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A hydrogel-based trojan horse for antitumor therapy

Paclitaxel (PTX) is among the most widely used chemotherapeutic agents in clinical settings. The drug imposes its anticancer effect by preventing cell division. Cancer cells learn to resist PTX over time by various mechanisms including creating alterations in the protein targeted by PTX and rewiring of cell survival pathways to evade cell death.

Clinicians combine PTX with suberoylanilide hydroxamic acid (SAHA) to suppress cancer drug resistance and improve treatment outcome. The benefits of combination therapy include improved accumulation of the drug at cancer sites, the ability to trigger cell death by complementary or synergistic mechanisms and longer retention of the drug within patients. Given the strong rationale for combination therapies, Shu and colleagues at the Department of Pharmaceutical Analysis, Key Laboratory on Protein Chemistry and Structural Biology, China developed a novel peptide hydrogel which encapsulates PTX and SAHA within a single co-delivery nano-carrier.

Graphical Abstract for C6RA19917H The researchers loaded PTX and SAHA onto the same nano-carrier in the following sequence: (1) an amino acid-based self assembling hydrogel precursor (Nap) was prepared, (2) PTX was conjugated to the self assembling hydrogel to form a pro-drug and (3) the pro-drug was allowed to encapsulate SAHA, forming the final drug (Nap-PTX-SAHA). The researchers subsequently characterized the mechanical features of their novel drug delivery system and tested it using a mouse model of liver cancer.

The study found that the Nap-PTX-SAHA hydrogels could be injected at room temperature into test mice, suggesting that no specialized equipment or storage conditions were necessary to administer the drug. The study also found that SAHA is released more readily than PTX from Nap-PTX-SAHA hydrogels. This could mean that cancer cells will be exposed to the two chemotherapy agents at different times, allowing for a one-two punch based tumor killing strategy.

When administered to tumor-bearing mice, the Nap-PTX-SAHA regimen was found to decrease tumor volume up to 2-fold compared to mice treated traditionally with PTX or SAHA alone. Interestingly, the researchers also noted that Nap-PTX-SAHA was associated with fewer side effects, as evidenced by normal eating behavior and weight in test mice. Interestingly, Nap-PTX-SAHA was absorbed lesser in non-target organs such as the heart, spleen and kidneys.

On the basis of these promising preclinical studies, the authors propose that Nap-PTX-SAHA represents a promising candidate for clinical trials in the years to come.

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Micelles meet transplantation medicine: How a novel nanoparticle based immune cell blocker might benefit human organ transplantation

Organ transplantation saves lives. According to the Organ Procurement and Transplantation Network, U.S Department of Health and Human Services, over 22,000 organs transplantation surgeries have been conducted between January and September 2016.

Ischemia Reperfusion Injury (IRI) is a well characterized cardiac transplantation-related complication wherein the host tissue (graft), deprived of blood supply for prolonged periods, undergoes damage when blood supply is restored post-implantation. Immune cells at the interface of the graft and recipient tissue mediate damage by releasing inflammation-promoting chemicals and free radicals.

In a study led by Nadig and colleagues at the Department of Surgery, Division of Transplant, Medical University of South Carolina, USA, researchers first acknowledge the central role played by endothelial cells (EC) in promoting IRI-associated tissue damage and subsequently developed a novel pH-sensitive, immunosuppressive drug-loaded, targeted micelle nanoparticle to curb the damaging effects of ECs. The team choose rapamycin as their immunosuppressive drug of choice given its dual roles in limiting cytotoxic immune cell functions and in protecting tissues that make up blood vessels.

While treating patients with immunosuppressive drugs prior to surgery is currently a standard practice, a major drawback of this approach is that these drugs prevent immune system activity throughout the body, placing patients at risk for diseases including diabetes and cancer. As an initial step in addressing this limitation, Nadig et al. coated the micelles with cyclic arginine-glycine-aspartate moieties, which specifically bind to and integrin protein (the alpha v beta 3 receptor protein) present almost exclusively on ECs. As a finishing touch, the team attached fluorescent chemical compounds to allow for tracking and visualization in their studies.

