Nanodiamond drug device could transform cancer treatment

Nanodiamond-embedded devices could be used to deliver a broad range of therapeutics for the treatment of cancer and inflammation and for regenerative medicine. The extremely thin and flexible devices also can be customized to any shape and thickness.

A Northwestern University research team has developed a promising nanomaterial-based biomedical device that could be used to deliver chemotherapy drugs locally to sites where cancerous tumors have been surgically removed.

The flexible microfilm device, which resembles a piece of plastic wrap and can be customized easily into different shapes, has the potential to transform conventional treatment strategies and reduce patients' unnecessary exposure to toxic drugs. The device takes advantage of nanodiamonds, an emergent technology, for sustained drug release.

In their study, Ho and his colleagues embedded millions of tiny drug-carrying nanodiamonds in the FDA-approved polymer parylene. Currently used as a coating for implants, the biostable parylene is a flexible and versatile material resembling plastic wrap. A substantial amount of drug can be loaded onto clusters of nanodiamonds, which have a high surface area. The nanodiamonds then are put between extremely thin films of parylene, resulting in a device that is minimally invasive.

To test the device's drug release performance, the researchers used Doxorubicin, a chemotherapeutic used to treat many types of cancer. They found the drug slowly and consistently released from the embedded nanodiamond clusters for one month, with more Doxorubicin in reserve, indicating a more prolonged release (several months and longer) was possible. The device also avoided the "burst" or massive initial release of the drug, a common disadvantage with conventional therapy.

In control experiments, where the drug was present but without the nanodiamonds, virtually all of the drug was released within one day. By adding the drug-laden nanodiamonds to the device, drug release was instantly lengthened to the months-long timescale.

In addition to their large surface area, nanodiamonds have many other advantages that can be utilized in drug delivery. They can be functionalized with nearly any type of therapeutic. They can be suspended easily in water, which is important for biomedical applications. The nanodiamonds, each being four to six nanometers in diameter, are minimally invasive to cells, biocompatible and do not cause inflammation, a serious complication. And they are very scalable and can be produced in large quantities.

The architecture of the device is amenable to housing small molecule, protein, antibody or RNA- or DNA-based therapeutics. This gives the technology the potential to impact a range of treatment strategies where implanted, long-term drug release is needed.

A complex hybrid Nanoparticle slightly smaller than a virus deliver drug cocktail

The nanometer-sized cargo ships look individually like a chocolate-covered nut cluster, in which a biocompatible lipid forms the chocolate shell and magnetic nanoparticles, quantum dots and the drug doxorubicin are the nuts. Credit: Ji-Ho Park, UCSD

Scientists at UC San Diego, UC Santa Barbara and MIT report that their nano-cargo-ship system integrates therapeutic and diagnostic functions into a single device that avoids rapid removal by the body’s natural immune system. It is 50 nanometers in size. So it has three times less volume than the typical virus.

1 nm    diameter of glucose molecule 
2 nm    diameter of DNA helix 
5 nm    diameter of insulin molecule 
6 nm    diameter of a hemoglobin molecule 
10 nm   thickness of cell wall (gram negative bacteria) 
75 nm   size of typical virus 
200 nm  diameter of smallest bacteria 
1000nm  diameter of sperm cell (smallest cell in the human body)

“The idea involves encapsulating imaging agents and drugs into a protective ‘mother ship’ that evades the natural processes that normally would remove these payloads if they were unprotected,” said Michael Sailor, a professor of chemistry and biochemistry at UCSD who headed the team of chemists, biologists and engineers that turned the fanciful concept into reality. “These mother ships are only 50 nanometers in diameter, or 1,000 times smaller than the diameter of a human hair, and are equipped with an array of molecules on their surfaces that enable them to find and penetrate tumor cells in the body.”

These microscopic cargo ships could one day provide the means to more effectively deliver toxic anti-cancer drugs to tumors in high concentrations without negatively impacting other parts of the body.

The researchers designed the hull of the ships to evade detection by constructing them of specially modified lipids--a primary component of the surface of natural cells. The lipids were modified in such a way as to enable them to circulate in the bloodstream for many hours before being eliminated. This was demonstrated by the researchers in a series of experiments with mice.

