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Cowpea Mosaic Virus Delivers Drugs to Kill Cancer Cells 10 Mar 2010 8:05 AM (15 years ago)

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Norwich BioScience Institutes have developed particles from the Cowpea mosaic virus can carry anti-cancer agents to cancer cells.

Materials View China - Cowpea Mosaic Virus Unmodified Empty Viruslike Particles Loaded with Metal and Metal Oxide

Empty (devoid of RNA) viruslike particles (eVLPs) of Cowpea mosaic virus can now be obtained readily. CPMV can encapsulate, within the protein capsid, cobalt or iron oxide by environmentally benign processes. The external surface also remains amenable to chemical modification. The development of eVLPs for targeted delivery of therapeutic agents is now a reality.

7 pagse of supplemental material

In 2008, there was the first work on using the tobacco mosaic virus to deliver siRNA to cells

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

“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.”

Block copolymer nanotemplating of tobacco mosaic and tobacco necrosis viruses (Nov 2008)

Joural of Virology -Interaction of the Tobacco Mosaic Virus Replicase Protein with a NAC Domain Transcription Factor Is Associated with the Suppression of Systemic Host Defenses (Oct 2009)



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Buckywire for drug delivery and more 17 Jun 2009 8:13 AM (15 years ago)

Synthesis of a fullerene-based one-dimensional nanopolymer
through topochemical transformation of the parent nanowire (30 page pdf)

Large-scale practical applications of fullerene (C60) in nanodevices could be significantly facilitated if the commercially-available micrometer-scale raw C60 powder were further processed into a one-dimensional (1D) nanowire-related polymer displaying covalent bonding as molecular interlinks and resembling traditional important conjugated polymers. However, there has been little study thus far in this area despite the abundant literature on fullerene. Here we report the synthesis and characterization of such a C60-based nanowire polymer, (-C60TMB-)n, where TMB=1,2,4-trimethylbenzene, which displays a well-defined crystalline structure, exceptionally large length-to-width ratio and excellent thermal stability. The material is prepared by first growing the corresponding nanowire through a solution phase of C60 followed by a topochemical polymerization reaction in the solid state. Gas chromatography, mass spectrometry and 13C nuclear magnetic resonance evidence is provided for the nature of the covalent bonding mode adopted by the polymeric chains. Theoretical analysis based on detailed calculations of the reaction energetics and structural analysis provides an in-depth understanding of the polymerization pathway. The nanopolymer promises important applications in biological fields and in the development of optical, electrical, and magnetic nanodevices.

From MIT Technology Review Blog:

The exciting thing about this breakthrough is the potential to grow buckywires on an industrial scale from buckyballs dissolved in a vat of bubbling oil. Since the buckywires are insoluble, they precipitate out, forming crystals. (Here it ought to be said that various other groups are said to have made buckywires of one kind or another, but none seem to have nailed it from an industrial perspective.)

So what might buckywires be good for? First up is photovoltaics: these buckywires look as if they could be hugely efficient light harvesters because of their great surface area and the way that they can conduct photon-liberated electrons. Then there are various electronic applications in wiring up molecular circuit boards.

But perhaps the area of greatest interest is drug delivery. Geng and co suggest that buckywires ought to be safer than carbon nanotubes because the production method is entirely metal-free.

We have demonstrated for the first time an approach to the synthesis of a C60-based nanowire polymer and established the chemical bonding mode involved in the polymeric chains based on both experimental measurements and theoretical calculations. Importantly, the material adopts a crystalline 1D nanostructure which resembles carbon nanotubes in shape and other important conjugated polymers in structure. Since the material does not contain any metal but is simply composed almost entirely of carbon (while it contains hydrogen, the content is only 1.4 wt %), it suggests biological compatibility and it is, perhaps, even more attractive than carbon nanotubes for bio-applications. In addition, the material has further important potential for applications in photo-electrical devices because of the intrinsically large magnitude of the nonlinear optical response of C60 and the excellence of its photoinduced charge transfer properties. Considering all these, we believe that this work represents a step toward true applications of C60 in nanotechnology by the ability of processing commercially available raw C60 powder into a one-dimensional, crystalline, and covalently-bonded fullerene nanopolymer.