Graphical abstract of "Immunosuppressive nano-therapeutic micelles downregulate endothelial cell inflammation and immunogenicity"Their studies showed that the rapamycin-loaded nanoparticles were stable and biocompatible when tested in human endothelial cells. Further, the rapamycin release could be controlled by adjusting the pH values lower than 7 or higher than 8. The study found that the micelles were being taken up by cells within 6h after incubation. The study also demonstrates the specificity of the micelles by showing that what the cells were pre-treated with an integrin inhibitor,  they were  less likely to take up the micelles.

To demonstrate the clinical utility of their idea, the researchers exposed human endothelial cell cultures to hydrogen peroxide to mimic IRI-like conditions. The cells responded by increasing their production of inflammation-promoting chemicals. Importantly, the rapamycin-loaded nanoparticle micelles significantly curbed this response. Nadig et al. propose that the ultimate goal is to incorporate this technology into organ storage media to minimize the harmful effects of IRI.

Read the full article here:

Satish N. Nadig, Suraj K. Dixit, Natalie Levey, Scott Esckilsen, Kayla Miller, William Dennis, Carl Atkinson and Ann-Marie Broome

RSC Adv., 2015, 5, 43552-43562

DOI: 10.1039/C5RA04057D

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The heat is on: cancer-drug loaded nanoparticles for photothermal therapy

Photothermal therapy is an emerging area of cancer treatment. Here, a photothermal agents, often nanoparticles (NPs) with a resonance peak in the 700-1200nm range, are delivered to the tumor site and are subsequently activated by light in the Near Infrared (NIR) range. As a consequence, tumor cells are thermally ablated.

In a study led by Xiaolin Li and colleagues at the Key Laboratory for Thin Film and Microfabrication and Changzheng Hospital in China, scientists used SiO2@Au core-shell NPs chemically conjugated via PEGylation to graphene oxide (GO) in conjunction with a chemotherapeutic agent to target prostate cancer cells in vitro. Using the chemotherapeutic agent Docetaxel (Dtxl),  which is among the leading front line treatments for patients diagnosed with prostate cancer, the team demonstrated that Dtxl-loaded SiO2@Au@GO NPs, when activated with light in the NIR range, significantly curbed the survival of DU145 prostate cancer cells.

While SiO2@Au core-shell NPs have been used previously by other research groups to study their ability to remove tumors, Li’s team fabricated SiO2@Au@GO NPs to take advantage of their relatively low cost, large specific surface area, and efficient loading and delivery of water-soluble aromatic drug molecules. This one-two punch strategy was realized via a double shell, multifunctional approach: the inner core SiO2@Au NPs served as a photothermal inducer to bring about cellular cytotoxicity; the outer GO NPs carried the antitumor drug, Dtxl. The study found that exposing DU145 cells to the NPs alone for 24h did not result in overt cell death, suggesting that the NPs have a good safety profile. Importantly, the study showed that when NP-treated cell cultures were irradiated with a 780nm NIR laser, there was a significant decline in viable cells over a 24h period.

The study demonstrates that Dtxl-loaded SiO2@Au@GO NPs could be manufactured and potentially used an an antitumor agent for the treatment of prostate cancer. Moreover, these findings illuminate the untapped potential of NP-based photothermal agents as adjuvant agents in oncology clinical trials in the near future.

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Xiaolin Li,   Zhi Yang,   Nantao Hu,   Liying Zhang,   Yafei Zhang and   Lei Yin
DOI: 10.1039/C6RA03886G
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Supramolecular cages for chemical weapons

The research of RSC Advances Chief Editor Mike Ward focussing on the development of supramolecular cages that trap chemical weapon stimulants, has been highlighted in Chemistry World.