The researchers loaded their ships with three payloads before injecting them in the mice. Two types of nanoparticles, superparamagnetic iron oxide and fluorescent quantum dots, were placed in the ship’s cargo hold, along with the anti-cancer drug doxorubicin. The iron oxide nanoparticles allow the ships to show up in a Magnetic Resonance Imaging, or MRI, scan, while the quantum dots can be seen with another type of imaging tool, a fluorescence scanner.

This study provides the first example of a single nanomaterial used for simultaneous drug delivery and multimode imaging of diseased tissue in a live animal," said Ji-Ho Park, a graduate student in Sailor's laboratory who was part of the team. Geoffrey von Maltzahn, a graduate student working in Bhatia's laboratory, was also involved in the project, which was financed by a grant from the National Cancer Institute of the National Institutes of Health.

The nano mother ships look individually like a chocolate-covered nut cluster, in which a biocompatible lipid forms the chocolate shell and magnetic nanoparticles, quantum dots and the drug doxorubicin are the nuts. They sail through the bloodstream in groups that, under the electron microscope, look like small, broken strands of pearls.

The researchers are now working on developing ways to chemically treat the exteriors of the nano ships with specific chemical "zip codes," that will allow them to be delivered to specific tumors, organs and other sites in the body.

Tobacco Mosaic Virus can deliver gene silencing RNA and enables new drugs in weeks

Tobacco mosaic virus is like a 18-nanometer wide straw, which can hold gene silencing RNA

The tobacco mosaic virus appears to be the key to safe and effective delivery of gene silencing RNA.

Bentley's team has successfully hollowed out the virus and filled it with siRNA, and then used it to slip the frail substance into all sorts of cells, from kidney tissue to cancer. The researchers have proven that the tiny capsules provide adequate protection, and that they release their payloads once inside -- hitting their target genes right on the mark.

The short, double-stranded RNA molecules known as siRNA can program cells to destroy disease-causing proteins. Their molecules turn on a cell's own built-in disease-fighting mechanisms. They can be programmed for a wide range of ailments -- from cancers to viruses -- and because they use the cell's own defense mechanisms, they produce minimal side effects.

In addition to treating cancers and genetic disorders, siRNA could prove useful against a variety of rare diseases that have, and always will be, overlooked by big pharmaceutical companies -- the long tail of disease.

People suffering from similar, exotic maladies could band together and recruit a small team of scientists, as if they were the Seven Samurai, to champion their cause and quickly design a cure.

“The speed with which you develop siRNA drugs is truly amazing,” said Stephen Hyde. “In the past, a traditional small molecule drug might take several years of intensive research effort by a large team of scientists to develop. Today, with siRNA technology, it is possible for a single researcher to develop a drug candidate in a few weeks.”

Bentley is optimistic that the virus will not cause health problems because most people already have traces of it in their blood -- from second-hand smoke -- and it does not seem to cause irritation or obvious immune-system problems.

Protecting the payload is not the only challenge, said Ben Berkhout, a biotechnology expert at the University of Amsterdam. Even if the delicate molecules are packaged in the perfect substance, they still need some sort of a guidance system.

"You want to efficiently get the siRNA drug into the cells where the therapeutic action should be,” said Berkhout.

By coating each tube with special proteins that can recognize and penetrate cancer cells, Bentley's team hopes to make smart drugs that will only go where they are needed.

If that trick works, tobacco may finally be able to turn over a new leaf.

Carbon nanotubes could reduce side effects from cancer treatment.

MIT Technology Review reports that carbon nanotubes could reduce the side effects of cancer drugs and mice tests show they are twice as effective at reducing tumor size. The researchers estimate that drug uptake within a tumor was 10 times higher for nanotube delivery than for Taxol. This uptake means that smaller doses could be used to achieve the same effects as other treatments, reducing side effects.

Research from Stanford University has shown that carbon nanotubes loaded with anticancer drugs can target tumor cells while steering clear of healthy tissue.

The nanotubes--on average 100 nanometers long and a few nanometers wide--pass easily through the leaky walls of tumor blood vessels but do not get into healthy blood vessels. So the researchers realized that drugs attached to the nanotubes could be carried inside tumors without harming normal tissue.

