Tag Archives: drug delivery

Antibiotic synthetic spider silk

I have a couple of questions, what is ‘click’ chemistry and how does a chance meeting lead to a five-year, interdisciplinary research project on synthetic spider silk? From a Jan. 4, 2017 news item on ScienceDaily,

A chance meeting between a spider expert and a chemist has led to the development of antibiotic synthetic spider silk.

After five years’ work an interdisciplinary team of scientists at The University of Nottingham has developed a technique to produce chemically functionalised spider silk that can be tailored to applications used in drug delivery, regenerative medicine and wound healing.

The Nottingham research team has shown for the first time how ‘click-chemistry’ can be used to attach molecules, such as antibiotics or fluorescent dyes, to artificially produced spider silk synthesised by E.coli bacteria. The research, funded by the Biotechnology and Biological Sciences Research Council (BBSRC) is published today in the online journal Advanced Materials.

A Jan. 3, 2016 University of Nottingham press release (also on EurekAlert), which originated the news item, provides a few more details about ‘click’ chemistry (not enough for me) and more information about the research,

The chosen molecules can be ‘clicked’ into place in soluble silk protein before it has been turned into fibres, or after the fibres have been formed. This means that the process can be easily controlled and more than one type of molecule can be used to ‘decorate’ individual silk strands.

Nottingham breakthrough

In a laboratory in the Centre of Biomolecular Sciences, Professor Neil Thomas from the School of Chemistry in collaboration with Dr Sara Goodacre from the School of Life Sciences, has led a team of BBSRC DTP-funded PhD students starting with David Harvey who was then joined by Victor Tudorica, Leah Ashley and Tom Coekin. They have developed and diversified this new approach to functionalising ‘recombinant’ — artificial — spider silk with a wide range of small molecules.

They have shown that when these ‘silk’ fibres are ‘decorated’ with the antibiotic levofloxacin it is slowly released from the silk, retaining its anti-bacterial activity for at least five days.

Neil Thomas, a Professor of Medicinal and Biological Chemistry, said: “Our technique allows the rapid generation of biocompatible, mono or multi-functionalised silk structures for use in a wide range of applications. These will be particularly useful in the fields of tissue engineering and biomedicine.”

Remarkable qualities of spider silk

Spider silk is strong, biocompatible and biodegradable. It is a protein-based material that does not appear to cause a strong immune, allergic or inflammatory reaction. With the recent development of recombinant spider silk, the race has been on to find ways of harnessing its remarkable qualities.

The Nottingham research team has shown that their technique can be used to create a biodegradable mesh which can do two jobs at once. It can replace the extra cellular matrix that our own cells generate, to accelerate growth of the new tissue. It can also be used for the slow release of antibiotics.

Professor Thomas said: “There is the possibility of using the silk in advanced dressings for the treatment of slow-healing wounds such as diabetic ulcers. Using our technique infection could be prevented over weeks or months by the controlled release of antibiotics. At the same time tissue regeneration is accelerated by silk fibres functioning as a temporary scaffold before being biodegraded.”

The medicinal properties of spider silk recognised for centuries.

The medicinal properties of spider silk have been recognised for centuries but not clearly understood. The Greeks and Romans treated wounded soldiers with spider webs to stop bleeding. It is said that soldiers would use a combination of honey and vinegar to clean deep wounds and then cover the whole thing with balled-up spider webs.

There is even a mention in Shakespeare’s Midsummer Night’s Dream: “I shall desire you of more acquaintance, good master cobweb,” the character ‘Bottom’ said. “If I cut my finger, I shall make bold of you.”

The press release goes on to describe the genesis of the project and how this multidisciplinary team was formed in more detail,

The idea came together at a discipline bridging university ‘sandpit’ meeting five years ago. Dr Goodacre says her chance meeting at that event with Professor Thomas proved to be one of the most productive afternoons of her career.

Dr Goodacre, who heads up the SpiderLab in the School of Life Sciences, said: “I got up at that meeting and showed the audience a picture of some spider silk. I said ‘I want to understand how this silk works, and then make some.’

“At the end of the session Neil came up to me and said ‘I think my group could make that.’ He also suggested that there might be more interesting ‘tweaks’ one could make so that the silk could be ‘decorated’ with different, useful, compounds either permanently or which could be released over time due to a change in the acidity of the environment.”

The approach required the production of the silk proteins in a bacterium where an amino acid not normally found in proteins was included. This amino acid contained an azide group which is widely used in ‘click’ reactions that only occur at that position in the protein. It was an approach that no-one had used before with spider silk — but the big question was — would it work?

Dr Goodacre said: “It was the start of a fascinating adventure that saw a postdoc undertake a very preliminary study to construct the synthetic silks. He was a former SpiderLab PhD student who had previously worked with our tarantulas. Thanks to his ground work we showed we could produce the silk proteins in bacteria. We were then joined by David Harvey, a new PhD student, who not only made the silk fibres, incorporating the unusual amino acid, but also decorated it and demonstrated its antibiotic activity. He has since extended those first ideas far beyond what we had thought might be possible.”

David Harvey’s work is described in this paper but Professor Thomas and Dr Goodacre say this is just the start. There are other joint SpiderLab/Thomas lab students working on uses for this technology in the hope of developing it further.

David Harvey, the lead author on this their first paper, has just been awarded his PhD and is now a postdoctoral researcher on a BBSRC follow-on grant so is still at the heart of the research. His current work is focused on driving the functionalised spider silk technology towards commercial application in wound healing and tissue regeneration.

