One Drug, Many Targets: Is This The Future?

Potential molecular targets of the anti-HIV drug nelfinavir have been identified, and may explain why the drug is also effective as a cancer therapy. Findings will be published in the open-access journal PLoS Computational Biology on 28th April 2011.
Nelfinavir is a protease inhibitor that prevents replication of the HIV virus. It has also been found to have a positive effect on a number of solid tumor types but the mechanism of how the drug worked in humans was unclear. Researchers from the University of California San Diego and the City University of New York (CUNY) combined a wide array of computational techniques to investigate the molecular mechanisms underlying nelfinavir's observed anti-cancer effect and found that there are weak interactions with a multitude of molecular targets, rather than a strong interaction with a single target.
While drug molecules are designed to bind to targeted proteins in order to achieve a therapeutic effect, small drug molecules can also attach to off-target proteins with similar binding sites. The result may be unwanted side effects or, as in the case of nelfinavir, a secondary and positive effect. Philip E. Bourne, professor of pharmacology at UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences, and his colleagues suggest that it is the collective effect of these weak interactions that leads to the clinical efficacy of nelfinavir.
The computational methods used by the researchers are a useful way of searching for potential drug targets: "Computer analysis allows us to search for other binding sites that match a particular drug-binding site - like looking for other locks that can be opened by the same key," said Lei Xie, associate professor at Hunter College, CUNY. However, it is a particularly complex route to validation of drug targets. Prof. Bourne adds "This is indeed challenging, but it is hard not to believe that this broad-based systems approach represents the future of drug discovery, at least as far as small-molecule drugs are concerned."
Funding: NIH, GM078596. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Source:Medicalnewstoday

Anatomy Of The Breast

The breast consists of a mixture of:

• Fat
• Milk glands - lobules that secrete milk during pregnancy and breastfeeding
• Mammary ducts – canals that carry milk from the lobules to the nipple openings
• Fibrous connective tissue
• Nerves
• Blood vessels
• Lymph vessels – delicate vessels that collect lymph fluid from tissues and drain it back into the bloodstream
• Small amounts of muscle tissue

In the nipple to allow it to become erect in response to sexual stimulation or breastfeeding
Around the lobules to help squeeze milk into the ducts.
Key muscles support the breasts rom behind and underneath.
Breast size and shape is unique to each woman and is determined by heredity and body size. However, breast tissue changes throughout a woman’s lifetime depending on hormonal changes.
Breasts develop at puberty as hormones stimulate the system to form and enlarge lobules and ducts. Full development can occur any time between the ages of 12 and 19.
A woman’s monthly menstrual cycle causes breast granularity to change. Swelling and tenderness of both breasts may occur during the second half of the menstrual cycle. Cysts may grow and then shrink.
During pregnancy, the lobules multiply and begin to produce milk.
When a baby is born, milk is released into the ducts for breastfeeding (lactation).
During menopause the number of lobules decreases and those remaining shrink. A larger proportion of the breast is made up of fat so breast density decreases.

Om Nanotech- Shining Star in the Indian IT Industry – First Company in India to undertake Die Testing facility

New Delhi, August 01, 2011: Om Nanotech Pvt. Ltd. the leading manufacturer, supplier and exporter of Memory Modules, Computer RAM, Pen Drives, Flash Cards, has been leading in innovation and bringing first-time technologies to India. After successfully establishing DRAM/Flash IC calibration/testing, Om Nanotech Pvt. Ltd. has now ventured into Die Testing for DRAM/Flash, which is again a First in India.
Explaining the die testing facility at Om Nanotech’s manufacturing unit, Mr. Atul Khosla, Director, Om Nanotech Pvt. Ltd. said, The Die Testing is a complex process which testing the Die before it is converted to an IC. Die is made from Wafers that are manufactured in highly complex FABS. There are only a handful of DRAM/FLASH FABs globally. Wafers are very thin disks of pure silicon on which minute circuits are etched using very nano-meter lasers. The wafer could have hundreds of Dies’ (circuits) etched in a single wafer. These wafers normally come in 8”, 10” and 12” diameter sizes, which are then cut to produce Die. Die can be perceived as the smallest unit which independently has the complete functionality desired from the IC. This Die is subsequently sent for packaging which involves encapsulating the Die with special plastics (black colored body), after connecting the connector pads on the Die to external terminals using extremely thin gold wires. Die probing requires specialized probes that need handling under a microscope.”
“Along with its contribution in the manufacturing of memory products, we are proud that our manufacturing unit has also resulted as a source of employment for a number of people,” added Mr. Khosla.
At the die testing facility, Om Nanotech conducts die probing which ensures that the Die has no inherent problems that may result in low yields after the Die has been packaged into IC . Obviously, the Die that is faulty, results in a faulty packaged IC, leading to wastage of investment on the packaging itself
To master this technology, Om Nanotech Pvt. Ltd. Organized specialized overseas training. The team got extended training and successfully replicated Die Testing at it’s Noida facility, without any further assistance from any external party. Om Nanotech Pvt. Ltd. has currently established a Die Testing capacity of 9 million die per annum.