To make working nano-drug transporters, the researchers coated the nanotubes with a molecule called polyethylene glycol (PEG), which has three branches on one end, then attached molecules of the anticancer drug paclitaxel to each branch. Each of the 100-nanometer-long nanotubes carried about 150 drug molecules in total. "Think of a carbon nanotube as a boat," says Steve Lippard, a chemistry professor at MIT, who was not involved in the research. "The advantage of the branched PEG is that you can have multiple passengers at each seat." Dai adds that the branched PEG is stable in the bloodstream for a relatively long time, giving the nanotubes more time to find and treat a tumor before leaving the body.

The drug-delivery technique was tested in mice that had been injected with breast cancer cells. Once the tumors grew to a specific size, the researchers administered a dose of the drug-laden nanotubes every six days. They gave another group of mice similar doses of different forms of paclitaxel, including the clinical drug Taxol, and left some untreated. After 22 days, they found that the tumors treated by nanotube delivery were less than half the size of the tumors treated by the second most effective treatment, Taxol.

Nanobialys can carry drugs to tumors or plaques

Ultra-miniature bialy-shaped particles — called nanobialys because they resemble tiny versions of the flat, onion-topped rolls popular in New York City — could soon be carrying medicinal compounds through patients' bloodstreams to tumors or atherosclerotic plaques.

The nanobialys answered a need for an alternative to the research group's gadolinium-containing nanoparticles, which were created for their high visibility in magnetic resonance imaging (MRI) scans.

Gadolinium is a common contrast agent for MRI scans, but recent studies have shown that it can be harmful to some patients with severe kidney disease.

"The nanobialys contain manganese instead of gadolinium," says first author Dipanjan Pan, Ph.D., research instructor in medicine in the Cardiovascular Division. "Manganese is an element found naturally in the body. In addition, the manganese in the nanobialys is tied up so it stays with the particles, making them very safe."

A bialy is a Polish roll like a bagel without a hole that can be made with different toppings.

Nanoworms (magnetic iron oxide particles with polymer coating) target cancer tumors

Segmented "nanoworms" composed of magnetic iron oxide and coated with a polymer are able to find and attach to tumors. Scientists at UC San Diego, UC Santa Barbara and MIT have developed nanometer-sized “nanoworms” that can cruise through the bloodstream without significant interference from the body’s immune defense system and—like tiny anti-cancer missiles—home in on tumors. They are superparamagnetic and show up very well on MRIs and can circulate in the body for hours since they do not trigger the immune system.

Using nanoworms, doctors should eventually be able to target and reveal the location of developing tumors that are too small to detect by conventional methods. Carrying payloads targeted to specific features on tumors, these microscopic vehicles could also one day provide the means to more effectively deliver toxic anti-cancer drugs to these tumors in high concentrations without negatively impacting other parts of the body.

“Most nanoparticles are recognized by the body's protective mechanisms, which capture and remove them from the bloodstream within a few minutes,” said Michael Sailor, a professor of chemistry and biochemistry at UC San Diego who headed the research team. “The reason these worms work so well is due to a combination of their shape and to a polymer coating on their surfaces that allows the nanoworms to evade these natural elimination processes. As a result, our nanoworms can circulate in the body of a mouse for many hours.”

The scientists constructed their nanoworms from spherical iron oxide nanoparticles that join together, like segments of an earthworm, to produce tiny gummy worm-like structures about 30 nanometers long—or about 3 million times smaller than an earthworm. Their iron-oxide composition allows the nanoworms to show up brightly in diagnostic devices, specifically the MRI, or magnetic resonance imaging, machines that are used to find tumors.

“The iron oxide used in the nanoworms has a property of superparamagnetism, which makes them show up very brightly in MRI,” said Sailor. “The magnetism of the individual iron oxide segments, typically eight per nanoworm, combine to provide a much larger signal than can be observed if the segments are separated. This translates to a better ability to see smaller tumors, hopefully enabling physicians to make their diagnosis of cancer at earlier stages of development.”

