mitochondria 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 cell organelles and then change the number of certain organelles in favor of other organelles. These changes were almost independent of the respective coating of the nanoparticles. This suggests that different coatings could have similar effects.Further studies with other types of nanoparticles and in particular other cell types must show whether this effect can be generalized.
3D Image of the Cell and its Organelles
X-ray microscopy offers significantly better resolution than light microscopy, and a much better overview than electron microscopy. – Gerd Schneider, Professor, Helmholtz-Zentrum Berlin
The researchers acquired, for the first time, comprehensive, 3D, high-resolution images of the cells treated with the nanoparticles, where the organelles—including mitochondria, lipid droplets, endosomes, and multivesicular bodies—were contained within. Lipid droplets act as energy stores in the cell, while mitochondria metabolize this energy.
Accumulation of Nanoparticles
Investigation of the images revealed that the nanoparticles tend to build up preferentially within a subset of the cell organelles. Moreover, the nanoparticles alter the number of particular organelles at the cost of other organelles.
The variations in the numbers of organelles were identical irrespective of the nanoparticle coating. This shows that various different types of nanoparticle coatings may produce a similar effect. Further research with other cell types and with other nanoparticle coatings is necessary to assess how general this effect is.
Number of Lipid Droplets Decreases
“X-ray microscopy allows us to see the cell as a whole, so we were able to observe this behavior for the first time,” McNally explained.
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. – Burcu Kepsutlu, Researcher, Helmholtz-Zentrum Berlin
Kepsutlu performed the experiments for her doctorate.
ACS Nano (2020): Cells Subject Major Changes in the Quantity of Cytoplasmic Organelles after Uptake of Gold Nanoparticles with Biologically Relevant Surface Coatings, Burcu Kepsutlu, Virginia Wycisk, Katharina Achazi, Sergey Kapishnikov, Ana Joaquina Pérez-Berná, Peter Guttmann, Antje Cossmer , Eva Pereiro, Helge Ewers, Matthias Ballauff, Gerd Schneider, James G. McNally
A new technique for treating lung cancer by inhaling nanoparticles created at Wake Forest School of Medicine, part of Wake Forest Baptist Health, has been reported by researchers.
As part of the proof-of-concept study, Dawen Zhao, MD, PhD, associate professor of biomedical engineering at Wake Forest School of Medicine, made use of a mouse model to ascertain whether metastatic lung tumors responded to an inhalable nanoparticle-immunotherapy system in combination with the radiation therapy that is usually used for the treatment of lung cancer.
The study has been reported in the current issue of Nature Communications.
The second most common type of cancer is lung cancer, which is also the leading cause of cancer-related deaths among both men and women. More people die due to lung cancer compared to breast, colon, and prostate cancers combined. Immunotherapy looks promising, but at present, it works in less than 20% of patients suffering from lung cancer.
Considerable clinical evidence indicates that during diagnosis, the tumors of a majority of the patients are poorly infiltrated by immune cells. Such a “cold” immune environment in tumors inhibits the immune system of the body from identifying and destroying the tumor cells.
QUT pharmaceutical scientist Dr. Nazrul Islam, from School of Clinical Sciences, said lung cancer was one of the most common cancers globally and one of the deadliest, being a leading cause of cancer deaths. Credit: Queensland University of Technology
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According to Zhao, the ability to overcome such an immunosuppressive tumor environment to work efficiently against the cancer is now an area of keen interest among the scientific community.
Earlier techniques include directly injecting immunomodulators into tumors to improve their immune response. But this technique is usually restricted to surface and tumors that can be easily accessed. Thus, it can be less effective if repeated injections are required to preserve immune response.
The goal of our research was to develop a novel means to convert cold tumors to hot, immune-responsive tumors. 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.