Alcohol's effects on gene expression in the central nervous system

Alcohol's primary target is the central nervous system (CNS), where it influences neurotransmission to produce intoxication. Scientists can now use microarray technology to study brain function gene by gene. Symposium proceedings published in the February issue of Alcoholism: Clinical & Experimental Research address the effects of alcohol on what is called "gene expression" in the CNS regions of animal models.
"All of our cells have exactly the same deoxyribonucleic acid (DNA), which means they all have the same genes," explained William J. McBride, symposium organizer and professor of neurobiology at the Indiana University School of Medicine. "The reason that different cells can appear and work so differently with the same genes – giving us, for example, unique eyes, skin, or hair – is that only some genes are used or 'turned on' in each cell. This is called gene expression."
McBride said that researchers now know that alcohol can change gene expression in the brain, and that these changes are likely responsible for many of the 'symptoms' of addiction, such as tolerance, physical dependence, and craving, as well as the 'consequences' of alcoholism, such as brain damage.
"The challenge has been to find out which genes – out of more than 50,000 – are turned on or off in the brains of alcoholics," he said. "Microarray studies – the examination of a small glass microscope slide that has thousands of different DNA samples attached to it – that are applied to brain function are just beginning in the field of alcoholism. Several years ago, it was impossible to analyze more than a handful of these genes, however, microarray technology has changed that."
Symposium speakers at the June 2004 Research Society on Alcoholism meeting in Vancouver, B.C. presented the following findings from recent studies that used genetic animal models:


# Gene expression profiling in the nucleus accumbens, prefrontal cortex, and ventral tegmental areas show that distinct biological pathways are associated with alcohol's action in specific brain regions and certain mouse strains.


"We were able to use gene expression profiling to determine that alcohol produces multiple effects on different biological processes," said McBride, "and that these changes are different in several brain regions which may be involved in alcohol addiction."


# Researchers have identified individual genes and gene networks that may play an important role in determining the behavioral responses to alcohol as well as possibly influencing drinking behavior.


"Thus far, genes that appear to be responsive to alcohol include genes involved in the intracellular signaling process (which can alter how the neuron functions), neuropeptide signaling (which modulates nerve cell activity), and myelin structure (which is needed for communication between nerve cells)," said McBride. "Gene expression profiling has also been used to identify chromosomes and chromosomal regions that influence alcohol drinking and response to alcohol."


# Intracranial self-administration of ethanol into the posterior ventral tegmental area (VTA) of alcohol-preferring rats produced results suggesting that the reinforcing effects of alcohol are activating VTA dopamine neurons and producing changes in synaptic connections that resemble those that occur in memory and learning.


"Learning and memory require enhanced synaptic function between neurons," explained McBride. "Enhanced synaptic function is characterized by increased formation of synaptic proteins. The stimulation of VTA dopamine neurons by alcohol increases the expression of genes involved in the synthesis of synaptic proteins in target regions of the VTA. In short, these results suggest that alcohol can produce changes in the brain reward system that can further increase the rewarding effects of alcohol."


# Microarray techniques confirmed earlier reports indicating that chronic alcohol exposure/withdrawal differentially alters gene expression in the prefrontal cortex of mice. More than 300 genes were found to be altered by acute alcohol treatment.