The researchers are now working on developing ways to attach drugs to the nanoworms and chemically treating their exteriors with specific chemical “zip codes,” that will allow them to be delivered to specific tumors, organs and other sites in the body.

“We are now using nanoworms to construct the next generation of smart tumor-targeting nanodevices,” said Ruoslahti. We hope that these devices will improve the diagnostic imaging of cancer and allow pinpoint targeting of treatments into cancerous tumors.”

Folded up micrometer-scale 'voxels' for drug delivery

After starting the folds using magnetic forces, the structure is sealed using capillary action.


USC researchers have made pyramid structures that are 40 micrometers on each side

Part one is the creation of flat patterns, origami, of exactly the fold up shapes familiar to kindergarten children making paper pyramids, cubes or other solids, except that these are as small 40 micrometers (µm) on a side. (1 inch = 25,400 µm)

Instead of paper, the USC researchers created the patterns in polysilicon sitting on top of a thin film of gold, using a well-established commercial silicon wafer process called PolyMUMPs. The next step was clearing the polysilicon off the hinge areas by etching.

When the blanks were later electrocoated with permalloy to make them magnetic, the photomask used left hinge areas uncoated, to make sure they were the places that folded.

Then the folding had to be accomplished. First the researchers bent the hinges by application of magnetic force to the permalloy. Water pressure and capillary forces generated by submerging the tiny blanks in water, and drying them off did the final folding into shape.

The experiments spend considerable time comparing various methods of controlling the closure effects of water drying with simple flaps designed to close over each other to form "envelops," the directing water from different directions sequence the closing. Varying the time of trying could produce tighter seams.

Nanodiamonds 100 times cheaper, used to track cells in the body and deliver chemotherapy drugs

Taiwanese scientists have found a way to slash the cost of making the diamond chips by around 100 times.

Nanodiamond's fluorescent properties could be used to track cells moving through the body. And, last year, researchers showed they could safely deliver chemotherapy drugs.

Cheaper alternatives to nanodiamonds, such as fluorescent dyes or small chunks of semiconductor known as quantum dots, are in use already. The diamonds, though, are less prone to blinking on and off than fluorescent dyes, and are not toxic to cells, unlike quantum dots.

FNDs are usually made by firing a high-energy electron beam into commercially available diamond powder and heating it up to 800 °C. Huan-Cheng Chang and colleagues at Academia Sinica in Taipei shoot a much less intense, and hence cheaper, beam of helium ions at diamond powder to make FNDs of the same quality.

Chang's team could track the movement of a single fluorescent nanodiamond within a cell for over 3 minutes.

The researchers have also explored other applications for their cheap diamonds, such as using them to monitor stem cells in developing tissue, or to carry drugs into cells.

"In particular, we have demonstrated that FNDs are able to interact with plasmid DNA and to deliver different genes into cultured human cells," Chang told New Scientist. That could be used for gene therapy, or DNA vaccines.

Chang and his colleagues have set up a commercial operation selling their nanodiamonds and are working on making them even smaller and to fluoresce more brightly.

The cheaper diamond chips need to be made smaller, though, if they are to perform well as markers to reveal the inner workings of cells, he adds.

Tiny Magnets for more effective Gene Therapy targeting for cancer, arthritis, heart disease and more

The technique involves inserting nanomagnets into monocytes - a type of white blood cell used to carry gene therapy - and injecting the cells into the bloodstream. The researchers then placed a small magnet over the tumour to create a magnetic field and found that this attracted many more monocytes into the tumour.

This new technique could also be used to help deliver therapeutic genes in other diseases like arthritic joints or ischemic heart tissue.

Though the concept of magnetic targeting for drug and gene delivery has been around for decades, major technical hurdles have prevented its translation into a clinical therapy. By harnessing and enhancing the monocytes' innate targeting abilities, this technique offers great potential to overcome some of these barriers and bring the technology closer to the clinic.

The team are now looking at how effective magnetic targeting is at delivering a variety of different cancer-fighting genes, including ones which could stop the spread of tumours to other parts of the body.

Nanoparticle enabled cooking of cancer tumors moving to clinical trials in about three year

Kanzius RF therapy attaches microscopic nanoparticles to cancer cells and then "cooks" tumors inside the body with harmless radio waves could be in clinical trials as early as 3 years. The treatment has been 100% effective in animal trials.