We consider that applications of the reported nanopolymer may be facilitated by a wet chemical approach through surface modification of the material using the rich chemistry of fullerene developed over the last 20 years. Since the nanopolymer is insoluble in common solvents, such surface modification or functionalization should be possible to achieve in either an aqueous or an organic solution without destructing its solid-state structure. Such a wet approach would benefit from low-cost processing, the need for only simple apparatus and the possibility of scaling-up to the industrial level. Moreover, the nanopolymer itself not only provides an example of phase transition of the parent nanowire driven by forming and breaking covalent bonds, but also illustrates the enduring significance of the original fullerene concept and its versatility as applied to new fullerene-related nanostructures. Finally, the host (C60) and guest (1,2,4-TMB) nature of the polymerization suggests a general host-guest route to the synthesis of new types of fullerene-based nanopolymers constructed by different organic monomers and fullerenes

Improved personalized cancer treatment with new RNAi delivery 17 May 2009 6:58 AM (15 years ago)

In technology that promises to one day allow drug delivery to be tailored to an individual patient and a particular cancer tumor, researchers at the University of California, San Diego School of Medicine, have developed an efficient system for delivering siRNA into primary cells. The work will be published in the May 17 in the advance on-line edition of Nature Biotechnology.

The team solved the problem of delivery of siRNAs into cells by making a PTD fusion protein with a double-stranded RNA-binding domain, termed PTD-DRBD, which masks the siRNA's negative charge. This allows the resultant fusion protein to enter the cell and deliver the siRNA into the cytoplasm where it specifically targets mRNAs from cancer-promoting genes and silences them.

The researchers have a startup, Traversa Therapeutics, which is commercializing this work.

Traversa's siRNA delivery technology is specifically designed to avoid the physical size and bioavailability problems inherent in the Liposome/cationic-lipid approach. The technology is non-cytotoxic, delivers to the entire cell population and all cell-types tested, and is dramatically smaller than a liposome. The Company expects the technology to provide improved pharmacokinetics, distribution and bioavailability over other methods. The technology supports delivery to primary and tumor cells, T cells, B cells, Macrophage, neuronal cells and human stem cells, where other approaches have failed. This ability to induce RNA interference in entire cell populations and all cell types in a non-cytotoxic fashion is unique to Traversa's technology and provides the Company's competitive advantage.

Traversa's siRNA delivery technology (PTD-DRBD) is a protein comprised of multiple Peptide Transduction Domains (PTD) linked to a Double-stranded RNA Binding Domain (DRBD). The PTD portion of the protein induces delivery into the cell through a fluid-uptake mechanism that all cells perform, called macropinocytosis. The DRBD portion of the protein initially binds to the siRNA, and later releases the siRNA once inside the cell.

RNA Interference (RNAi) is a recently discovered natural biological process. The Central Dogma of biology is that DNA makes RNA, and RNA subsequently makes protein. Because undesired proteins are the cause of most human disease, pharmaceutical drugs typically target select proteins and block their function. RNAi works upstream from the manufacture of protein in cells, silencing genes and thereby blocking the creation of these disease-causing proteins before they are made.

This breakthrough discovery is being harnessed by RNAi researchers to develop an entirely new class of human therapeutic that could potentially treat sixty percent of all human disease – the Interfering RNA. This new class of drugs brings with it enormous potential:

- Significantly improved specificity of target molecules
- Greater efficacy with fewer side effects
- New drugs for rare or difficult to treat diseases
- Reduced drug discovery timelines
- Faster response to pandemic infection

Interfering RNAs have tremendous selectivity, degrade only target RNAs, and yield specific gene silencing. However, due to their relatively large size (~14,000-18,000 Daltons), they require an additional delivery technology in order to enter cells and produce their intended effect.

"RNAi has an unbelievable potential to manage cancer and treat it," said Steven Dowdy, PhD, Howard Hughes Medical Institute Investigator and professor of cellular and molecular medicine at UC San Diego School of Medicine. "While there's still a long way to go, we have successfully developed a technology that allows for siRNA drug delivery into the entire population of cells, both primary and tumor-causing, without being toxic to the cells."

For many years, Dowdy has studied the cancer therapy potential of RNA inhibition which can be used to silence genes through short interfering, double-stranded RNA fragments called siRNAs. But delivery of siRNAs has proven difficult due to their size and negative electrical charge – which prohibits them from readily entering cells.

A small section of protein called a peptide transduction domain (PTD) has the ability to permeate cell membranes. Dowdy and colleagues saw the potential for PTDs as a delivery mechanism for getting siRNAs into cancer cells. He and his team had previously generated more than 50 "fusion proteins" using PTDs linked to tumor-suppressor proteins.

"Simply adding the siRNAs to a PTD didn't work, because siRNAs are highly negatively charged, while PTDs are positively charged, which results in aggregation with no cellular delivery," Dowdy explained. The team solved the problem by making a PTD fusion protein with a double-stranded RNA-binding domain, termed PTD-DRBD, which masks the siRNA's negative charge. This allows the resultant fusion protein to enter the cell and deliver the siRNA into the cytoplasm where it specifically targets mRNAs from cancer-promoting genes and silences them.