"The prefrontal cortex is involved in motivated behaviors," noted McBride. "Studies with humans indicate that this brain region is sensitive to the effects of heavy alcohol drinking and repeated withdrawals. The microarray technique provides insight into cellular changes that occur over time with chronic alcohol drinking and repeated withdrawals."


Collectively speaking, added McBride, findings presented at the symposium demonstrate the quantitative and qualitative applications of microarrays to studying the genetic and biological bases of alcoholism and alcohol abuse within discrete brain regions.
"For researchers, microarray technology has the potential of studying the genetic and biological bases of alcohol's rewarding effects, sensitivity to the effects of alcohol, development of tolerance to the effects of alcohol, development of alcohol dependence, and alcohol withdrawal severity," he said. "For the average reader, knowing which genetic profiles might contribute to excessive alcohol drinking could be used to identify risk factors that contribute to alcoholism and alcohol abuse, and could aid in the development of selective treatment strategies for different subgroups of alcoholics."
McBride added that, despite recent advances, researchers need further developments in microarray technologies and bioinformatic approaches to better understand the complex neurobiological mechanisms underlying alcohol addiction. "Future research will need to determine changes in gene expression in very discrete neuronal pathways that may be involved in mediating the effects of alcohol that lead to addiction," he said. "Future studies will also require the integrative efforts of many investigators working with different animal models in order to identify the multiple genetic factors that contribute to the risk for alcoholism and alcohol abuse."

Source : Indiana University School of Medicine

Memories may skew visual perception

Taking a trip down memory lane while you are driving could land you in a roadside ditch, new research indicates. Vanderbilt University psychologists have found that our visual perception can be contaminated by memories of what we have recently seen, impairing our ability to properly understand and act on what we are currently seeing.


"This study shows that holding the memory of a visual event in our mind for a short period of time can 'contaminate' visual perception during the time that we're remembering," Randolph Blake, study co-author and Centennial Professor of Psychology, said.


"Our study represents the first conclusive evidence for such contamination, and the results strongly suggest that remembering and perceiving engage at least some of the same brain areas."


The study, led by research associate Min-Suk Kang, was recently published in the journal Psychonomic Bulletin & Review.


"There are numerous instances where we engage in visually guided activities, such as driving, while rehashing visual events in our mind's eye. Common sense tells us that this mental replay is harmless in that it does not interfere with our ability to register and react to objects within our visual field," Kang and his co-authors wrote. "Evidently, however, that is not always true when the contents of our working memories overlap with the contents of our perceptual world."


In this study, the researchers used a visual illusion called motion repulsion to learn whether information held in working memory affects perception. This illusion is produced when two sets of moving dots are superimposed, with dots in one set moving in a different direction from those in the other set. Under these conditions, people tend to misperceive the actual directions of motion, and perceive a larger difference between the two sets of motions than actually exists.


Ordinarily this illusion is produced by having people view both sets of motion at the same time. Kang and colleagues set out to determine if the illusion would occur when one set of motions, rather than being physically present, was held in working memory.


In the experiment, participants were shown a random pattern of dots and were asked to remember the direction in which the dots were moving. They were then were shown a second pattern of moving dots. They were asked to report on the direction of second dots' movement.


The research subjects' reports of the second dots' movement was exaggerated and influenced by what they had previously seen. If they were first shown dots moving in one direction and later shown dots moving in a slightly counterclockwise direction relative to the first presented dots, they reported the counterclockwise movement to be more dramatic than it had actually been.


"We find that observers misperceive the actual direction of motion of a single motion stimulus if, while viewing that stimulus, they are holding a different motion direction in visual working memory," the authors wrote.


The results provide further support for previous findings by Vanderbilt researchers Frank Tong and Stephanie Harrison that the contents of working memory may be represented in early visual areas in the brain, including the primary visual cortex, that were previously thought to play no role in higher cognitive functions such as memory.


"Our findings provide compelling evidence that visual working memory representations directly interact with the same neural mechanisms involved in processing basic sensory events," Kang and his colleagues wrote.

