New disease-fighting nanoparticles look like miniature pastries

July 29, 2008
By Gwen Ericson

-- 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 are an important addition to the stock of diagnostic and disease-fighting nanoparticles developed by researchers in the Consortium for Translational Research in Advanced Imaging and Nanomedicine (C-TRAIN) at Washington University School of Medicine in St. Louis. C-TRAIN's "smart" nanoparticles can deliver drugs and imaging agents directly to the site of tumors and plaques.

The new nanobialys weren't cooked up for their appealing shape — that's a natural result of the manufacturing process. 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."

The bulk of a nanobialy is a synthetic polymer that can accept a variety of medical, imaging or targeting components. In the July 2008 issue of the Journal of the American Chemical Society the researchers report that targeted manganese-carrying nanobialys readily attached themselves to fibrin molecules, which are found in atherosclerotic plaques and blood clots. Laboratory-made clots then glowed brightly in MRI scans. They also showed that the nanobialys could carry both water-soluble and insoluble drugs.

Pan, who is a research instructor in medicine, played a leading role in the creation of nanobialys and chose the particles' name. "When we looked at the particles with an electron microscope, we saw they are round and flat, with a dimple in the center, like red blood cells, but also a little irregular, like bagels," he says. "I came across the word bialy, which is a Polish roll like a bagel without a hole that can be made with different toppings. So I called the particles nanobialys."

Pan is one of a group of researchers headed by Gregory M. Lanza, M.D., Ph.D., and Samuel A. Wickline, M.D. Lanza is an associate professor of medicine and biomedical engineering. Wickline is a professor of medicine, physics, biomedical engineering and cell biology and physiology. Lanza and Wickline are Washington University cardiologists at Barnes-Jewish Hospital.

Nanoparticles can be a more effective way to administer medications and imaging contrast agents because they are targeted, packaged units — drugs and imaging agents stay on the nanoparticles, which can be made to concentrate at a specific site in the body.

In animal studies, the research group has shown that their original, spherical nanoparticles can carry therapeutic compounds to tumors and atherosclerotic plaques. These nanoparticles also can hold thousands of molecules of gadolinium, which allows the researchers to use standard MRI scanning equipment to see where the nanoparticles congregate. The scans can then detect the size of lesions as well as the effect of drugs delivered by the nanoparticles.

But gadolinium has recently been linked to nephrogenic systemic fibrosis (NSF). First described in 2000, NSF is an unusual progressive, incurable disease seen in about 3 percent of patients with severe kidney disease who have had MRI scans using gadolinium. In NSF, collagen accumulates in tissues causing skin hardening and thickening, joint stiffening that can lead to physical disability, and disorders of the liver, lungs, muscles and heart.

"Even though it seems that gadolinium affects only those with severe renal failure, physicians have decided not to use gadolinium even in those with moderate renal failure," Lanza says. "A lot of patients with diabetes or hypertension develop renal failure, so that decision potentially affects many people. Our goal has always been that our nanoparticle technology should be able to help everyone. And with a growing number of people having diabetes and related cardiovascular problems, we knew we needed to find a substitute for gadolinium-based particles — nanobialys are our first step in that direction."

The researchers will continue to adapt the nanobialys for a variety of medicinal applications and work to develop other types of nanoparticles so that they can supply a wide range of medical needs.

"We're not sitting in the lab generating nanoparticles and then looking for what they could be used for," Lanza says. "We see a medical problem and ask what kind of particle might overcome it and then try to create it."

---

Pan D, Caruthers SD, Hu G, Senpan A, Scott MJ, Gaffney PJ, Wickline SA, Lanza GM. Ligand-directed nanobialys as theranostic agent for drug delivery and manganese-based magnetic resonance imaging of vascular targets. Journal of the American Chemical Society 2008 Jul 23;130(29):9186-7.

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New structural information may help stop the flu

By Yun Xie | Published: July 29, 2008 - 10:47AM CT

Influenza A virus: H5N1.

The Influenza A virus population contains variants and subtypes that have the potential to spread virulently across the globe, including H5N1. A strain of H5N1 is behind the avian flu, which kills over 50 percent of the humans who are infected with it. H5N1 has the potential of mutating to increase its transmission efficiency among humans, making it a major concern for world health.