Stanford uses gold nanoparticles, carbon nanotubes and lasers to image to the nanometer in the body

Stanford University School of Medicine researchers has developed a new type of imaging system that can illuminate tumors in living subjects—getting pictures with a precision of nearly on nanometer (one-trillionth of a meter).

This technique, called Raman spectroscopy, expands the available toolbox for the field of molecular imaging, said team leader Sanjiv Sam Gambhir, MD, PhD, professor of radiology. signals from Raman spectroscopy are stronger and longer-lived than other available methods, and the type of particles used in this method can transmit information about multiple types of molecular targets simultaneously.

“Usually we can measure one or two things at a time,” he said. “With this, we can now likely see 10, 20, 30 things at once.”

Gambhir said he believes this is the first time Raman spectroscopy has been used to image deep within the body, using tiny nanoparticles injected into the body to serve as beacons.

When laser light is beamed from a source outside the body, these specialized particles emit signals that can be measured and converted into a visible indicator of their location in the body.

Imaging of animals and humans can be done using a few different methods, including PET, magnetic resonance imaging, computed tomography, optical bioluminescence and fluorescence and ultrasound. However, said Gambhir, none of these methods so far can fulfill all the desired qualities of an imaging tool, which include being able to finely detect small biochemical details, being able to detect more than one target at a time and being cheap and easy to use.

Postdoctoral scholars Shay Keren, PhD, and Cristina Zavaleta, PhD, co-first authors of the study, found a way to make Raman spectroscopy a medical tool. To get there, they used two types of engineered Raman nanoparticles: gold nanoparticles and single-wall carbon nanotubes.

First, they injected mice with the some of the nanoparticles. To see the nanoparticles, they used a special microscope that the group had adapted to view anesthetized mice exposed to laser light. The researchers could see that the nanoparticles migrated to the liver, where they were processed for excretion.

Using a microscope they modified to detect Raman nanoparticles, the team was able to see targets on a scale 1,000 times smaller than what is now obtainable by the most precise fluorescence imaging using quantum dots.

When adapted for human use, they said, the technique has the potential to be useful during surgery, for example, in the removal of cancerous tissue. The extreme sensitivity of the imager could enable detection of even the most minute malignant tissues.

Nested' nanoparticles increase efficiency of drug delivery

University of Texas researchers believe that by encasing their drugs in a series of nanoparticles they can produce a highly targeted treatment that bypasses the body's immune defences which have typically plagued other nanotechnology therapies.

These defences protect the body from foreign bodies that enter the bloodstream, including therapeutic nanoparticles. The different levels of attack include enzymes in the blood corrode the particles and microphage cells that actively attack and destroy the particles and remove them from the bloodstream.

These defences are so effective that on average just one out of every 100,000 drug molecules actually end up in the area they were meant to be targeting. In the past it had been difficult to find particles that could both penetrate these "biobarriers" and effectively find and target the correct tumour cells.

Mauro Ferrari's multistage delivery system overcomes these defences using a series of nanoparticles, contained one inside the other. As it passes through each barrier the drug sheds a shell to reveal a new particle that is best suited to the next line of immune defence

1. First the largest nanoparticle is a mesoporous silicon particle, designed to avoid attack by the microphages and which can withstand enzyme corrosion.

2. Once in their desired position, the silicon particles can release quantum dots or carbon nanotubes - both of which act as contrast agents for imaging applications. The carbon nanotubes can also be stimulated to produce heat, which itself could be used as a therapy.

These particles can also be used to deliver other therapeutic agents, to achieve high concentrations within the tumour without needing to increase the actual dosage of the drug. Ferrari is currently investigating the possibility of using the particles to deliver short interfering RNA (siRNA) molecules that could silence messenger RNA within a tumour cell to stop it reproducing.