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

Antibiotic Spider Silk: Site-Specific Functionalization of Recombinant Spider Silk Using “Click” Chemistry by David Harvey, Philip Bardelang, Sara L. Goodacre, Alan Cockayne, and Neil R. Thomas. Advanced Materials DOI: 10.1002/adma.201604245 Version of Record online: 28 DEC 2016

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

I imagine Mr. Cockayne’s name has led to much teasing over the years. People who have names with that kind of potential tend to either change them or double down and refuse to compromise.

A biocompatible (implantable) micromachine (microrobot)

I appreciate the detail and information in this well written Jan. 4, 2017 Columbia University news release (h/t Jan. 4, 2016 Nanowerk; Note: Links have been removed),

A team of researchers led by Biomedical Engineering Professor Sam Sia has developed a way to manufacture microscale-sized machines from biomaterials that can safely be implanted in the body. Working with hydrogels, which are biocompatible materials that engineers have been studying for decades, Sia has invented a new technique that stacks the soft material in layers to make devices that have three-dimensional, freely moving parts. The study, published online January 4, 2017, in Science Robotics, demonstrates a fast manufacturing method Sia calls “implantable microelectromechanical systems” (iMEMS).

By exploiting the unique mechanical properties of hydrogels, the researchers developed a “locking mechanism” for precise actuation and movement of freely moving parts, which can provide functions such as valves, manifolds, rotors, pumps, and drug delivery. They were able to tune the biomaterials within a wide range of mechanical and diffusive properties and to control them after implantation without a sustained power supply such as a toxic battery. They then tested the “payload” delivery in a bone cancer model and found that the triggering of release of doxorubicin from the device over 10 days showed high treatment efficacy and low toxicity, at 1/10 of the standard systemic chemotherapy dose.

“Overall, our iMEMS platform enables development of biocompatible implantable microdevices with a wide range of intricate moving components that can be wirelessly controlled on demand and solves issues of device powering and biocompatibility,” says Sia, also a member of the Data Science Institute. “We’re really excited about this because we’ve been able to connect the world of biomaterials with that of complex, elaborate medical devices. Our platform has a large number of potential applications, including the drug delivery system demonstrated in our paper which is linked to providing tailored drug doses for precision medicine.”

I particularly like this bit about hydrogels being a challenge to work with and the difficulties of integrating both rigid and soft materials,

Most current implantable microdevices have static components rather than moving parts and, because they require batteries or other toxic electronics, have limited biocompatibility. Sia’s team spent more than eight years working on how to solve this problem. “Hydrogels are difficult to work with, as they are soft and not compatible with traditional machining techniques,” says Sau Yin Chin, lead author of the study who worked with Sia. “We have tuned the mechanical properties and carefully matched the stiffness of structures that come in contact with each other within the device. Gears that interlock have to be stiff in order to allow for force transmission and to withstand repeated actuation. Conversely, structures that form locking mechanisms have to be soft and flexible to allow for the gears to slip by them during actuation, while at the same time they have to be stiff enough to hold the gears in place when the device is not actuated. We also studied the diffusive properties of the hydrogels to ensure that the loaded drugs do not easily diffuse through the hydrogel layers.”

The team used light to polymerize sheets of gel and incorporated a stepper mechanization to control the z-axis and pattern the sheets layer by layer, giving them three-dimensionality. Controlling the z-axis enabled the researchers to create composite structures within one layer of the hydrogel while managing the thickness of each layer throughout the fabrication process. They were able to stack multiple layers that are precisely aligned and, because they could polymerize a layer at a time, one right after the other, the complex structure was built in under 30 minutes.

Sia’s iMEMS technique addresses several fundamental considerations in building biocompatible microdevices, micromachines, and microrobots: how to power small robotic devices without using toxic batteries, how to make small biocompatible moveable components that are not silicon which has limited biocompatibility, and how to communicate wirelessly once implanted (radio frequency microelectronics require power, are relatively large, and are not biocompatible). The researchers were able to trigger the iMEMS device to release additional payloads over days to weeks after implantation. They were also able to achieve precise actuation by using magnetic forces to induce gear movements that, in turn, bend structural beams made of hydrogels with highly tunable properties. (Magnetic iron particles are commonly used and FDA-approved for human use as contrast agents.)

In collaboration with Francis Lee, an orthopedic surgeon at Columbia University Medical Center at the time of the study, the team tested the drug delivery system on mice with bone cancer. The iMEMS system delivered chemotherapy adjacent to the cancer, and limited tumor growth while showing less toxicity than chemotherapy administered throughout the body.

“These microscale components can be used for microelectromechanical systems, for larger devices ranging from drug delivery to catheters to cardiac pacemakers, and soft robotics,” notes Sia. “People are already making replacement tissues and now we can make small implantable devices, sensors, or robots that we can talk to wirelessly. Our iMEMS system could bring the field a step closer in developing soft miniaturized robots that can safely interact with humans and other living systems.”

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

Additive manufacturing of hydrogel-based materials for next-generation implantable medical devices by Sau Yin Chin, Yukkee Cheung Poh, Anne-Céline Kohler, Jocelyn T. Compton, Lauren L. Hsu, Kathryn M. Lau, Sohyun Kim, Benjamin W. Lee, Francis Y. Lee, and Samuel K. Sia. Science Robotics  04 Jan 2017: Vol. 2, Issue 2, DOI: 10.1126/scirobotics.aah6451

This paper appears to be open access.