To determine the ability of this PTD-DRBD fusion protein to deliver siRNA, the researchers generated a human lung cancer reporter cell line. Using green and fluorescent protein and analyzing the cells using flow cytometry analysis, they were able to determine the magnitude of RNA inhibitory response and the percentage of cells undergoing this response. They found that the entire cellular population underwent a maximum RNAi response. Similar results were obtained in primary cells and cancer cell lines.

"We were subsequently able to introduce gene silencing proteins into a large percentage of various cell types, including T cells, endothelial cells and human embryonic stem cells," said Dowdy. "Importantly, we observed no toxicity to the cells or innate immune responses, and a minimal number of transcriptional off-target changes."

These RNAi methods can be continually tweaked to combat new mutations – a way to overcome a major problem associated with current cancer therapies. "Such therapies can't be used a second time if a cancer tumor returns, because the tumor has mutated the target gene to avoid the drug binding," said Dowdy. "But since the synthetic siRNA is designed to bind to a single mutation and only that mutation on the genome, it can be easily and rapidly changed while maintaining the delivery system – the PTD-DRBD fusion protein."

"Cancer is a complex, genetic disease that is different in every patient," Dowdy added. "This is still in early stages, but I believe the siRNA-induced RNAi approach to personalized cancer treatment is the only thing on the table."

DNA Boxes Could Deliver Drugs 6 May 2009 10:25 PM (15 years ago)

Chemistry World is reporting that Danish researchers have made a nano-sized box out of DNA that can be locked or opened in response to 'keys' made from short strands of DNA. By changing the nature or number of these keys, it should be possible to use the boxes as sensors, drug delivery systems or even molecular computers.

To make the box shape, the team took a long, circular single strand of DNA from a virus that infects bacteria called bacteriophage M13. This M13 sequence is a cheap source of single-stranded DNA and is convenient size for building with. To turn this ring of DNA into a box, the team used a computer to work out exactly the right combination of short strands of complementary DNA which could 'staple' the appropriate areas of the ring together to get the desired box shape. When they mixed the M13 strand with the 220 short 'staple strands' and heated them up for an hour, the boxes neatly self-assembled.

Kjems reveals that the group have already had some success with putting cargo inside the boxes, including enzymes and quantum dots. 'It's quite big (about 30nm) inside - it could fit virus particles or quite big enzymes and other macromolecules.' In terms of applications, Kjems can foresee three main purposes for the box: 'One is as a calculator or logic gate; the second is for controlled release, for example of drugs, in response to external stimuli; and the last is as a sensor - where the thing you are sensing causes the box to open or close and give a readout.'

The DNA origami technique is quite straightforward, Mao comments, so could be applied to all sorts of similar structures. The fact that the box can be easily opened and closed also makes it ideal for moving guest molecules around. 'I'm really looking forward to seeing what the group do next,' he adds.

MIT Technology Review also has coverage.

Deoxyribose sugar cubes: Because complementary regions of DNA like to pair up, researchers were able to design a long strand of DNA that, combined with many tiny DNA staples, would automatically assemble itself into a nano-sized box. This technique is known as DNA origami. Here, the boxes were imaged using cryo-electron tomography to confirm their cubelike structures and hollow interior.
Credit: : Ebbe S. Andersen, Aarhus University

21 pages of supplemental information from the Journal Nature article.

The abstract in the journal Nature. [Nature 459, 73-76 (7 May 2009) | doi:10.1038/nature07971; Received 9 November 2008; Accepted 6 March 2009]
Self-assembly of a nanoscale DNA box with a controllable lid

The unique structural motifs and self-recognition properties of DNA can be exploited to generate self-assembling DNA nanostructures of specific shapes using a 'bottom-up' approach1. Several assembly strategies have been developed for building complex three-dimensional (3D) DNA nanostructures. Recently, the DNA 'origami' method was used to build two-dimensional addressable DNA structures of arbitrary shape that can be used as platforms to arrange nanomaterials with high precision and specificity. A long-term goal of this field has been to construct fully addressable 3D DNA nanostructures. Here we extend the DNA origami method into three dimensions by creating an addressable DNA box 42 36 36 nm3 in size that can be opened in the presence of externally supplied DNA 'keys'. We thoroughly characterize the structure of this DNA box using cryogenic transmission electron microscopy, small-angle X-ray scattering and atomic force microscopy, and use fluorescence resonance energy transfer to optically monitor the opening of the lid. Controlled access to the interior compartment of this DNA nanocontainer could yield several interesting applications, for example as a logic sensor for multiple-sequence signals or for the controlled release of nanocargos.