It is known that there are three subunits (PB1, PB2 and PA) in an Influenza A protein complex that are essential for its replication. The structures of these subunits, however, were not well understood. Thus, it was impossible to create drugs that inhibit their function. Currently, most drugs either target major antigens at the surface of the virus or specific proteins like a proton channel. Antigens and proteins vary among different types of Influenza A, so it is difficult to find drugs that work on all of them and mutations that slightly alter a protein or antigen can easily make drugs useless. Knowing the structures of the Influenza A subunits would open new avenues for drug design.

The binding site of PA(green) and PB1(orange).

In an early release paper that will appear in Nature, scientists from Japan presented the crystal structures of two large fragments of subunits PA and PB1 bound to one another. The binding of PA to PB1 is vital for viral replication and RNA polymerase activity. From the structure, the authors discovered that this crucial interaction comes from an array of hydrogen bonds and hydrophobic interfaces at the binding site. The binding sites that link PA and PB1 are highly conserved, which means that they are very similar for most variants and subtypes of Influenza A. It also means that mutations are less likely to occur in this site.

Because of these features, drugs that can bind and disrupt the interaction of PA and PB1 are likely to be effective against many viral strains and will be less likely to see the virus evolve a resistance to them. The authors' solved structures will serve as a valuable reference point for future drug design.

Nature, 2008. DOI: doi:10.1038/nature07225

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Flexible Display Center redefines ultrathin display process

The Flexible Display Center at Arizona State University has developed a new process for manufacturing high-performance flexible displays on transparent plastic.

FDC researchers, working with industrial partners DuPont Teijin Films and E Ink Corp., have developed a method for making high-performance amorphous silicon thin film transistors on planarized Teonex® PEN films. The FDC team integrated 3.8-in. QVGA arrays of these transistors with Vizplex-100™ imaging layer film from E Ink to fabricate glass-free high-performance flexible electrophoretic displays that are only 15 mils (375 micrometers) thick.

The displays are quite rugged and readily withstand severe vibration and impact tests performed at industry partner General Dynamics’ labs. To download video highlights of these tests go to http://flexdisplay.asu.edu/Flex-display-test_revB.wmv.

The FDC process uses a proprietary technique for temporarily bonding the planarized Teonex PEN film (from DuPont Teijin) to a rigid carrier using a specially developed adhesive. Amorphous silicon circuits then are fabricated with conventional flat panel display manufacturing equipment. Despite exposure of the bonded film to temperatures as high as 200 C (392 F) during the fabrication process, essentially no plastic substrate distortion is observed. The film bearing the completed transistor arrays is removed from the carrier using a mechanical force that is gentle enough to permit automation of the process.

“Most of the technology development in our pilot line environment is realized through steady improvements over several cycles of learning,” said Greg Raupp, director of FDC. “In this case, integrated learning came together as we viewed the entire flexible substrate system of carrier, adhesive, substrate, planarization and associated process protocols to point to a directed solution that yielded a dramatic technical advance.”

The FDC thin film transistors are produced using the highest semiconductor and gate-dielectric deposition temperatures reported for a process on Teonex PEN. The higher temperatures permit the fabrication of transistors with higher on-off ratio, better sub-threshold slope, and – most importantly – greater bias-stress stability. These performance characteristics translate directly into higher pixel densities for enhanced display resolution and an enlarged number of grey levels for improved image quality.

The ability to produce high quality arrays of thin film transistors with low defects is aided by the use of DTF’s planarized Teonex PEN, which has been developed to meet the needs of demanding display applications. The temporarily bonded Teonex PEN with its newly developed planarization coating provides a surface smooth enough and sufficiently defect-free to enable the fabrication of micrometer-scale electronics.

Development of methods for the handling of mechanically flexible substrates such as Teonex PEN in automated manufacturing equipment has been a significant challenge to creating practical and economical processes for flexible displays and electronics. The FDC advance in temporarily bonding plastic films to a carrier is a significant move forward for advancing engineering prototypes of flexible displays to commercial manufacturing.