Source : Vanderbilt University

Stem cell study could aid motor neurone disease research

Scientists have discovered a new way to generate human motor nerve cells in a development that will help research into motor neurone disease.



A team from the Universities of Edinburgh, Cambridge and Cardiff has created a range of motor neurons – nerves cells that send messages from the brain and spine to other parts of the body – from human embryonic stem cells in the laboratory.


It is the first time that researchers have been able to generate a variety of human motor neurons, which differ in their make-up and display properties depending on where they are located in the spinal cord.


The research, published in the journal Nature Communications, could help scientists better understand motor neurone disease. The process will enable scientists to create different types of motor neurons and study why some are more vulnerable to disease than others.


Motor neurons control muscle activity such as speaking, walking, swallowing and breathing. However, in motor neurone disease – a progressive and ultimately fatal disorder – these cells break down leading to paralysis, difficulty speaking, breathing and swallowing.


Previously scientists had only been able to generate one particular kind of motor neuron, which they did by using retinoic acid, a vitamin A derivative.


In the latest study, scientists have found a way to generate a wider range of motor neurons using a new process without retinoic acid.


Professor Siddharthan Chandran, Director of the Euan MacDonald Centre for Motor Neurone Disease Research at the University of Edinburgh, said: "Motor neurons differ in their make-up, so understanding why some are more vulnerable than others to disease is important for developing treatment for this devastating condition."


Dr Rickie Patani, of the University of Cambridge, said: "Although motor neurons are often considered as a single group, they represent a diverse collection of neuronal subtypes. The ability to create a range of different motor neurons is a key step in understanding the basis of selective subtype vulnerability in conditions such as motor neuron disease and spinal muscular atrophy."

Source : University of Edinburgh

Bodyguard for the brain

Humans are getting older and older, and the number of people with dementia is increasing. The factors controlling degeneration of the brain are still mostly unknown. However, researchers assume that factors such as stress, accumulation of toxic waste products as well as inflammation accelerate aging. But, vice versa, there are also mechanisms that can - like a bodyguard - protect the brain from degenerating, or repair defective structures.


Researchers from the Universities of Bonn and Mainz have now discovered a hitherto unknown function of the cannabinoid-1 receptor (CB1). A receptor is a protein that can bind to other substances, triggering a chain of signals. Cannabinoids such as THC – the active agent in cannabis sativa – and endocannabinoids formed by the body bind to the CB1 receptors. The existence of this receptor is also the reason for the intoxicating effect of hashish and marijuana.


Not only does the CB1 receptor have an addictive potential, but it also plays a role in the degeneration of the brain. "If we switch off the receptor using gene technology, mouse brains age much faster," said Önder Albayram, principal author of the publication and a doctoral student on the team of Professor Dr. Andreas Zimmer from the Institut für Molekulare Psychiatrie at the University of Bonn. "This means that the CB1 signal system has a protective effect for nerve cells."


Mice prove their brain power in a pool


The researchers studied mice in different age categories – young six week old animals, middle-aged ones at five months, and those of an advanced age at 12 months. The animals had to master various tasks – first, they had to find a submerged platform in the pool. Once the mice knew its location, the platform was moved, and the animals had to find it again. This was how the researchers tested how well the rodents learned and remembered.


The animals in which the CB1 receptor had been switched off (the knock-out mice) clearly differed from their kind. "The knock-out mice showed clearly diminished learning and memory capacity," said Privatdozent Dr. Andras Bilkei-Gorzo from Professor Zimmer's team, who led the study. So, animals that did not have the receptor were less successful in their search for the platform. "In addition, they showed a clear loss of nerve cells in the hippocampus," he explained further. This part of the brain is the central area for forming and storing information. In addition, the researchers found inflammation processes in the brain. As the mice advanced in age, the degenerative processes became increasingly noticeable.


Amazing parallels with the human brain


The animals with the intact CB1 receptor, to the contrary, did clearly better with regard to their learning and memory capabilities, as well as the health of their nerve cells. "The root cause of aging is one of the secrets of life," commented Albayram. This study has begun to open the door to solving this enigma. The processes in the mouse brains have a surprising number of parallels with age-related changes in human brains. So, the endocannabinoid system may also present a protective mechanism in the aging of the human brain.