FURTHER INVESTIGATION

The DNA origami design software program with documentation and tutorials is
available here: http://www.cdna.dk/origami/.

Nanodiamond drug device could transform cancer treatment 3 Oct 2008 9:13 AM (16 years ago)

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 12 Sep 2008 10:23 AM (16 years ago)

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 4 Sep 2008 10:03 AM (16 years ago)

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. 29 Aug 2008 10:24 AM (16 years ago)

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 30 Jul 2008 2:33 PM (16 years ago)

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 7 May 2008 6:17 PM (16 years ago)

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 29 Apr 2008 12:01 PM (16 years ago)

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 29 Apr 2008 11:54 AM (16 years ago)

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 18 Apr 2008 4:08 PM (17 years ago)

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 13 Apr 2008 3:16 PM (17 years ago)

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 31 Mar 2008 7:22 PM (17 years ago)

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 27 Mar 2008 8:21 PM (17 years ago)

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 21 Mar 2008 3:33 PM (17 years ago)

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 21 Mar 2008 1:50 PM (17 years ago)

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 21 Mar 2008 1:47 PM (17 years ago)

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 27 Feb 2008 3:58 PM (17 years ago)

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 27 Feb 2008 3:44 PM (17 years ago)

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 22 Jan 2008 4:05 PM (17 years ago)

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 18 Jan 2008 9:40 AM (17 years ago)

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.

Nanorobot drug delivery 10 Dec 2007 6:15 AM (17 years ago)

Adriano Cavalcanti is CEO and chairman of CAN Center for Automation in Nanobiotech. Adriano and his coleagues have proposed a nanorobot platform should enable patient pervasive monitoring, and details are given in prognosis with nanorobots application for intracranial treatments. This integrated system also points towards precise diagnosis and smart drug delivery for cancer therapy.


nanorobot for nanomedicine drug delivery


Simulated nanorobot for drug delivery

Fully operational nanorobots for biomedical instrumentation should be achieved as a result of nanobioelectronics and proteomics integration. The proposed platform should enable patient pervasive monitoring, and details are given in prognosis with nanorobots application for intracranial treatments. This integrated system also points towards precise diagnosis and smart drug delivery for cancer therapy.

The methodologies and the implemented 3D simulation described in our study served as a test bed for molecular machine prototyping. The numerical analysis and advanced simulations provided a better understanding on how nanorobots should interact inside the human body. Hence, based on such information, we have proposed the innovative hardware architecture with a nanorobot model for use in common medical applications. The nanorobot takes chemical and thermal gradient changes as interaction choices for in vivo treatments. The use of mobile phones with RF is adopted in this platform as the most effective approach for control upload, helping to interface nanorobots communication and energy supply.

The next steps in our work can be defined as follows: (a) model manufacturing with CNT-CMOS biochip integration; (b) laboratory studies for in vivo tests; and (c) commercialization. The pipeline for development in the medical sector typically requires research and efforts to get new ideas out of laboratories and into the marketplace

FURTHER READING
Nanorobot design website

They have written many papers on this work. Robert Freitas is involved in some of them.

Nanorobot architecture for medical target identification.

The nanorobot interaction with the described workspace shows how time actuation is improved based on sensor capabilities. Therefore, our work addresses the control and the architecture design for developing practical molecular machines. Advances in nanotechnology are enabling manufacturing nanosensors and actuators through nanobioelectronics and biologically inspired devices. Analysis of integrated system modeling is one important aspect for supporting nanotechnology in the fast development towards one of the most challenging new fields of science: molecular machines. The use of 3D simulation can provide interactive tools for addressing nanorobot choices on sensing, hardware architecture design, manufacturing approaches, and control methodology investigation.

Earlier work was with CMOS versions of small robots

Hardware architecture for nanorobots

Freitas' nanomedicine site

Center for Automation in Nanobiotech website

Remote-control nanoparticles deliver drugs directly into tumors 24 Nov 2007 3:01 PM (17 years ago)

MIT scientists have devised remotely controlled nanoparticles that, when pulsed with an electromagnetic field, release drugs to attack tumors.


Here, dark gray nanoparticles carry different drug payloads (one red, one green). A remotely generated five-minute pulse of a low-energy electromagnetic field releases the green drug but not the red. A five-minute pulse of a higher-energy electromagnetic field releases the red drug, which had been tethered using a DNA strand twice as long as the green tether, as measured in base pairs. Image courtesy / Bhatia/von Maltzahn, MIT. Derfus, UCSD