Skip Derra, skip.derra@asu.edu

480-965-4823

Media Relations

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Nano-inks could advance printed electronics

R. Colin Johnson
EE Times
(07/28/2008 10:48 AM EDT)

PORTLAND, Ore. — Nano-inks for aerosol printing of electronics circuitry are being jointly developed by Applied Nanotech Inc. and Optomec for its M3D aerosol jet printer.

Optomec's jet printer transfers metallic, semiconducting and insulating inks onto any shaped substrate. Aerosol Jet printing like ink-jet printing can reproduce electronic circuits on inexpensive flexible polymer films.

Optomec's printer is designed for rapid prototyping of new devices and short production runs, but printable electronics is also poised to debut in consumer electronics devices later this year, according to IDTechEx Ltd. (Cambridge, Mass.) Printed electronics applications include patterning circuit boards, solar panels, on-battery testers, RFID tags, interconnection planes and other flexible electronics.

Most ink-jet printing is currently done with silver inks, which are expensive compared to copper nano-inks announced by Applied Nanotech (Austin, Texas) and Optomec (Albuquerque, N.M.). Current copper inks copper flakes over 250 nanometers in size, requiring 424-degree F annealing. Applied Nanotech said its copper nanoparticles 10 to 20 nanometers and can be deposited at annealing temperatures below 212 degrees F.

The Optomec printer's minimum feature size of 10 microns prompted it to partner with Applied Nanotech to optimize its ultra-small-particle nano-inks for the M3D, which uses a finer nozzle configuration than ink-jet printers. Optomec also employed an aerodynamic flow guidance deposition head which can be focused to a virtual nozzle size of 10 microns. Since the deposition head is over 5 millimeters away from the substrate, it allows 3-D surfaces to be "painted" with electronic circuitry.

Applied Nanotech said it is also developing other nano-inks based on other nanoparticles formulations, including carbon nanotubes.

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INOVIO - INO

Since I just bought some INO I figured I should spell out why I bought and what I expect.

It all centers around this VGX merger that is now proposed and underway. Inovio has an electroporation device which injects a vaccine into humans. VGX has the DNA vaccine which in mouse studies worked to provide 100% immunity against highly pathogenic H5N1 - avian flu:

1)
Inovio/VGX merger to expedite DNA vaccine development

By Gareth Macdonald

09-Jul-2008 - Electroporation specialist Inovio Biomedical Corp and vaccine developer VGX Pharmaceuticals believe that their recently announced merger will create a firm capable of rapidly moving DNA vaccine candidates from the laboratory to the clinic.

The definitive agreement, which has been approved by the boards of both firms but is still subject to clearance by stockholders, will integrate Inovio's electroporation technology with VGX's pipeline of developmental DNA vaccines and Cellectra delivery platform.

In January this year, BCC research forecast that the global market for therapeutic vaccines, which is valued at around $20bn (€12.7bn), will be worth $34bn by 2013, representing a compound annual growth rate of nearly 11 per cent.

While traditional antigen-based products will continue to dominate the sector, the benefits offered by DNA vaccines in terms of minimized side effect profile make any successful technology an attractive proposition.

"We are highly confident that the combined company will advance the potential of developing and delivering new DNA vaccines that could play a significant role in treating or even preventing diseases. Leadership of both companies could not forego this medical and market opportunity," commented Avtar Dhillon, Inovio Biomedical's CEO.

Joseph Kim, co-founder, president and CEO of VGX Pharmaceuticals, said that: "Significant, growing evidence indicates that electroporation has a pivotal role to play in enabling the potency of this promising new generation of vaccines and VGX has already made a strong commitment to this DNA delivery technology."

FDA accepts VGX's DNA cervical cancer vacc IND

Earlier this month, the US Food and Drug Administration (FDA) approved VGX's Investigational New Drug (IND) application for the DNA vaccine for cervical cancer, VGX-3100. Following the decision, the firm announced plans to initiate a Phase I clinical trial in the third quarter this year.

At present, the cervical cancer vaccine market is shared between Merck and Sanofi Pasteur's Gardasil and GlaxoSmithKline's (GSK) Cervarix. Both products are traditional antigen-based vaccines that incorporate a limited range of antigens present in the most commonly circulating human papilloma virus (HPV) strains.