The researchers have provided a video demonstrating their work (you may want to read the caption below before watching),

Magnetic actuation of the Geneva drive device. A magnet is placed about 1cm below and without contact with the device. The rotating magnet results in the rotational movement of the smaller driving gear. With each full rotation of this driving gear, the larger driven gear is engaged and rotates by 60º, exposing the next reservoir to the aperture on the top layer of the device.

—Video courtesy of Sau Yin Chin/Columbia Engineering

You can hear some background conversation but it doesn’t seem to have been included for informational purposes.

A carbon nanomaterial ‘pot’ for drug delivery

Japanese scientists have developed a new material, which could be used as a carrier for drugs. From an Aug. 5, 2016 news item on phys.org,

A novel, pot-shaped, carbon nanomaterial developed by researchers from Kumamoto University, Japan is several times deeper than any hollow carbon nanostructure previously produced. This unique characteristic enables the material to gradually release substances contained within and is expected to be beneficial in applications such as drug delivery systems.

An Aug. 5, 2016 Kumamoto University press release on EurekAlert, which despite the discrepancy in the dates originated the news item, discusses carbon and the discovery in more detail,

Carbon is an element that is light, abundant, has a strong binding force, and eco-friendly. The range of carbon-based materials is expected to become more widespread in the eco-friendly society of the future. Recently, nanosized (one-billionth of a meter) carbon materials have been developed with lengths, widths, or heights below 100 nm [nanometre]. These materials take extreme forms such as tiny grained substances, thin sheet-like substances, and slim fibrous substances. Example of these new materials are fullerenes, which are hollow cage-like carbon molecules; carbon nanotubes, cylindrical nanostructures of carbon molecules; and graphene, one-atom thick sheets of carbon molecules.

Why are these tiny substances needed? One reason is that reactions with other materials can be much larger if a substance has an increased surface area. When using nanomaterials in place of existing materials, it is possible to significantly change surface area without changing weight and volume, thereby improving both size and performance. The development of carbon nanomaterials has provided novel nanostructured materials with shapes and characteristics that surpass existing materials.

Now, research from the laboratory of Kumamoto University’s Associate Prof. Yokoi has resulted in the successful development of a container-type carbon nanomaterial with a much deeper orifice than that found in similar materials. To create the new material, researchers used their own, newly developed method of material synthesis. The container-shaped nanomaterial has a complex form consisting of varied layers of stacked graphene at the bottom, the body, and the neck areas of the container, and the graphene edges along the outer surface of the body were found to be very dense. Due to these innovate features, Associate Prof. Yokoi and colleagues named the material the “carbon nanopot.”

The carbon nanopot has an outer diameter of 20 ~ 40 nm, an inner diameter of 5 ~ 30 nm, and a length of 100 ~ 200 nm. During its creation, the carbon nanopot is linked to a carbon nanofiber with a length of 20 ~ 100 μm [micrometre] meaning that the carbon nanopot is also available as a carbon nanofiber. At the junction between nanopots, the bottom of one pot simply sits on the opening of the next without sharing a graphene sheet connection. Consequently, separating nanopots is very easy.

“From a detailed surface analysis, hydrophilic hydroxyl groups were found clustered along the outer surface of the carbon nanopot body,” said Associate Prof. Yokoi. “Graphene is usually hydrophobic however, if hydroxyl groups are densely packed on the outer surface of the body, that area will be hydrophilic. In other words, carbon nanopots could be a unique nanomaterial with both hydrophobic and hydrophilic characteristics. We are currently in the process of performing a more sophisticated surface analysis in order to get that assurance.”

Since this new carbon nanopot has a relatively deep orifice, one of its expected uses is to improve drug delivery systems by acting as a new foundation for medicine to be carried into and be absorbed by the body.

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

Novel pot-shaped carbon nanomaterial synthesized in a submarine-style substrate heating CVD method by Hiroyuki Yokoi, Kazuto Hatakeyama, Takaaki Taniguchi, Michio Koinuma, Masahiro Hara, and Yasumichi Matsumoto. Journal of Materials Research / Volume 31 / Issue 01 / 2016, pp 117-126 DOI: http://dx.doi.org/10.1557/jmr.2015.389 (About DOI) Published online: 13 January 2016

Copyright © Materials Research Society 2016

I’m not sure why there’s this push for publicity so long after the publication date. In any event, this paper is behind a paywall.

Combining chitosan, agarose, and protein gelatine with clay nanotubes to create scaffolds for tissue engineering

Russian scientists have published work on clay nanotube-bipolymer composite scaffolds according to an April 29, 2016 news item on ScienceDaily,

Scientists combined three biopolymers, chitosan and agarose (polysaccharides), and a protein gelatine, as the materials to produce tissue engineering scaffolds and demonstrated the enhancement of mechanical strength (doubled pick load), higher water uptake and thermal properties in chitosan-gelatine-agarose hydrogels doped with halloysite [a clay mineral and a naturally occurring nanotube].

An April 29, 2016 Kazan Federal University (Russia) press release on EurekAlert, which originated the news item, provides more detail and context,

The fabrication of a prototype tissue having functional properties close to the natural ones is crucial for effective transplantation. Tissue engineering scaffolds are typically used as supports which allow cells to form tissue-like structures essentially required for the correct functioning of the cells under the conditions close to the three-dimensional tissue.