FURTHER READING
Abstract of the paper : Mesoporous silicon particles as a multistage delivery system for imaging and therapeutic applications

Lipid Polymer Nanocontainers with controlled permeability

From Nano Letters, "Biofunctionalized Lipid−Polymer Hybrid Nanocontainers with Controlled Permeability"

We have successfully developed, for the first time, a novel polymer–lipid hybrid nanocontainer with controlled permeability functionality. The nanocontainer is made by nanofabricating holes with desired dimensions in an impermeable polymer scaffold by focused ion beam drilling and sealing them with lipid bilayers containing remote-controlled pore-forming channel proteins. This system allows exchange of solutions only after channel activation at will to form temporary pores in the container. Potential applications are foreseen in bionanosensors, nanoreactors, nanomedicine, and triggered delivery.

FURTHER READING
Alma Dudia's PhD thesis "Nanofabricated biohybrid structures for controlled drug delivery"

Nanoparticle synthesis techniques could grow functional devices out of solution

Nanowerk reports on an important research direction in nanoparticle synthesis is the expansion from single-component nanoparticles to hybrid nanostructures that possess two or more functional properties thanks to the integration of different materials.

In their research, Zeng and Sun have been trying to find a cost-effective approach to hierarchically assemble nanoscale building blocks for functional materials and devices. "In the past, this has been largely done by complicated microfabrication techniques involving multi-step lithography" explains Zeng. "The core of our work is the development of a general route for synthesizing multi-component, hybrid nanostructures where different nanoscale building blocks are directly grown onto one another to realize materials with multifunctionality. We envision that one day scientists will be able to grow completely functional sensors or even computer chips out of the solution phase. Our work is one small step towards realizing this goal."

Using their general synthesis approach, the two groups have produced a rather comprehensive list of hybrid materials that can be grouped into four classes: magnetic-metallic, magnetic-semiconductor, semiconductor-metallic, and magnetic-metallic-semiconductor.

The range of applications for these multicomponent nanoparticles is wide. For instance, they can be used as multi-modal bio-markers combining the functionalities of imaging, guided drug delivery and hyperthermia. Integrating different material properties at the nanoscale may also provide new opportunities for discovering enhanced or entirely novel material properties. Zeng uses the example of a ferroelectric-ferromagnetic multicomponent structure that could be used for electric field control of magnetism. "Such new functionality may one day allow new device concepts in nanoelectronics" he says.

Three sets of challenges before we can see large-scale practical applications:
1) gaining a fundamental understanding of the chemistry and materials science issues involved, so that hybrid structures can be designed with a high degree of control;

2) gaining a fundamental understanding of the interactions at the nanoscale between different components, so that the novel physical properties that may originate from such coupling can be predicted and exploited; and

3) finally, the controlled assembly of such hybrid nanoscale building blocks into bulk materials

Novozymes and Upperton Collaborate on New Nanoparticle Drug Delivery

Nanowerk reports that Novozymes announced a new collaboration agreement with Upperton Limited, a UK based Biotech Company specialising in novel nanoparticle-based drug delivery systems.

The two companies and will focus on the commercial exploitation of the jointly-owned rP-nano™ technology: a highly targeted drug delivery system which utilises the natural binding properties of recombinant protein nanoparticles to enhance drug and gene bioavailability.

They generate nanoparticles from recombinant proteins in a yeast-based expression system. rP-nano™ technology can generate precisely-sized nanoparticles within the range of 10nm to 120nm and can be optimised for Enhanced Permeability and Retention effect. The nanoparticles produced through this process retain the natural binding properties of the recombinant proteins from which they are made, and bind to specific cell types to enable more targeted drug delivery and improved bioavailability.

Nanoemulsion vaccines

A novel technique for vaccinating against a variety of infectious diseases – using an oil-based emulsion placed in the nose, rather than needles – has proved able to produce a strong immune response against smallpox and HIV in two new studies.

The results build on previous success in animal studies with a nasal nanoemulsion vaccine for influenza, reported by University of Michigan researchers in 2003.

Nanoemulsion vaccines developed at the Michigan Nanotechnology Institute for Medicine and the Biological Sciences at U-M are based on a mixture of soybean oil, alcohol, water and detergents emulsified into ultra-small particles smaller than 400 nanometers wide, or 1/200th the width of a human hair. These are combined with part or all of the disease-causing microbe to trigger the body’s immune response.