In contrast, VGX-3100 is a DNA vaccine that has been designed to offer protection against a wide range of HPV viruses. The product was developed using VGX's SynCon DNA antigen platform, which aligns a selection of primary DNA sequences for each antigen and selects the base that is most common or relevant at each position using a series of sophisticated statistical algorithms.

The selected composite antigens are then included in the vaccine. VGX claims that the approach allows it to identify the DNA sequences that are most likely to elicit cross-reactive immunity to the widest range of HPV viruses, thereby providing enhanced immune protection.

Source

2)
Inovio Biomedical's First Proprietary DNA Vaccine Achieves 100% Protection Against Avian Flu in Pre-Clinical Testing

Wednesday July 16, 6:00 am ET

Results Suggest Experimental DNA Vaccine May Protect Against Multiple Seasonal and Pandemic Influenza Strains

SAN DIEGO--(BUSINESS WIRE)--Inovio Biomedical Corporation (AMEX:INO - News), a leader in enabling the development of DNA vaccines using a proprietary electroporation-based DNA delivery platform, announced today pre-clinical results from two proprietary plasmid DNA-based universal influenza vaccine candidates using the company’s proprietary electroporation delivery technology and, specifically, a new intradermal device. In this study, 100% of the immunized mice given a lethal challenge of highly pathogenic H5N1 influenza virus (A/Vietnam/1203/04) survived and showed only minor weight loss.

The DNA vaccine design was based on a different influenza strain (H1N1) than the influenza strain used in the challenge, providing evidence that a universal vaccine based on conserved genes common to multiple strains of seasonal influenza and even potential pandemic influenza may have the possibility to provide widespread protection against such viruses. In collaboration with Vandalia Research Inc., Inovio also tested the use of fully synthetic linear expressing cassettes (LEC) to express the same antigens and achieved similar results. These results were presented by Dr. Michael Fons, VP Corporate Development, on July 15^th at the Controlled Release Society 35th Annual Meeting and Exposition.

“We’re enthusiastic about these very early results because today’s strain-specific (homologous) influenza vaccines cannot provide universal protection against seasonal influenzas and potential pandemic influenza strains. Only a broad-spectrum (heterologous) influenza DNA vaccine, such as the one we’re testing, would have the potential to provide protection against multiple known and unknown influenza strains. Our hope is that such a universal vaccine may one day replace the standard seasonal vaccine and provide protection against the generally inconvenient symptoms as well as the more severe effects, including death, that can result from seasonal and pandemic influenzas,” said Inovio CEO Dr. Avtar Dhillon.

Current strain-specific influenza vaccines are designed to stimulate an immune response specific to a single influenza strain. Given that seasonal flu can rapidly mutate, such homologous vaccines may provide modest protection against variant influenza strains but cannot fully prevent the contagion from widely spreading and causing not only the familiar symptoms of the common cold but, in some cases, death. The major risk of pandemic influenza is that new virulent strains of influenza, such as the avian flu, which have never spread widely through a human population, would potentially result in harsher symptoms and widespread death because of the body’s delay in naturally building immunity to the virus and the inability to develop and distribute in a timely manner a vaccine specific to that influenza strain.

The concept of a universal broad-spectrum vaccine is based on emerging scientific knowledge that “conserved” regions of the influenza genome are not under dramatic selective pressure to mutate. These genes and the antigens they express are common across most strains of influenza. This creates the possibility to develop heterologous influenza vaccines without knowing the genetic make-up of a future influenza strain that may have the potential to, for example, migrate from animals to man and pose pandemic risk.

This pre-clinical work involved two other technology advancements Inovio has been developing or co-developing:

1) Fully synthetic linear expressing cassettes (LEC), or linear constructs, represent a new type of carrier mechanism for the genes that comprise a DNA vaccine. Numerous clinical studies have provided evidence that DNA plasmids are inexpensive, safe, and effective for delivering DNA vaccines. LECs are a next generation of synthetic DNA constructs that are easier, faster and cheaper to make, while providing equivalent utility.

2) Inovio has developed a multi-product line of electroporation devices that can provide different electroporation parameters in different types of tissue. This pre-clinical work used a new intradermal device intended to deliver a DNA vaccine into skin rather than muscle, the tissue type that is the focus of Inovio’s existing clinical studies. Delivering a vaccine into skin creates the potential for greater tolerability and would therefore make such a device more acceptable for prophylactic (preventive) vaccination.