The principal author cautioned, "This will require additional research." The scientists would like to better understand the mechanism by which CB1 receptors protect the brain from inflammation processes. And based on these signal chains, it might then be possible to develop substances for new therapies.


Source : University of Bonn

1 tiny electron could be key to furture drugs that repair sunburn

Researchers who have been working for nearly a decade to piece together the process by which an enzyme repairs sun-damaged DNA have finally witnessed the entire process in full detail in the laboratory.



What they saw contradicts fundamental notions of how key biological molecules break up during the repair of sunburn – and that knowledge could someday lead to drugs or even lotions that could heal sunburn in humans.


In the Proceedings of the National Academy of Sciences, the Ohio State University researchers and their colleagues confirm what was previously known about the enzyme photolyase, which is naturally produced in the cells of plants and some animals – though not in mammals, including humans. The enzyme repairs DNA by tearing open the misshapen, damaged area of the DNA in two places and reforming it into its original, undamaged shape.


But the enzyme doesn't break up the injury in both places at once, as researchers previously suspected from theoretical calculations. Instead, it's a two-step process that sends an electron through the DNA molecule in a circuitous route from one breakup site to the other, the new study revealed.


The research was led by Dongping Zhong, the Robert Smith Professor of Physics and professor in the departments of chemistry and biochemistry at Ohio State.


Zhong and his team literally shed light on the process in the laboratory using a laser with a kind of strobe effect to take super-fast measurements of the enzyme in action.


What they saw surprised them.


The two key chemical bond sites broke up one after the other – the first in just a few trillionths of a second, and the next after a 90-trillionths-of-a-second delay.


The reason? The single electron ejected from the enzyme – the source of energy for the breakup – took time and energy to travel from one bond site to the other, tunneling along the outer edge of the ring-shaped damage site.


Also, it turns out that for the enzyme taking the long way around is the most efficient way for the electron to do the job, Zhong explained.


"The enzyme needs to inject an electron into damaged DNA -- but how?" he said. "There are two pathways. One is direct jump from the enzyme across the ring from one side to the other, which is a short distance. But instead the electron takes the scenic route. We found that along the way, there is another molecule that acts as a bridge to speed the electron flow, and in this way, the long route actually takes less time."


Now that they have revealed how the enzyme actually works, the researchers hope that others can use this knowledge to create synthetic photolyase for drugs or even lotions that can repair DNA.


Ultraviolet (UV) light damages DNA by exciting the atoms in the DNA molecule, causing accidental bonds to form between the atoms. The bond is called a photo-lesion, and can lead to a kind of molecular injury called a dimer. Dimers prevent DNA from replicating properly, and cause genetic mutations that lead to diseases such as cancer.


The dimer in question is called a cyclobutane pyrimidine dimer, and it is shaped like a ring that juts out from the side of the DNA.


For those organisms lucky enough to have photolyase in their cells, the enzyme absorbs energy from visible light – specifically, blue light – to shoot an electron into the cyclobutane ring to break it up. The result is a perfectly repaired strand of DNA.


That's why photolyase-carrying insects, fish, birds, amphibians, marsupials, and even bacteria, viruses and yeast are all protected from cancer-causing UV rays from the sun. Meanwhile, humans and all other mammals lack the enzyme, and so are particularly vulnerable to UV.


A synthetic form of photolyase could make up for our enzymatic shortfall. But Zhong's group will leave that discovery to other researchers; they have now set their sights on photoreceptors – the proteins that absorb light and initiate signaling for many biological functions.

Source : Ohio State University

Artificial lung mimics real organ's design and efficiency

An artificial lung built by Cleveland researchers has reached efficiencies akin to the genuine organ, using air – not pure oxygen as current man-made lungs require - for the source of the essential element.



Use in humans is still years away, but for the 200 million lung disease sufferers worldwide, the device is a major step toward creating an easily portable and implantable artificial lung, said Joe Potkay, a research assistant professor in electrical engineering and computer science at Case Western Reserve University. Potkay is the lead author of the paper describing the device and research, in the journal Lab on a Chip.