Dawen Zhao, Associate Professor of Biomedical Engineering, Wake Forest School of Medicine
The nanoparticle-immunotherapy system developed by Zhao and his colleagues administered immunostimulants through inhalation to a mouse model of metastatic lung cancer. When the immunostimulant-loaded nanoparticle was deposited in the air sacs of the lungs, they were absorbed by one particular type of immune cells, known as antigen-presenting cells (APC).
Then cGAMP, an immunostimulant in the nanoparticle, was discharged within the cell, where the APC cell was activated by the stimulation of a specific immune pathway (STING). This is a crucial step in inducing systemic immune response.
The researchers also demonstrated that when the nanoparticle inhalation was combined with radiation applied onto a part of one lung, the result was the regression of tumors in both lungs and prolonged survival of the mice. Moreover, the researchers noted that it thoroughly removed lung tumors in a few of the mice.
The researchers then performed mechanistic studies and showed that the inhalation system transformed the initially cold tumors in both lungs to hot tumors desirable for powerful anti-cancer immunity.
The inhalable immunotherapy developed by Zhao offers various key benefits to earlier techniques—specifically the capability to access deep-rooted lung tumors, since the aerosol that carries the nanoparticulate was designed such that it reaches all portions of the lung—and the viability of repeated treatment by employing a non-irritating aerosol formulation.
It was demonstrated that the treatment was well-tolerated and safe without any adverse immune-related distress in the mice.
The Wake Forest School of Medicine scientists have filed a provisional patent application for their inhalable nanoparticle-immunotherapy system.
An international research team has used nanoparticles to convert carbon dioxide into valuable raw materials. The team transferred this mechanism to metallic nanoparticles, also known as nanozymes. The chemists used carbon dioxide to produce ethanol and propanol, which are common raw materials for the chemical industry.
An international research team has used nanoparticles to convert carbon dioxide into valuable raw materials. Scientists at Ruhr-Universität Bochum in Germany and the University of New South Wales in Australia have adopted the principle from enzymes that produce complex molecules in multi-step reactions. The team transferred this mechanism to metallic nanoparticles, also known as nanozymes. The chemists used carbon dioxide to produce ethanol and propanol, which are common raw materials for the chemical industry.
The team led by Professor Wolfgang Schuhmann from the Center for Electrochemistry in Bochum and Professor Corina Andronescu from the University of Duisburg-Essen, together with the Australian team led by Professor Justin Gooding and Professor Richard Tilley, reported in the Journal of the American Chemical Society on 25 August 2019.
“Transferring the cascade reactions of the enzymes to catalytically active nanoparticles could be a decisive step in the design of catalysts,” says Wolfgang Schuhmann.
Credit: CC0 Public Domain
Particle with two active centres
Enzymes have different active centres for cascade reactions, which are specialised in certain reaction steps. For example, a single enzyme can produce a complex product from a relatively simple starting material. In order to imitate this concept, the researchers synthesised a particle with a silver core surrounded by a porous layer of copper. The silver core serves as the first active centre, the copper layer as the second. Intermediate products formed at the silver core then react in the copper layer to form more complex molecules, which ultimately leave the particle.
In the present work, the German-Australian team showed that the electrochemical reduction of carbon dioxide can take place with the help of the nanozymes. Several reaction steps on the silver core and copper shell transform the starting material into ethanol or propanol.
“There are also other nanoparticles that can produce these products from CO2 without the cascade principle,” says Wolfgang Schuhmann. “However, they require considerably more energy.”
The researchers now want to further develop the concept of the cascade reaction in nanoparticles in order to be able to selectively produce even more valuable products such as ethylene or butanol.
Peter B. O’Mara, Patrick Wilde, Tania M. Benedetti, Corina Andronescu, Soshan Cheong, J. Justin Gooding, Richard D. Tilley, Wolfgang Schuhmann. Cascade Reactions in Nanozymes: Spatially Separated Active Sites inside Ag-Core–Porous-Cu-Shell Nanoparticles for Multistep Carbon Dioxide Reduction to Higher Organic Molecules. Journal of the American Chemical Society, 2019; 141 (36): 14093 DOI: 10.1021/jacs.9b07310
Many wastewater treatment plants do not completely remove chemical substances from wastewater. Credit: Symbol image: Shutterstock
Microcontaminants place a considerable burden on our water courses, but removing them from wastewater requires considerable technical resources. Now, ETH researchers have developed an approach that allows the efficient removal of these problematic substances.