Chitosan, a natural biodegradable and chemically versatile biopolymer, has been effectively used in antibacterial, antifungal, anti-tumour and immunostimulating formulations. To overcome the disadvantages of pure chitosan scaffolds such as mechanical fragility and low biological resistance, chitosan scaffolds are typically doped with other supporting compounds which allow for mechanical strengthening, thus yielding ?omposite biologically resistant scaffolds.

Agarose is a galactose-based backbone polysaccharide isolated from red algae, having remarkable mechanical properties which are useful in the design of tissue engineering scaffolds.

Gelatine is formed from collagen by hydrolysis (breaking the triple-helix structure into single-strand molecules) and has a number of advantages over its precursor. It is less immunogenic compared with collagen and it retains informational signal sequences promoting cell adhesion, migration, differentiation and proliferation.

The surface irregularities of the scaffold pores due to the insoluble nanosized components promote the best adhesion of the cells on scaffold materials, while the nanoparticle fillers increase the composites’ strength. Thus, researchers doped halloysite nanotubes into a chitosan-agarose-gelatine matrix to design the implantable 3D cell scaffolds.

The resulting scaffolds demonstrate the shape memory upon deformation and have the porous structure suitable for cell adhesion and proliferation which is essential for artificial tissue fabrication. Macroscopic observations have confirmed that all the samples of scaffolds exhibited the sponge-like behaviour with the shape memory and shape reconstitution after deformation both in wet and dry states.

The swelling experiments indicated that the addition of halloysite can greatly improve the hydrophilicity and wetting of composite scaffolds. The incorporation of halloysite nanotubes into the scaffolds increases the water uptake and subsequently improves the biocompatibility. The intrinsic properties of halloysite nanotubes can be used for further improving the biocompatibility of scaffolds by the loading and sustained release of different bioactive compounds. This opens the prospect for fabrication of scaffolds with defined properties for directed differentiation of cells on matrixes due to gradual release of differentiation factors.

Experiments on two types of human cancer cells (A549 and Hep3B) show that in vitro cell adhesion and proliferation on the nanocomposites occur without changes in viability and cytoskeleton formation.

Further in vivo biocompatibility and biodegradability evaluation in rats has confirmed that the scaffolds promote the formation of novel blood vessels around the implantation sites. The scaffolds show excellent resorption within six weeks after implantation in rats. Neo-vascularization observed in newly formed connective tissue placed near the scaffold allows for the complete restoration of blood flow.

The results obtained indicate that the halloysite doped scaffolds are biocompatible as demonstrated both in vitro and in vivo. In addition, they confirm the great potential of chitosan-agarose-gelatine nanocomposite porous scaffolds doped with halloysite in tissue engineering with potential for sustained nanotube drug delivery.

For anyone interested about drug delivery and nanoparticles, there’s some interesting research profiled in my April 27, 2016 posting which describes how very few nanoparticles are actually delivered to specific sites.

Getting back to the regular program, here’s a link to and a citation for the paper on scaffolds and clay nanotubes,

Clay nanotube–biopolymer composite scaffolds for tissue engineering by Ekaterina A. Naumenko, Ivan D. Guryanov, Raghuvara Yendluri, Yuri M. Lvova, and Rawil F. Fakhrullin. Nanoscale, 2016,8, 7257-7271 DOI: 10.1039/C6NR00641H First published online 01 Mar 2016

This paper is behind a paywall.

Eggshell-based bioplastics

Adding eggshell nanoparticles to a bioplastic (shown above) increases the strength and flexibility of the material, potentially making it more attractive for use in the packaging industry. Credit: Vijaya Rangari/Tuskegee University

Adding eggshell nanoparticles to a bioplastic (shown above) increases the strength and flexibility of the material, potentially making it more attractive for use in the packaging industry. Credit: Vijaya Rangari/Tuskegee University

A March 15, 2016 news item on Nanowerk describes the research,

Eggshells are both marvels and afterthoughts. Placed on end, they are as strong as the arches supporting ancient Roman aqueducts. Yet they readily crack in the middle, and once that happens, we discard them without a second thought. But now scientists report that adding tiny shards of eggshell to bioplastic could create a first-of-its-kind biodegradable packaging material that bends but does not easily break.

The researchers present their work today [March 15, 2016] at the 251st National Meeting & Exposition of the American Chemical Society (ACS).

A March 15, 2016 ACS news release (also on EurekAlert), which originated the news item, describes the work further,

“We’re breaking eggshells down into their most minute components and then infusing them into a special blend of bioplastics that we have developed,” says Vijaya K. Rangari, Ph.D. “These nano-sized eggshell particles add strength to the material and make them far more flexible than other bioplastics on the market. We believe that these traits — along with its biodegradability in the soil — could make this eggshell bioplastic a very attractive alternative packaging material.”

Worldwide, manufacturers produce about 300 million tons of plastic annually. Almost 99 percent of it is made with crude oil and other fossil fuels. Once it is discarded, petroleum-based plastics can last for centuries without breaking down. If burned, these plastics release carbon dioxide into the atmosphere, which can contribute to global climate change.

As an alternative, some manufacturers are producing bioplastics — a form of plastic derived from cornstarch, sweet potatoes or other renewable plant-based sources — that readily decompose or biodegrade once they are in the ground. However, most of these materials lack the strength and flexibility needed to work well in the packaging industry. And that’s a problem since the vast majority of plastic is used to hold, wrap and encase products. So petroleum-based materials continue to dominate the market, particularly in grocery and other retail stores, where estimates suggest that up to a trillion plastic bags are distributed worldwide every year.