The scientists built the prototype device by following the natural lung's design and tiny dimensions. The artificial lung is filled with breathable silicone rubber versions of blood vessels that branch down to a diameter less than one-fourth the diameter of human hair.


"Based on current device performance, we estimate that a unit that could be used in humans would be about 6 inches by 6 inches by 4 inches tall, or about the volume of the human lung. In addition, the device could be driven by the heart and would not require a mechanical pump," Potkay said.


Current artificial lung systems require heavy tanks of oxygen, limiting their portability. Due to their inefficient oxygen exchange, they can be used only on patients at rest, and not while active. And, the lifetime of the system is measured in days.


The Cleveland researchers focused first on improving efficiency and portability.


Potkay, who specializes in micro- and nano-technology, worked with Brian Cmolik, MD, an assistant clinical professor at Case Western Reserve School of Medicine and researcher at the Advanced Platform Technology Center and the Cardiothoracic Surgery department at the Louis Stokes Cleveland VA Medical Center. Michael Magnetta and Abigail Vinson, biomedical engineers and third-year students at Case Western Reserve University School of Medicine, joined the team and helped develop the prototype during the past two years.


The researchers first built a mould with miniature features and then layered on a liquid silicone rubber that solidified into artificial capillaries and alveoli, and separated the air and blood channels with a gas diffusion membrane.


By making the parts on the same scale as the natural lung, the team was able to create a very large surface-area-to-volume ratio and shrink the distances for gas diffusion compared to the current state of the art. Tests using pig blood show oxygen exchange efficiency is three to five times better, which enables them to use plain air instead of pure oxygen as the ventilating gas.


Potkay's team is now collaborating with researchers from Case Western Reserve's departments of biomedical engineering and chemical engineering to develop a coating to prevent clogging in the narrow artificial capillaries and on construction techniques needed to build a durable artificial lung large enough to test in rodent models of lung disease.


Within a decade, the group expects to have human-scale artificial lungs in use in clinical trials.


They envision patients would tap into the devices while allowing their own diseased lungs to heal, or maybe implant one as a bridge while awaiting a lung transplant – a wait that lasts, on average, more than a year.


Source : Case Western Reserve University

potentials of nanotechnology

Back in September 2004, the US National Cancer Institute (NCI) launched the Alliance for Nanotechnology in Cancer to stimulate and coordinate research in biology, engineering and materials science to push cancer nanotechnology forward. Just over 2 years on, such research is attracting increasing attention: in a round-up of last year's breakthroughs in the burgeoning field of nanotechnology from Forbes magazine, anticancer nanoparticles featured in the top five.

Nanotechnology is being applied to cancer in two broad areas: the development of nanovectors, such as nanoparticles, which can be loaded with drugs or imaging agents and then targeted to tumours, and high-throughput nanosensor devices for detecting the biological signatures of cancer. Combined, such technologies could lead to earlier diagnosis and better treatment for patients with cancer.

Spearheading efforts to expedite the clinical application of these technologies, the NCI currently funds eight Centers of Cancer Nanotechnology Excellence (CCNE) in the United States, in addition to 12 other smaller programmes. "We've pulled most of the key players in medical nanotechnology into this programme, and we're spending about US$35–40 million a year on these approaches," says Piotr Grodzinski, Director of the NCI Alliance. The NCI Alliance is actively pursuing both the therapeutic and diagnostics aspects of cancer nanotechnology with follow-up programmes in sight. Grodzinski hopes that by then nanotechnology will have matured into a clinically useful approach.


Robert Langer's team have shown the potential of targeted nanoparticles to deliver anticancer drugs.
Early signs are promising. The research highlighted in the Forbes list was conducted by a team led by Robert Langer, a chemical engineer who is Institute Professor at the Massachusetts Institute of Technology (MIT), USA, and also one of the two principal investigators for the MIT–Harvard CCNE. Langer, with Omid Farokhzad, Assistant Professor of Anaesthesia at Brigham and Women's Hospital, Boston, USA, and colleagues, uses polymeric nanoparticles coated with aptamers — RNA-based targeting moieties — to guide them towards the tumour, where they bind, enter the cells and then dissolve to spill out their contents — the anticancer drug docetaxel. The nanoparticles are also coated with polyethylene glycol (PEG) to aid their safe passage through the bloodstream and into the tumour cells. A single injection of such nanoparticles coated with aptamers that bind to prostate-membrane-specific antigen eradicated tumours in a mouse model of prostate cancer (PNAS 103, 6315–6320; 2006). "Extensive animal models show that this approach is both safe and efficacious," says Langer.