Mike and his team at Sheffield University have developed new supramolecular cages that exploit the hydrophic effect and bind alkyl phosphonates inside. These phosphonates are very similar to organophosphorous chemical weapons. Cobalt or cadmium dications form the cage vertices and bis(pyrazolyl-pyridine) ligands run along each edge, forming a hydrophobic centre lined with CH groups. So, in water, the phosphonate hydrophobic alkyl tails are attracted to the inside of the cage. Whats more, the cage is luminescent and this luminescence reduces when alkyl phosphonate enters, meaning that the cages can also be used to signal the presence of chemical weapons.

The supramolecular structure

To find out more, read the full Chemistry World article based on this paper:

Binding of chemical warfare agent simulants as guests in a coordination cage: contributions to binding and a fluorescence-based response
Christopher G. P. Taylor, Jerico R. Piper and Michael D. Ward
Chem. Commun., 2016
DOI: 10.1039/C6CC02021F

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Modelling lung cancer: tumor cells on collagen scaffolds

Non-small-cell lung cancer (NSCLC) is among the leading causes of cancer-related deaths globally. Our understanding of the way tumors grow, spread and respond to therapy is driven largely by studies conducted on tumor cells growing as monolayers in plastic cell culture flasks in laboratories across the world. The ability to develop novel and more effective cancer-fighting drugs is dependent, in part, on developing cell culture systems that allow scientists to better observe how tumor cells grow in a three dimensional, physiologically relevant environment.

SEM images of the collagen meshwork and A549 cell aggregates (noted by the arrow head) formed during the
3D cultivation in vitro.

The tumor microenvironment (TM) is the area that immediately surrounds a tumor and includes non-cancer cells together with secreted proteins called the extracellular matrix (ECM), which supports tumor growth. Monolayer cell cultures, although utilized widely, cannot accurately mimic the TM. For instance, cell-cell and cell-ECM interactions that influence tumor growth cannot be observed in great detail with conventional monolayer cultures. Inspired by the up-and-coming field of tumor engineering, which aims to construct culture models that recapitulate aspects of the TM, a team of researchers led by Dr. Dan-Dan Wang at the Chinese Academy of Sciences developed a 3D culture system wherein A549 cells (immortal lung cancer cells of human origin) grow on a collagen hydrogel scaffold.

To demonstrate the utility of the 3D culture system, the study measured cell viability and showed that cells in the collagen hydrogel scaffold were alive for extended periods (>12 days) in vitro. The study also assessed the appearance of artificial A549 tumors growing on the hydrogel to demonstrate that 3D cultures more closely recapitulate the morphology of tumors growing within human tissues.

The proliferation of A549 cells is driven by the activation of a cell surface protein called Epidermal Growth Factor Receptor (EGFR), which in turn switches on genes that sustain cell growth and cell division. The team observed that Gefitinib, a drug known to disrupt growth-promoting signals arising at EGFR, was able to significantly constrain A549 cell proliferation in 3D cultures. Interestingly, the team reports that a higher concentration of Gefitinib was required to curb cell growth in 3D cultures compared to monolayers due to the complex architecture of the artificial tumors in 3D cultures.

Collectively, this study demonstrates an improved culture model of human lung cancer. Since collagen is an important component of the ECM, the study sets the stage for future efforts to better recapitulate the TM in vitro. The collagen hydrogel scaffold system could serve as in important tool in the discovery of targeted therapies for lung cancer.

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Dan-Dan Wang,   Wei Liu,   Jing-Jie Chang,   Xu Cheng,   Xiu-Zhen Zhang,   Hong Xu,   Di Feng,   Li-Jun Yu and   Xiu-Li Wang
RSC Adv., 2016, 6, 24083-24090
DOI: 10.1039/C6RA00229C
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Hitching a ride: recombinant DNA delivery into mammalian cells via nanoparticle-based vehicles

Transfection is the process of introducing genetic material, typically DNA, into mammalian cells. This technique has proven indispensable in understanding signaling networks that govern cellular function. To better understand the function of a given protein, molecular biologists routinely transfect cells with DNA (i.e. recombinant DNA). This enters cells in culture and subsequently encodes the specific protein under study. The recombinant DNA is combined with a transfection reagent, typically Lipofectamine, to facilitate its entry into cells.