The surface tension of the nanoparticles disrupts membranes and destroys microbes but does not harm most human cells due to their location within body tissues. Nanoemulsion vaccines are highly effective at penetrating the mucous membranes in the nose and initiating strong and protective types of immune response, Baker says. U-M researchers are also exploring nasal nanoemulsion vaccines to protect against bioterrorism agents and hepatitis B.

The smallpox results, which appear in the February issue of Clinical Vaccine Immunology, could lead to an effective human vaccine against smallpox that is safer than the present live-vaccinia virus vaccine because it would use nanoemulsion-killed vaccinia virus, says Baker.

Anna U. Bielinska, Ph.D., a research assistant professor in internal medicine at the U-M Medical School, and others on Baker’s research team developed a killed-vaccinia virus nanoemulsion vaccine which they placed in the noses of mice to trigger an immune response. They found the vaccine produced both mucosal and antibody immunity, as well as Th1 cellular immunity, an important measure of protective immunity.

When the mice were exposed to live vaccinia virus to test the vaccine’s protective effect, all of them survived, while none of the unvaccinated control mice did. The researchers conclude that the nanoemulsion vaccinia vaccine offers protection equal to that of the existing vaccine, without the risk of using a live virus or the need for an inflammatory adjuvant such as alum hydroxide.

In antibody immunity, antibodies bind invading microbes as they circulate through the body. In cellular immunity, the immune system attacks invaders inside infected cells. There is growing interest in vaccines that induce mucosal immunity, in which the immune system stops and kills the invader in mucous membranes before it enters body systems.

A National Institutes of Health program, the Great Lakes Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases, funded the research. If the federal government conducts further studies and finds the nanoemulsion smallpox vaccine effective in people, it could be a safer way to protect citizens and health care workers in the event of a bioterrorism attack involving smallpox, Baker says.

That would allay concerns about the current vaccine’s safety which arose in 2002. On the eve of the Iraq War, the Bush administration proposed a voluntary program to vaccinate military personnel and 500,000 health care workers with the existing vaccine to prepare for the possible use of smallpox virus as a biological weapon.

Silica nanoparticles more effectively deliver bacteria killing nitric oxide

Mark Schoenfisch and his lab of analytical chemists at UNC have created nano-scale scaffolds made of silica and loaded with nitric oxide (NO) which can be released in a precisely controlled way. Nitric Oxide can be used to kill bacteria.

Schoenfisch, Hetrick and their colleagues tested their silica scaffolds head-to-head with small molecules against the bacteria Pseudomonas aeruginosa, which is commonly found in burn and other wound infections.

NO delivered by both methods completely killed the bacteria. But the silica nanoparticles delivered the NO right to the bacteria’s doorstep. In contrast, the small molecules released NO indiscriminately, and the concentration of NO is lost as it makes its way toward bacterial cells.

“With the silica particles, more NO actually reached the inside of the cells, enhancing the efficacy of the nanoparticles compared to the small molecule. So, the overall amount of NO needed to kill bacteria is much less with silica nanoparticles,” Schoenfisch said. “And, with small molecules, you’re left with potentially toxic byproducts,” Schoenfisch said. Using mouse cells, they proved that the silica nanoparticles weren’t toxic to healthy cells, but the small molecules were.

Future research will include studying additional bacterial strains, active targeting, preferential uptake and biodistribution studies.

Nanomaterials used to localize and control drug delivery

Nanoscale polymer films, about four nanometers per layer, were used to build a sort of matrix or platform to hold and slowly release an anti-inflammatory drug. The films are orders of magnitude thinner than conventional drug deliver coatings, said Genhong Cheng, a researcher at UCLA’s Jonsson Comprehensive Cancer Center and one of the study’s authors. A nanometer is one billionth of a meter.

“Using this system, drugs could be released slowly and under control for weeks or longer,” said Cheng, a professor of microbiology, immunology and molecular genetics. “A drug that is given orally or through the bloodstream travels throughout the system and dissipates from the body much more quickly. Using a more localized and controlled approach could limit side effects, particularly with chemotherapy drugs.”