One of the key challenges in creating effective nanoparticles is targeting them to appropriate tissues and cells. Although biological targeting using aptamers or antibodies on the surface of nanoparticles is one popular option, other researchers are beginning to exploit the physical characteristics of the particles to guide them to desired locations. "The size, shape, physical properties, density and charge all affect how particles travel through the body, and whether or not they will cross biological membranes," says Mauro Ferrari, a professor of nanotechnology at the University of Texas Health Science Center, the M.D. Anderson Cancer Center, and Rice University in Houston, USA. His work shows that biological barriers such as the vascular wall dominate the distribution of injected nanoparticles in the body, even for particles that are decorated with exquisite biological recognition moieties. A judicious choice of size and shape of a nanovector particle can enhance by orders of magnitude the amount of drug delivered to the target lesion site. "I believe that the era of 'rational design' of nanoparticles has arrived, and that optimal design will occur based on principles of engineering and physics," Ferrari says.


Joseph DeSimone, professor of chemistry and chemical engineering at the University of North Carolina at Chapel Hill, USA, is putting these principles into practice. DeSimone has adapted fabrication technologies from the electronics industry to produce shape-specific organic nanoparticles. "We basically make moulds out of a really low-surface-energy fluoropolymer that allows us to synthesize truly engineered particles with desired characteristics," says DeSimone. DeSimone's engineered process allows the precise control over particle size (20 nm to >100 m), particle shape (spheres, cylinders, discs, toroidal), particle composition (organic or inorganic, solid or porous), particle cargo (hydrophilic or hydrophobic therapeutics, biologicals, imaging agents), particle compliance (stiff, deformable) and particle surface properties (Avidin–biotin complexes, targeting peptides, antibodies, aptamers, PEG chains).

Nanoparticles are not the only way to encapsulate a drug or imaging agent into a small carrier, but DeSimone suggests that the nanotechnology approach offers crucial advantages. "With liposomes [which have previously been used to deliver drugs] you kinetically trap what cargo molecule you can, but you can't modify the amount that gets trapped," says DeSimone. "Our moulds enable us to make organic particles loaded with therapeutic cargoes at any amount — 5%, 20% or whatever we want."

DeSimone is also taking a cue from naturally occurring particles, such as red blood cells, to produce compliant nanoparticles that can deform to pass across biological barriers such as sinusoids in the spleen or the blood–brain barrier. "The ability to get through these barriers and the flow characteristics of particles — whether they flow through the centre of a capillary or along cell walls — are dictated by size, shape, surface chemistry and compliance," says DeSimone.

Liquidia Technologies Inc., based in Morrisville, North Carolina, USA, was spun-off from DeSimone's laboratory a few years ago to develop this technology platform. Right now, the company is working on feasibility studies, as well as research collaborations with some large pharmaceutical and medical device companies. "These feasibility studies will run through the rest of 2007, with the goal of focused out-licensing and joint product development deals within the next 18 months," says Luke Roush, Vice President of Business Development at Liquidia. "These studies will also provide data that will validate application of our technology platform, and help us advance knowledge about how to apply it in areas of clinical need," adds Roush.

The synergy between the therapeutic and diagnostic/monitoring applications of nanotechnology could be particularly potent. Linda Molnar, a programme officer at the NCI Alliance, sees a future in which new imaging agents, new diagnostic chips and new targeted therapies come together to facilitate a form of personalized medicine in which early and more accurate detection leads to rapid initiation of treatment, followed by diagnostic tests to see whether the patient is responding. If they do, good; if not, another therapy can be tried and the process repeated — what Molnar refers to as real-time therapeutic monitoring. "The sooner you can detect the cancer and start treatment, and know that you're treating that patient with a therapy that they respond to, the better," says Molnar. "That's why people are excited, and why people at the NCI have made such a large investment in nanotechnology for cancer."