To find a solution, Rangari, graduate student Boniface Tiimob and colleagues at Tuskegee University experimented with various plastic polymers. Eventually, they latched onto a mixture of 70 percent polybutyrate adipate terephthalate (PBAT), a petroleum polymer, and 30 percent polylactic acid (PLA), a polymer derived from cornstarch. PBAT, unlike other oil-based plastic polymers, is designed to begin degrading as soon as three months after it is put into the soil.

This mixture had many of the traits that the researchers were looking for, but they wanted to further enhance the flexibility of the material. So they created nanoparticles made of eggshells. They chose eggshells, in part, because they are porous, lightweight and mainly composed of calcium carbonate, a natural compound that easily decays.

The shells were washed, ground up in polypropylene glycol and then exposed to ultrasonic waves that broke the shell fragments down into nanoparticles more than 350,000 times smaller than the diameter of a human hair. Then, in a laboratory study, they infused a small fraction of these particles, each shaped like a deck of cards, into the 70/30 mixture of PBAT and PLA. The researchers found that this addition made the mixture 700 percent more flexible than other bioplastic blends. They say this pliability could make it ideal for use in retail packaging, grocery bags and food containers — including egg cartons.

In addition to bioplastics, Rangari’s team is investigating using eggshell nanoparticles to enhance wound healing, bone regeneration and drug delivery.

Making carbon nanoparticles at home with honey or molasses

No need to rush and buy any ingredients as the University of Illinois at Urbana-Champaign researchers do not provide a recipe for cooking up carbon nanoparticles. However, it is diverting to think that one day we might be able to make these items at home. From a June 19, 2015 news item by Stuart Milne on the Azonano website,

Researchers at the University of Illinois have discovered an easy method to produce carbon nanoparticles for biomedical applications. These carbon nanoparticles can be made at home within a couple of hours using easily available ingredients and molasses.

A June 19 (?), 2015 University of Illinois at Urbana-Champaign news release (also on EurekAlert) provides more detail about the research,

“If you have a microwave and honey or molasses, you can pretty much make these particles at home,” Pan [professor Dipanjan Pan] said. “You just mix them together and cook it for a few minutes, and you get something that looks like char, but that is nanoparticles with high luminescence. This is one of the simplest systems that we can think of. It is safe and highly scalable for eventual clinical use.”

These “next-generation” carbon spheres have several attractive properties, the researchers found. They naturally scatter light in a manner that makes them easy to differentiate from human tissues, eliminating the need for added dyes or fluorescing molecules to help detect them in the body.

The nanoparticles are coated with polymers that fine-tune their optical properties and their rate of degradation in the body. The polymers can be loaded with drugs that are gradually released.

The nanoparticles also can be made quite small, less than eight nanometers in diameter (a human hair is 80,000 to 100,000 nanometers thick).

“Our immune system fails to recognize anything under 10 nanometers,” Pan said. “So, these tiny particles are kind of camouflaged, I would say; they are hiding from the human immune system.”

The team tested the therapeutic potential of the nanoparticles by loading them with an anti-melanoma drug and mixing them in a topical solution that was applied to pig skin.

Bhargava’s [professor Rohit Bhargava] laboratory used vibrational spectroscopic techniques to identify the molecular structure of the nanoparticles and their cargo.

“Raman and infrared spectroscopy are the two tools that one uses to see molecular structure,” Bhargava said. “We think we coated this particle with a specific polymer and with specific drug-loading – but did we really? We use spectroscopy to confirm the formulation as well as visualize the delivery of the particles and drug molecules.”

The team found that the nanoparticles did not release the drug payload at room temperature, but at body temperature began to release the anti-cancer drug. The researchers also determined which topical applications penetrated the skin to a desired depth.

In further experiments, the researchers found they could alter the infusion of the particles into melanoma cells by adjusting the polymer coatings. Imaging confirmed that the infused cells began to swell, a sign of impending cell death.

“This is a versatile platform to carry a multitude of drugs – for melanoma, for other kinds of cancers and for other diseases,” Bhargava said. “You can coat it with different polymers to give it a different optical response. You can load it with two drugs, or three, or four, so you can do multidrug therapy with the same particles.”

“By using defined surface chemistry, we can change the properties of these particles,” Pan said. “We can make them glow at a certain wavelength and also we can tune them to release the drugs in the presence of the cellular environment. That is, I think, the beauty of the work.”

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

Tunable Luminescent Carbon Nanospheres with Well-Defined Nanoscale Chemistry for Synchronized Imaging and Therapy by Prabuddha Mukherjee, Santosh K. Misra, Mark C. Gryka, Huei-Huei Chang, Saumya Tiwari, William L. Wilson, John W. Scott, Rohit Bhargava, and Dipanjan Pan. Small
DOI: 10.1002/smll.201500728 Article first published online: 20 MAY 2015

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

Microbubbles reform into nanoparticles after bursting

It seems researchers at the Toronto-based (Canada), Princess Margaret Cancer Centre, have developed a new theranostic tool made of microbubbles used for imaging that are then burst into nanoparticles delivering therapeutics. From a March 30, 2015 news item on phys.org,

Biomedical researchers led by Dr. Gang Zheng at Princess Margaret Cancer Centre have successfully converted microbubble technology already used in diagnostic imaging into nanoparticles that stay trapped in tumours to potentially deliver targeted, therapeutic payloads.

The discovery, published online today [March 30, 2015] in Nature Nanotechnology, details how Dr. Zheng and his research team created a new type of microbubble using a compound called porphyrin – a naturally occurring pigment in nature that harvests light.