In our everyday lives, we all use a multitude of chemical substances, including cosmetics, medications, contraceptive pills, plant fertilisers and detergents—all of which help to make our lives easier. However, the use of such products has an adverse effect on the environment, because many of them cannot be fully removed from wastewater at today’s watertreatment plants. As micropollutants, they ultimately end up in the environment, where they place a burden on fauna and flora in our water courses.
As part of a revision of the Waters Protection Act, parliament therefore decided in 2014 to fit an additional purification stage to selected water treatment plants by 2040 with a view to removing microcontaminants. Although the funding for this has in principle been secured, the project presents a challenge for plant operators because it is only possible to remove the critical substances using complex procedures, which are typically based on ozone, activated carbon or light.
Nanoparticles aid degradation
Now, researchers at ETH Zurich’s Institute of Robotics and Intelligent Systems have developed an elegant approach that could allow these substances to be removed more easily. Using multiferroic nanoparticles, they have succeeded in inducing the decomposition of chemical residues in contaminated water. Here, the nanoparticles are not directly involved in the chemical reaction but rather act as a catalyst, speeding up the conversion of the substances into harmless compounds.
“Nanoparticles such as these are already used as a catalyst in chemical reactions in numerous areas of industry,” explains Salvador Pané, who has played a key role in advancing this research in his capacity as Senior Scientist. “Now, we’ve managed to show that they can also be useful for wastewater purification.”
Based on the example of various organic pigments, such as those used in the textile industry, the researchers are able to demonstrate the effectiveness of their approach. Picture left before treatment, right after treatment. Credit: ETH Zurich / Fajer Mushtaq
An 80 percent reduction
For their experiments, the researchers used aqueous solutions containing trace quantities of five common medications. The experiments confirmed that the nanoparticles can reduce the concentration of these substances in water by at least 80 percent. Fajer Mushtaq, a doctoral student in the group, underlines the importance of these results: “These substances also included two compounds that can’t be removed using the conventional ozone-based method.”
“Remarkably, we’re able to precisely tune the catalytic output of the nanoparticles using magnetic fields,” explains Xiangzhong Chen, a postdoc who also participated in the project. The particles have a cobalt ferrite core surrounded by a bismuth ferrite shell. If an external alternating magnetic field is applied, some regions of the particle surface adopt positive electric charges, while others become negatively charged. These charges lead to the formation of reactive oxygen species in water, which break down the organic pollutants into harmless compounds. The magnetic nanoparticles can then be easily removed from water using magnetic field, says Chen.
Positive responses from industry
The researchers believe that the new approach is a promising one, citing its easier technical implementation than that of ozone-based wastewater treatment, for example. “The wastewater industry is very interested in our findings,” says Pané.
However, it will be some time before the method can be applied in practice, as it has been investigated only in the laboratory so far. At any rate, Mushtaq says that approval has already been given for a BRIDGE project jointly funded by the Swiss National Science Foundation and Innosuisse with a view to support the method’s transfer into practical applications. In addition, plans are already in place to establish a spin-off company, in which the researchers intend to develop their idea to market maturity.
For patients with malignant brain tumors, the prognosis remains dismal. With the most aggressive treatments available, patients are usually only expected to live about 14 months after a diagnosis
3D architecture of the cell with different organelles: mitochondria (green), lysosomes (purple), multivesicular bodies (red), endoplasmic reticulum (cream). Image Credit: © Burcu Kepsutlu/HZB.
Many wastewater treatment plants do not completely remove chemical substances from wastewater. Credit: Symbol image: Shutterstock
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