As novel nanomedicine products move from the laboratory to the clinic, the issue of regulatory approval of these new technologies will come to the fore. In many cases these products will combine established drugs with materials already used in FDA-approved therapies, and no special provisions are in place to deal with nanomedicine at present. An FDA spokesperson said, "All nanotechnology applications will at this point fall within the existing framework for review of all products submitted to CDER [Center for Drug Evaluation and Research]; [however], CDER is discussing how nanotech products may be treated differently, if necessary."

role of nanotechnology in biology

Nanotechnology refers to the interactions of cellular and molecular components and engineered materials—typically clusters of atoms, molecules, and molecular fragments—at the most elemental level of biology. Such nanoscale objects— typically, though not exclusively, with dimensions smaller than 100 nanometers—can be useful by themselves or as part of larger devices containing multiple nanoscale objects. At the nanoscale, the physical, chemical, and biological properties of materials differ fundamentally and often noninvasive access to the interior of a living cell affords the opportunity for unprecedented gains on both clinical and basic research frontiers.
unexpectedly from those of the corresponding bulk material because the quantum mechanical properties of atomic interactions are influenced by material variations on the nanometer scale. In fact, by creating nanometer-scale structures, it is possible to control fundamental characteristics of a material, including its melting point, magnetic properties, and even color, without changing the material’s chemical composition.

Nanoscale devices and nanoscale components of larger devices are of the same size as biological entities. They are smaller than human cells (10,000 to 20,000 nanometers in diameter) and organelles and similar in size to large biological macromolecules such as enzymes and receptors— hemoglobin, for example, is approximately 5 nm in diameter, while the lipid bilayer surrounding cells is on the order of 6 nm thick. Nanoscale devices smaller than 50 nanometers can easily enter most cells, while those smaller than 20 nanometers can transit out of blood vessels. As a result, nanoscale devices can readily interact with biomolecules on both the cell surface and within the cell, often in ways that do not alter the behavior and biochemical properties
of those molecules. From a scientific viewpoint, the actual construction and characterization of nanoscale devices may contribute to understanding carcinogenesis.
Noninvasive access to the interior of a living cell affords the opportunity for unprecedented gains on both clinical and basic research frontiers. The ability to simultaneously interact with multiple critical proteins and nucleic acids at the molecular scale should provide better understanding of the complex regulatory and signaling networks that govern the behavior of cells in their normal state and as they undergo malignant transformation.

Nanotechnology provides a platform for integrating efforts in proteomics with other scientific investigations into the molecular nature of cancer by giving researchers the opportunity to simultaneously measure gene and protein expression, recognize specific protein structures and structural domains, and follow protein transport among different cellular compartments. Similarly, nanoscale devices are already proving that they can deliver therapeutic agents that can act where they are likely to be most effective, that is, within the cell or even within specific organelles. Yet despite their small size, nanoscale devices can also hold tens of thousands of small molecules, such as a contrast agent or a multicomponent diagnostic system capable of assaying a cell’s metabolic state, creating the opportunity for unmatched sensitivity in detecting cancer in its earliest stages. For example, current approaches may link a monoclonal antibody to a single molecule of an MRI contrast agent, requiring that many hundreds or thousands of this construct reach and bind to a targeted cancer cell in order to create a strong enough signal to be detected via MRI. Now imagine the same cancer-homing monoclonal antibody attached to a nanoparticle that contains tens of thousands of the same contrast agent—if even one such construct reaches and binds to a cancer cell, it would be detectable.

FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR

Human lung adenocarcinomas with activating mutations in EGFR (epidermal growth factor receptor) often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs), but the magnitude of tumour regression is variable and transient1, 2. This heterogeneity in treatment response could result from genetic modifiers that regulate the degree to which tumour cells are dependent on mutant EGFR. Through a pooled RNA interference screen, we show that knockdown of FAS and several components of the NF-κB pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-κB through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respectively), or silencing of IκB (also known as NFKBIA), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-κB enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-κB inhibitor IκB predicted for improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-κB as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provide insight into the mechanisms by which tumour cells escape from oncogene dependence.