Researchers coated tiny chips with layers of the nanoscale polymer films, which are inert and helped provide a Harry Potter-like invisibility cloak for the chips, hiding them from the body’s natural defenses. They then added Dexamethasone, an anti-inflammatory drug, between the layers. The chips were implanted in mice, and researchers found that the Dexamethasone-coated films suppressed the expression of cytokines, proteins released by the cells of the immune system to initiate a response to a foreign invader. Mice without implants and those with uncoated implants were studied to compare immune response.

The uncoated implants generated an inflammatory response from the surrounding tissue, which ultimately would have led to the body’s rejection of the implant and the breakdown of its functionality. However, tissue from the mice without implants and the mice with the nano-cloaked implants were virtually identical, proving that the film-coated implants were effectively shielded from the body’s defense system, said Edward Chow, a former UCLA graduate student who participated in the study and is one of its authors.

The nanomaterial technology serves as a non-invasive and biocompatible platform for the delivery of a broad range of therapeutics, said Dean Ho, an assistant professor of biomedical and mechanical engineering with the McCormick School of Engineering and Applied Science, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and the study’s senior author.

The technology also may prove to be an effective approach for delivering multiple drugs, controlling the sequence of multi-drug delivery strategies and enhancing the life spans of commonly implanted devises such as cardiac stents, pacemakers and continuous glucose monitors

Magnetic Nanoparticles could be used to control uptake of drugs by cell receptors

For the first time, researchers have demonstrated a means of controlling cell functions with a physical, rather than chemical, signal. Immune cells coated with nanoparticles take up calcium in the presence of a magnetic field. Each nanoparticle measures approximately 30 nanometers in diameter.

In this image, yellow cells are taking up calcium in response to a localized magnetic field. Cells that are farther away from the field are shown in purple and do not take up calcium. Credit: Donald Ingber, Harvard Medical School

Using a magnetic field to pull together tiny beads targeted to particular cell receptors, Harvard researchers made cells take up calcium, and then stop, then take it up again.

This is another important step to cellular and molecular control to enable nanomedicine

Ingber's group demonstrated its method for biomagnetic control using a type of immune-system cell that mediates allergic reactions.

Targeted nanoparticles with iron oxide cores were used to mimic antigens in vitro. Each is attached to a molecule that in turn can attach to a single receptor on an immune cell. When Ingber exposes cells bound with these particles to a weak magnetic field, the nanoparticles become magnetic and draw together, pulling the attached cell receptors into clusters. This causes the cells to take in calcium. (In the body, this would initiate a chain of events that leads the cells to release histamine.) When the magnetic field is turned off, the particles are no longer attracted to each other, the receptors move apart, and the influx of calcium stops.

"It's not the chemistry; it's the proximity" that activates such receptors, says Ingber.

The approach could have a far-reaching impact, as many important cell receptors are activated in a similar way and might be controlled using Ingber's method.

"In recent years, there has been a realization that physical events, not just chemical events, are important" to cell function, says Shu Chien, a bioengineer at the University of California, San Diego. Researchers have probed the effects of physical forces on cells by, for example, squishing them between plates or pulling probes across their surfaces. But none of these techniques work at as fine a level of control as Ingber's magnetic beads, which act on single biomolecules.

Many drugs, from anticancer antibodies to hormones, work by activating cell receptors. Once a hormone is in the blood, however, there's no turning it on or off. "This shows that you can turn on and off the signal, and that you can do it instantly," says Christopher Chen, a bioengineer at the University of Pennsylvania. "That's something that's hard to do, for example, with an antibody."

Ingber has many ideas for devices that might integrate his method of cellular control. Magnetic pacemakers could use cells instead of electrodes to send electrical pulses to the heart. Implantable drug factories might contain many groups of cells, each of which makes a different drug when activated by a magnetic signal. Biomagnetic control might lead to computers that can take advantage of cells' processing power. "Cells do complex things like image processing so much better than computers," says Ingber. Ingber, who began the project in response to a call by the Defense Advanced Research Projects Agency for new cell-machine interfaces, acknowledges that his work is in its early stages. In fifty years, however, he expects that there will be devices that "seamlessly interface between living cells and machines."

FURTHER READING
Harvard Institute for Biologically Inspired Engineering.