A March 30, 2015 University Health Network news release on EurekAlert, which originated the news item, describes the laboratory research on mice,

In the lab in pre-clinical experiments, the team used low-frequency ultrasound to burst the porphyrin containing bubbles and observed that they fragmented into nanoparticles. Most importantly, the nanoparticles stayed within the tumour and could be tracked using imaging.

“Our work provides the first evidence that the microbubble reforms into nanoparticles after bursting and that it also retains its intrinsic imaging properties. We have identified a new mechanism for the delivery of nanoparticles to tumours, potentially overcoming one of the biggest translational challenges of cancer nanotechnology. In addition, we have demonstrated that imaging can be used to validate and track the delivery mechanism,” says Dr. Zheng, Senior Scientist at the Princess Margaret and also Professor of Medical Biophysics at the University of Toronto.

Conventional microbubbles, on the other hand, lose all intrinsic imaging and therapeutic properties once they burst, he says, in a blink-of-an-eye process that takes only a minute or so after bubbles are infused into the bloodstream.

“So for clinicians, harnessing microbubble to nanoparticle conversion may be a powerful new tool that enhances drug delivery to tumours, prolongs tumour visualization and enables them to treat cancerous tumours with greater precision.”

For the past decade, Dr. Zheng’s research focus has been on finding novel ways to use heat, light and sound to advance multi-modality imaging and create unique, organic nanoparticle delivery platforms capable of transporting cancer therapeutics directly to tumours.

Interesting development, although I suspect there are many challenges yet to be met such as ensuring the microbubbles consistently arrive at their intended destination in sufficient mass to be effective both for imaging purposes and, later, as nanoparticles for drug delivery purposes.

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

In situ conversion of porphyrin microbubbles to nanoparticles for multimodality imaging by Elizabeth Huynh, Ben Y. C. Leung, Brandon L. Helfield, Mojdeh Shakiba, Julie-Anne Gandier, Cheng S. Jin, Emma R. Master, Brian C. Wilson, David E. Goertz, & Gang Zheng. Nature Nanotechnology (2015) doi:10.1038/nnano.2015.25 Published online 30 March 2015

This paper is behind a paywall but a free preview is available via ReadCube Access.

This is one of those times where I’m including the funding agencies and the ‘About’ portions of the news release,

The research published today was funded by the Canadian Institutes of Health Research (CIHR) Frederick Banting and Charles Best Canada Graduate Scholarship, the Emerging Team Grant on Regenerative Medicine and Nanomedicine co-funded by the CIHR and the Canadian Space Agency, the Natural Sciences and Engineering Research Council of Canada, the Ontario Institute for Cancer Research, the International Collaborative R&D Project of the Ministry of Knowledge Economy, South Korea, the Joey and Toby Tanenbaum/Brazilian Ball Chair in Prostate Cancer Research, the Canada Foundation for Innovation and The Princess Margaret Cancer Foundation.

About Princess Margaret Cancer Centre, University Health Network

The Princess Margaret Cancer Centre has achieved an international reputation as a global leader in the fight against cancer and delivering personalized cancer medicine. The Princess Margaret, one of the top five international cancer research centres, is a member of the University Health Network, which also includes Toronto General Hospital, Toronto Western Hospital and Toronto Rehabilitation Institute. All are research hospitals affiliated with the University of Toronto. For more information, go to http://www.theprincessmargaret.ca or http://www.uhn.ca .

I was not expecting to see South Korea or Brazil mentioned in the funding. Generally, when multiple countries are funding research, their own research institutions are also involved. As for the Princess Margaret Cancer Centre being one of the top five such centres internationally, I wonder how these rankings are determined.

Researching a curcumin delivery system—a nutraceutical story

A Nov. 6, 2014 news item on ScienceDaily features research on delivering curcumin’s (a constituent of turmeric) health benefits more efficiently (there is a twist; for the impatient, you may want to scroll down to where I provide an excerpt from the university’s news release) from Ohio State University (US),

The health benefits of over-the-counter curcumin supplements might not get past your gut, but new research shows that a modified formulation of the spice releases its anti-inflammatory goodness throughout the body.

Curcumin is a naturally occurring compound found in the spice turmeric that has been used for centuries as an Ayurvedic medicine treatment for such ailments as allergies, diabetes and ulcers.

Anecdotal and scientific evidence suggests curcumin promotes health because it lowers inflammation, but it is not absorbed well by the body. Most curcumin in food or supplements stays in the gastrointestinal tract, and any portion that’s absorbed is metabolized quickly.

A Nov. 6, 2014 Ohio State University news release by Emily Caldwell (also on EurekAlert), which originated the news item, explains the interest in curcumin in more detail and describes the research in more detail,

Many research groups are testing the compound’s effects on disorders ranging from colon cancer to osteoarthritis. Others, like these Ohio State University scientists, are investigating whether enabling widespread availability of curcumin’s biological effects to the entire body could make it useful both therapeutically and as a daily supplement to combat disease.

“There’s a reason why this compound has been used for hundreds of years in Eastern medicine. And this study suggests that we have identified a better and more effective way to deliver curcumin and know what diseases to use it for so that we can take advantage of its anti-inflammatory power,” said Nicholas Young, a postdoctoral researcher in rheumatology and immunology at Ohio State and lead author of the study.

Curcumin powder was mixed with castor oil and polyethylene glycol in a process called nano-emulsion (think vinaigrette salad dressing), creating fluid teeming with microvesicles that contain curcumin. This process allows the compound to dissolve and be more easily absorbed by the gut to enter the bloodstream and tissues.