About Inovio Biomedical Corporation

Inovio Biomedical (AMEX:INO - News) is focused on developing multiple DNA-based immunotherapies. Inovio is a leader in developing human applications of electroporation using brief, controlled electrical pulses to increase cellular uptake of a useful biopharmaceutical. Interim human data has shown that Inovio’s DNA delivery technology, which is protected by an extensive patent portfolio covering in vivo electroporation, can significantly increase gene expression and immune responses from DNA vaccines. Immunotherapy partners include Merck, Wyeth, Vical, University of Southampton, Moffitt Cancer Center, the U.S. Army, National Cancer Institute, and International Aids Vaccine Initiative. Inovio and VGX Pharmaceuticals have announced a proposed merger. More information is available at www.inovio.com.

Source

3)
Inovio says Tripep reported addnl. interim results from hepatitis C virus phase I/II clinical study - Quick Facts

06/30/2008 6:36AM - RTT News

(RTTNews) - Inovio Biomedical Corp. (INO) said Monday that its partner, Tripep AB, reported additional interim results from its ongoing phase I/II clinical study of its ChronVac-C therapeutic DNA vaccine, which is delivered using Inovio's electroporation-based DNA delivery system.

The preliminary results are from the first two patients in the intermediate dose group to complete treatment against hepatitis C virus infection. Samples taken before, during and after treatment showed that the viral levels in blood decreased up to 87% and 98%, respectively, during treatment. Simultaneous activation of the patients' T-cell responses to the hepatitis C virus was recorded in conjunction with the viral load reductions. Inovio's electroporation delivery technology is intended to enhance the potency of DNA vaccines against cancers and infectious diseases.

ChronVac-C is a therapeutic vaccine given to individuals already infected with the hepatitis C virus with the aim of clearing the infection from the liver by boosting the body's immune response against the virus.

For comments and feedback: contact editorial@rttnews.com

Source

4)

Why the merger?:

Commercialization
Vaccine: owned by VGX.
Delivery technology: owned by Inovio.
Source

That kinda says it all - all under one roof, now.

5)
What do I expect?

Great things - a single DNA vaccine for multiple viruses of the same family, concocted to avoid mutations.

6)
iHub Message Board
_

The current status of nanotechnology-based therapeutics in humans

Posted: July 25, 2008

(Nanowerk Spotlight) Modern pharmaceutics is a very imprecise, wasteful and sometimes even dangerous discipline. Not only do most drugs fail even before they make it to market (about 80% of drugs never make it through clinical trials) but even the efficacy of many drugs that are being prescribed for certain diseases is questionable. The most important challenge, though, is to deliver the correct dose of a particular therapeutic (small molecules, proteins, or nuclei acids) to a specific disease site. Since this is generally unachievable, therapeutics have to be administered in excessively high doses, thereby increasing the odds of toxic side effects.

Nanotechnology offers great visions of improved, personalized treatment of disease. The hope is that personalized medicine will make it possible to develop and administer for each individual patient the appropriate drug, at the appropriate dose, at the appropriate time. The benefits of this approach are accuracy, efficacy, safety and speed.

Large pharmaceutical companies have yet to come to terms with the emerging nanomedicine landscape (see our Spotlight "Nanotechnology patents and the future of the pharma industry "). While nanomedicine potentially offers promising new value propositions and revenue streams, for instance in diagnostics, it also could completely displace certain classes of drugs such as current chemotherapy agents with novel nanoparticle reformulations. In addition, nanoparticle-based drugs may pose an entirely new level of development challenges: The number of potential combinatorial variations that can be developed by choosing different nanoparticle core materials, targeting moieties, and payload molecules is very large which renders the problem of selecting the candidates for biological testing astronomically more complex (see "Mathematical engines of nanomedicine").

Today, commercial nanomedicine is at a nascent stage of development and the full potential of nanomedicine is years or decades away. Currently the most advanced area of nanomedicine is the development and use of nanoparticles for drug delivery.