A study conducted by Neuhaus and colleagues, at the Inorganic Chemistry and Center for Nanointegration (CeNIDE) in Germany, utilizes calcium phosphate nanoparticles (CPNPs) as vehicles to deliver recombinant DNA into cells. CPNPs have previously been shown to spontaneously bind DNA, thus supporting the notion that they could be used as transfection agents. The approach requires that CPNPs first be mixed with a buffer containing recombinant DNA before being added to cultures containing actively growing mammalian cells.

Despite its simplistic approach, the transfection process in general has a few technical limitations. First, not all cells in culture uptake the recombinant DNA. This leads to reduced transfection efficiency. Second, the transfection efficiency is strongly influenced by the cell type (i.e. distinct cell forms within a species). And third, cells interpret recombinant DNA as ‘foreign’ genetic material and trigger alarms which culminate in cell death.

Images demonstrating the uptake of green flourescent nanoparticles by different cell types

To better assess the utility of CPNPs as transfection agents, the study’s authors first transfected ten different cell types with DNA. The DNA in their study encoded a protein that fluoresces green when excited at a specific wavelength. Using Lipofectamine as a comparator reagent, the study assessed the transfection efficiency of CPNPs by measuring the proportion of cells that glowed green under a fluorescent microscope. The study also highlighted the differences in transfection efficiencies between different cell types. The authors propose that CPNPs represent promising candidates as transfection agents and therefore warrant further study.

Clinical trials utilizing nucleotide-based targeted therapies for multiple human diseases are on the rise. CPNPs may represent the new breed of nucleotide-based drug delivery agents in the years to come.

Read the full article here:

Nanoparticles as transfection reagents: a comprehensive study with ten different cell lines
Bernhard Neuhaus,  Benjamin Tosun, Olga Rotan, Annika Frede, Astrid M. Westendorf and Matthias Epple
RSC Adv., 2016,6, 18102-18112
DOI: 10.1039/C5RA25333K

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Magnetic leathers

Leather is a natural, durable and flexible material that has been prepared and used by humans for millennia. Now, scientists in India have developed magnetic leathers that can make this material evermore versatile.

Made from animal hide, leather is largely made of a chromium-collagen matrix and is paramagnetic. Despite this, it does not interact effectively with magnetic fields. Introducing ferromagnetic properties to leather could enable this material to be used in smart or intelligent garments, electromagnetic interference shielding, adhesive-free wall covering and even in energy harvesting from human motion. As such, a team lead by Dr Krishbaraj Kaliappa at the Central Leather Institute in Chennai, added iron oxide nanoparticles to leather that show significant magnetic behaviour.

The team prepared leather samples using conventional finishing techniques. During this process, they applied a coating of  iron oxide nanoparticles produced by co-precipitation, or a commercially available magnetic pigment. The presence of Fe3O2 in both samples was confirmed by X-ray diffraction analysis. When compared to the paramagnetic control leather, magnetic hysteresis revealed considerable ferromagnetic behavior in the two samples. In addition, the leathers show significant response to permanent magnets. Further tests revealed that particle incorporation leaves other physical properties of the leather, largely unchanged.

Investigations in to the applications of these magnetic leathers have already shown them to be promising adhesive-free wall tiles. The team also demonstrate that their properties may also enable application in electromagnetic energy generation from human motion.

Digital images of the control leather , that with iron oxide nanoparticles and that with the commercially available magnetic pigment added during finishing.

Read the full article:

Magnetic leathers
P. Thanikaivelan, R. Murali and K. Krishnaraj
RSC Adv., 2016,6, 6496-6503 DOI: 10.1039/C5RA21909D

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Canine tea time

Researchers in China have manufactured dog food containing tea polyphenols. They have shown that when dogs are fed tea polyphenol containg food, antioxidant and antimicrobial effects, similar to those observed in humans, are demonstrated.