Feeding mice this curcumin-based drug shut down an acute inflammatory reaction by blocking activation of a key protein that triggers the immune response. The researchers were also the first to show that curcumin stops recruitment of specific immune cells that, when overactive, are linked to such problems as heart disease and obesity.

Young and his colleagues, including co-senior authors Lai-Chu Wu and Wael Jarjour of the Division of Rheumatology and Immunology at Ohio State’s Wexner Medical Center, now want to know if curcumin in this form can counter the chronic inflammation that is linked to sickness and age-related frailty. They have started with animal studies testing nano-emulsified curcumin’s ability to prevent or control inflammation in a lupus model.

“We envision that this nutraceutical could be used one day both as a daily supplement to help prevent certain diseases and as a therapeutic drug to help combat the bad inflammation observed in many diseases,” Young said. “The distinction will then be in the amount given – perhaps a low dose for daily prevention and higher doses for disease suppression.”

The term nutraceutical refers to foods or nutrients that provide medical or health benefits.

This news release notes the latest research is built on previous work,

The curcumin delivery system was created in Ohio State’s College of Pharmacy, and these researchers previously showed that concentrations of the emulsified curcumin in blood were more than 10 times higher than of curcumin powder suspended in water.

A more precise description of the current research is then provided (from the news release),

… From there, the researchers launched experiments in mice and cell cultures, generating artificial inflammation and comparing the effects of the nano-emulsified curcumin with the effects of curcumin powder in water or no treatment at all. [emphasis mine]

The researchers injected mice with lipopolysaccharide, a bacteria cell wall extract that stimulates an immune reaction in animals. Curcumin can target many molecules, but the research team zeroed in on NF-kB, a protein that is known to play an important role in the immune response.

In a specialized imaging machine, mice receiving plain curcumin lit up with bioluminescent signals indicating that NF-kB was actively triggering an immune response, while mice receiving nano-emulsified curcumin showed minimal signs – a 22-fold reduction – that the protein had been activated at all.

Knowing that curcumin delivered in this way could shut down NF-kB activation throughout the animals’ bodies, researchers looked for further details about the compound’s effects on inflammation. They found that nano-emulsified curcumin halted the recruitment of immune cells called macrophages that “eat” invading pathogens but also contribute to inflammation by secreting pro-inflammatory chemicals. And in cells isolated from human blood samples, macrophages were stopped in their tracks.

“This macrophage-specific effect of curcumin had not been described before,” Young said. “Because of that finding, we propose nano-emulsified curcumin has the best potential against macrophage-associated inflammation.”

Inflammation triggered by overactive macrophages has been linked to cardiovascular disease, disorders that accompany obesity, Crohn’s disease, rheumatoid arthritis, inflammatory bowel disease, diabetes and lupus-related nephritis.

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

Oral Administration of Nano-Emulsion Curcumin in Mice Suppresses Inflammatory-Induced NFκB Signaling and Macrophage Migration by Nicholas A. Young, Michael S. Bruss, Mark Gardner, William L. Willis, Xiaokui Mo, Giancarlo R. Valiente, Yu Cao, Zhongfa Liu, Wael N. Jarjour, and Lai-Chu Wu. PLOS ONE Published: November 04, 2014 DOI: 10.1371/journal.pone.0111559

This paper is open accesss.

I have an Oct. 1, 2014 posting which features research on curcumin for healing wounds and on tumerone for stimulating the formation of stem cells in the brain.

No need for eye drops when your contact lenses can dispense your eye medication

Anyone who has difficulty getting or allowing drops into their eyes (I once slid out of an ophthalmologist’s examination chair trying to avoid the eye drops he was administering at the end of my appointment) is going appreciate this Dec. 9, 2013 news item on Nanowerk,

For nearly half a century, contact lenses have been proposed as a means of ocular drug delivery that may someday replace eye drops, but achieving controlled drug release has been a significant challenge. Researchers at Massachusetts Eye and Ear/Harvard Medical School Department of Ophthalmology, Boston Children’s Hospital, and the Massachusetts Institute of Technology are one step closer to an eye drop-free reality with the development of a drug-eluting contact lens designed for prolonged delivery of latanoprost, a common drug used for the treatment of glaucoma, the leading cause of irreversible blindness worldwide.

The Dec. 9, 2013 Massachusetts Eye and Ear Infirmary press release (also on EurekAlert), which originated the news item, notes that a lot of people have problems with eye drops and gives a general description of the research,

“In general, eye drops are an inefficient method of drug delivery that has notoriously poor patient adherence. This contact lens design can potentially be used as a treatment for glaucoma and as a platform for other ocular drug delivery applications,” said Joseph Ciolino, M.D, Mass. Eye and Ear cornea specialist and lead author of the paper.

The contacts were designed with materials that are FDA-approved for use on the eye. The latanoprost-eluting contact lenses were created by encapsulating latanoprost-polymer films in commonly used contact lens hydrogel. Their findings are described online and will be in the January 2014 printed issue of Biomaterials.

“The lens we have developed is capable of delivering large amounts of drug at substantially constant rates over weeks to months,” said Professor Daniel Kohane, director of the Laboratory for Biomaterials and Drug Delivery at Boston Children’s Hospital.

In vivo, single contact lenses were able to achieve, for one month, latanoprost concentrations in the aqueous humor that were comparable to those achieved with daily topical latanoprost solution, the current first-line treatment for glaucoma.