The last few years saw tremendous progress in the use of nanoparticles to enhance the in vivo efficacy of many drugs. Currently used pharmaceutical nanocarriers – liposomes, micelles, nanoemulsions, polymeric nanoparticles and many others – demonstrate a broad variety of useful properties, such as for instance increased longevity in the blood, specific targeting to certain disease sites, or enhanced intracellular penetration.

Some of these pharmaceutical carriers have already made their way into clinics, while others are still under preclinical development. There are two types of nanoparticle-based therapeutic formulations: those where the therapeutic molecules are the nanoparticles (therapeutic functions as its own carrier); and those where the therapeutic molecules are directly coupled (functionalized, entrapped or coated) to a carrier.

A newly published survey by Dr. Raj Bawa takes a look at the current state of nanoparticle-based therapeutics with regard to actual products on the market or in various phases of clinical trials ("Nanoparticle-based Therapeutics in Humans: A Survey").

"All nanoparticulate nanomedicines currently on the market have been approved by the FDA (the U.S. Food and Drug Administration) according to pre-existing laws," Bawa tells Nanowerk. "Although the FDA has not required any special testing of nanoparticle-based therapeutics (e.g., with respect to their pharmacokinetic profiles), there are not many marketed nanoparticle-based therapeutics. This is an obvious consequence of the extremely complex and demanding requirements of clinical trials by the FDA. There are, however, numerous nanoparticle-based therapeutics under development."

In his survey, Bawa gives several specific examples of companies and their nanoparticulate drug products. The following descriptions are quoted from Bawa's survey:

Elan Corporation – NanoCrystal Technology

Because consumers prefer oral drugs over implantables or injectables, nano-engineering traditional or shelved compounds could greatly enhance oral bioavailability in some cases, says Bawa. A classic example of improving the bioavailability of poorly soluble drugs is Ireland-based Elan Corporation’s NanoCrystal technology. This technology is: (a) an enabling technology for evaluating new molecular entities that exhibit poor water solubility and/or (b) a valuable tool for optimizing the performance of current drugs.

Abraxis BioScience, Inc. – Paclitaxel-Albumin Nanoparticles

The company's Abraxane is an albumin-bound nanoparticle formulation of the widely used anticancer drug, Paclitaxel (Taxol). Bawa describes it as the only albumin-bound solvent-free taxane nanoparticulate formulation (∼130 nm) that takes advantage of albumin to transport Paclitaxel into tumor cells. It was approved by the FDA in 2005 for use in patients with metastatic breast cancer who have failed combination therapy. Because Abraxane is free of toxic solvents typically associated with other approved Paclitaxel preparations, there is no need for pre-medication with steroids or antihistamines often needed to prevent these side effects. Another advantage is that it is administered in 30 minutes, as compared to three hours for solvent-based Paclitaxel.

Nanospectra Biosciences – AuroShell Particles

AuroShell particles (previously known as Nanoshells) were developed by Drs. Naomi Halas and Jennifer West of Rice University in the 1990s which eventually led to the formation of Nanospectra Biosciences. Formal operations began in 2002 to commercialize applications using AuroShell particles. Nanospectra has obtained FDA approval to commence human trial for the treatment of head and neck cancers. According to Nanospectra, AuroShell particles are a new type of optically tunable particles composed of a dielectric core coated with an ultra-thin metallic layer. For their oncology applications a silica core is surrounded by an ultra-thin gold shell (gold-coated glass nanoparticles).

Calando Pharmaceuticals, Inc. – RONDEL Technology

Calando Pharmaceuticals, Inc. is a privately held biopharmaceutical company funded by Arrowhead Research Corporation. The company has developed proprietary therapeutic cyclodextrin-containing polymer RNA interference (RNAi) delivery technology and demonstrated the first clear in vivo sequence-specific gene inhibition in tumors. Calando’s technology for RNAi is called RONDEL. Specifically, it employs small interfering RNA (siRNA) as the therapeutic RNA. Calando’s nanoparticle delivery system is designed for IV injection. According to the company, upon delivery of the RNA-containing nanoparticles, the targeting ligand binds to membrane receptors on the targeted cell surface enabling the nanoparticles to be taken up into the cell via endocytosis.