Fang Zhong and colleagues also wanted to test the foods palpability to find out if the dogs would actually enjoy eating it. Following a five day trial, it emerged that dogs actually preferred eating food that contained 0.5% tea polyphenols. The dogs’ diet was then restricted to either tea polyphenol containing food or the control food. Subsequent tests revealed higher levels of antioxidant activity in the dogs on the tea polyphenol diet, along with lower levels of fecal bacteria in their stool.

To find out more, read the full Chemistry World article.

Quantitative optimization and assessments of supplemented tea polyphenols in dry dog food considering palatability, levels of serum oxidative stress biomarkers and fecal pathogenic bacteria,
Maoshen Chen, Xuemei Chen, Wenli Cheng, Yue Li, Jianguo Ma and Fang Zhong
RSC Adv., 2016,6, 16802-16807
DOI: 10.1039/C5RA22790A

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Stencilling self-propulsion engines

Researchers in the US have designed and made millimetre-sized motors in the shape of fish that could be produced on an enormous scale and used to purify water.

Catalytic fish in action

Nano- and micro-sized machines that convert chemical reactions into motion have been on the drawing board for many years. However, they are complicated and expensive to make. Now, researchers led by Joseph Wang at the University of California San Diego have developed a simple way to print 2D millimetre-sized motors. The motors are shaped like fish, swim autonomously while performing specific functions and avoid the costs and complications of more traditional fabrication processes, such as electrodeposition, sputtering and lithography.

To read the full article please visit Chemistry World.

Self-propelled screen-printable catalytic swimmers
Rajan Kumar, Melek Kiristi, Fernando Soto, Jinxing Li, Virendra V. Singh and Joseph Wang �
RSC Adv., 2015,5, 78986-78993
DOI: 10.1039/C5RA16615B, Paper

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Smartphones develop a taste for red wine

Colormetric sensor array that can distinguish red wines by grape and oxidation state using principal component analysisYou can find me with great infrequency (ahem) pacing the wine, beers and spirit aisles of the supermarket trying to select the best wine for the occasion that I may be attending, be it dinner at friends or watching season four of Game of Thrones, alone, with a pizza. It may amaze you to know that, despite this penchant for the finer things in life, my wine tasting ability is a work in constant progress. Currently, my selection criterion for a bottle comprises two factors; 1) how pretty is the bottle and 2) how special is the special offer on it?

Finally, to save me from my ignorance, Tu San Park and co-workers have developed a paper microfluidic chip for red wine tasting. Their recent publication in RSC Advances details the development of a colormetric sensor array that can distinguish red wines by grape and oxidation state using principal component analysis. This isn’t just good news for me; This could be employed in the wine industry as a simple  and low cost quality control check, helping to minimise the variation inherent by employing taste panellists.

What is exciting about this assay is the room for development. The authors have been investigating the alignment of the assay with a smartphone application that would be able to image the areas of interest and measure the red, green and blue pixel intensities. This data would then be reduced for principal component analysis.

The benefits of this low cost, portable check are obvious, especially for small wineries and also, small wine drinkers, like myself.

To find out more, click below to read the full article in RSC Advances. It’s free to access for the next 4 weeks:

Paper microfluidics for red wine tasting, Tu San Park, Cayla Baynes, Seong-In Cho and Jeong-Yeol Yoon, RSC Adv., 2014, 4, 24356–24362 (DOI: 10.1039/C4RA01471E)


Sarah Brown Sarah Brown is a guest web-writer for RSC Advances. Sarah hung up her lab coat after finishing her PhD and post-doctorate in nanotechnology for diagnostics and therapeutics and now works in academic publishing. When not trying to explain science through ridiculous analogies, you can often find her crocheting, baking or climbing, but not all at once.

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