The lenses appeared safe in cell culture and animal studies. This is the first contact lens that has been shown to release drugs for this long in animal models.

The newly designed contact lens has a clear central aperture and contains a drug-polymer film in the periphery, which helps to control drug release. The lenses can be made with no refractive power or with the ability to correct the refractive error in near sided or far sided eyes.

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

In vivo performance of a drug-eluting contact lens to treat glaucoma for a month by Joseph B. Ciolino, Cristina F. Stefanescu, Amy E. Ross, Borja Salvador-Culla, Priscila Cortez, Eden M. Ford, Kate A. Wymbs, Sarah L. Sprague, Daniel R. Mascoop, Shireen S. Rudina, Sunia A. Trauger, Fabiano Cade, Daniel S. Kohane. Biomaterials Volume 35, Issue 1, January 2014, Pages 432–439 DOI: S0142961213011150

This article is behind a paywall.

At the nanoscale, grapefruit swings from being medication danger to medication enhancer

It’s known that grapefruit, despite its health benefits, can inhibit (or even a pose danger) to a medication’s effectiveness. Most of us have been warned at one time or another to avoid grapefruit juice when downing a pill. So, the news from the University of Louisville (Kentucky; UofL) about grapefruit as part of a drug delivery system seems a little counter-intuitive (from the May 22, 2013 news item on Azonano),

Grapefruits have long been known for their health benefits, and the subtropical fruit may revolutionize how medical therapies like anti-cancer drugs are delivered to specific tumor cells.

University of Louisville researchers have uncovered how to create nanoparticles using natural lipids derived from grapefruit, and have discovered how to use them as drug delivery vehicles. UofL scientists Huang-Ge Zhang, D.V.M., Ph.D., Qilong Wang, Ph.D., and their team today (May 21, 2013), published their findings in Nature Communications.

The May 21, 2013 University of Louisville news release by Julie Heflin, which originated the news item, describes how the nanoparticles are derived and their advantages,

“These nanoparticles, which we’ve named grapefruit-derived nanovectors (GNVs), are derived from an edible plant, and we believe they are less toxic for patients, result in less biohazardous waste for the environment and are much cheaper to produce at large scale than nanoparticles made from synthetic materials,” said Zhang, who holds the Founders Chair in Cancer Research at the Brown Cancer Center.

The researchers demonstrated that GNVs can transport various therapeutic agents, including anti-cancer drugs, DNA/RNA and proteins such as antibodies. Treatment of animals with GNVs seemed to cause less adverse effects than treatment with drugs encapsulated in synthetic lipids.

“Our GNVs can be modified to target specific cells — we can use them like missiles to carry a variety of therapeutic agents for the purpose of destroying diseased cells,” he said. “Furthermore, we can do this at an affordable price.”

The therapeutic potential of grapefruit derived nanoparticles was further validated through a Phase 1 clinical trial for treatment of colon cancer patients. So far, researchers have observed no toxicity in the patients who orally took the anti-inflammatory agent curcumin encapsulated in grapefruit nanoparticles.

The UofL scientists also plan to test whether this technology can be applied in the treatment of inflammation related autoimmune diseases like rheumatoid arthritis.

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

Delivery of therapeutic agents by nanoparticles made of grapefruit-derived lipids by Qilong Wang, Xiaoying Zhuang, Jingyao Mu, Zhong-Bin Deng, Hong Jiang, Xiaoyu Xiang, Baomei Wang, Jun Yan, Donald Miller, & Huang-Ge Zhang. Nature Communications 4, 1867 doi:10.1038/ncomms2886 Published 21 May 2013

This paper is behind a paywall.

As for the dangers of grapefruit-medication interactions, ABC (American Broadcasting Corporation) has a Nov. 26, 2012 news item featuring then new research suggesting that even more medications are affected by grapefruit/grapefruit juice than had previously been believed,

It has long been known that grapefruit juice can pose dangerous — and even deadly — risks when taken along with certain medications. Now, experts warn the list of medications that can result in these interactions is longer than many may have believed.

In a new report released Monday in the Canadian Medical Association Journal [CMAJ], researchers at the University of Western Ontario said that while 17 drugs were identified in 2008 as having the potential to cause serious problems when taken with grapefruit, this number has now grown to 43.

So how does a common breakfast fruit cause these problems? Grapefruits contain chemicals called furanocoumarins that interfere with how your body breaks down drugs before they enter the bloodstream. By preventing this normal breakdown of a drug, these chemicals in grapefruit can effectively cause a drug overdose and more severe side-effects.

Among the side effects sometimes seen with grapefruit-induced overdoses are heart rhythm problems, kidney failure, muscle breakdown, difficulty with breathing and blood clots. …

ABC provides a list of drugs that are affected by grapefruit here.

For interested parties, here’s a link to and a citation for the research on grapefruit-medication interactions,

Grapefruit–medication interactions: Forbidden fruit or avoidable consequences? by David G. Bailey, George Dresser, and J. Malcolm O. Arnold. CMAJ March 5, 2013 185:309-316; published ahead of print November 26, 2012,

This paper is behind a paywall.

I have a couple of final comments. (1) It would seem that the grapefruit’s characteristics at the macroscale are not echoed at the nanoscale. (2) Interestingly, the grapefruit nanoparticles (grapefruit nanovectors [GNVs]) are being used to encapsulate curcumin (a constituent of turmeric). I wrote about turmeric and its healing properties in a Dec. 26, 2011 posting, which features a number of links to research in this area.