Starpharma Holdings, Ltd. – Dendrimer-based VivaGel

Starpharma Holdings Limited, a leader in the development of dendrimer nanotechnology products, is principally composed of two operating companies, Starpharma Pty. Ltd. and Dendritic Nanotechnologies, Inc. Products based on Starpharma’s dendrimer technology are already on the market in the form of diagnostic elements and laboratory reagents. Starpharma’s lead nanopharmaceutical development product is VivaGel (SPL7013 Gel) which is based on a dendrimer.

Mersana—Fleximer – Camptothecin Conjugate

Mersana Therapeutics, Inc. (formerly Nanopharma Corp.) is a privately held, venture backed company that utilizes its proprietary nanotechnology platform to transform existing and experimental anti-cancer agents into new, patentable drugs with superior pharmaceutical properties. Mersana’s key component of this platform is a “stealth” material derived from dextran called Fleximer. Fleximer is a biodegradable, hydrophilic and multivalent polymer that can be chemically linked to small molecules and biologics to enhance their pharmacokinetics and safety.

"So far, the process of converting basic research in nanomedicine into commercially viable products has been difficult," Bawa sums up the current status. "In the future, several variables will determine whether advances in the laboratory will translate into commercial products available in the clinic. Presently, multiple challenges and risks beset the commercialization of nanoparticle-based therapeutics." Among the risks that he lists are:

nanoparticle separation from undesired nanostructures like byproducts, catalysts, and starting materials; scalability issues and enhancing the production rate; reproducibility from batch to batch with respect to particle size distribution, charge, porosity, and mass; high fabrication costs; lack of knowledge regarding the interaction between therapeutic nanoparticles and living cells (the issue of biocompatibility and toxicity); big pharma’s reluctance to seriously invest in nanomedicine.

Nevertheless, it appears to be just a question of time when nanoparticle-based therapeutics will become an integral part of mainstream medicine and a standard in the drug industry.

By Michael Berger. Copyright 2008 Nanowerk LLC

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UC Santa Barbara Chemist Goes Nano with CoQ10

July 24, 2008


Bruce Lipshutz, professor of chemistry at UC Santa Barbara.
Click for downloadable image
Bruce Lipshutz,
professor of chemistry
at UC Santa Barbara.

(Santa Barbara, Calif.) – If Bruce Lipshutz has his way, you may soon be buying bottles of water brimming with the life-sustaining coenzyme CoQ10 at your local Costco.

Lipshutz, a professor of chemistry at UC Santa Barbara, is the principal author of an upcoming review, "Transition Metal Catalyzed Cross-Couplings Going Green: in Water at Room Temperature," which will be published in Aldrichimica Acta in September. In it, Lipshutz and post-doctoral researcher Subir Ghorai discuss how recent advances in chemistry can be used to solubilize otherwise naturally insoluble compounds like CoQ10 into water.

Never heard of CoQ10? Lipshutz says you're not alone. "If you don't know anything about it," Lipshutz said during a recent interview, "that's not surprising to me. Much of the public hasn't heard of it." But he's on a mission to correct what he views as a major oversight. "In a sense, I'm just a messenger. People need to not only know about CoQ10, they need to take it."

Like vitamin C, CoQ10 is a compound that's vital to our survival. It's a coenzyme that our cells synthesize, albeit in 21 steps, and it's in every cell. This contrasts with a vitamin, such as vitamin C, which is not made by the body. Both CoQ10 and vitamin C are "compounds of evolution," Lipshutz said. "Everybody accepts the importance of vitamin C. The reason the public does not fully appreciate it is that there's no Linus Pauling for CoQ10. There is no champion."

Pauling, a Nobel Prize-winning scientist, was also an advocate for greater consumption of vitamin C. "CoQ is not really in that category of public awareness yet," Lipshutz said.

While the body produces its own CoQ10, that production decreases with age. "Nature gave us, through 2.5 billion years of evolution, a number of fundamental anti-aging, free-radical scavengers that helped us to survive, on average, only to about 40 years of age, until modern medicine came along," Lipshutz said.

A large percentage of the body is made up of water, "but there are also the lipophilic portions of our cells that make up the non-aqueous part," Lipshutz explained. At some point in our evolution, the water-soluble antioxidant vitamin C was produced in vivo, or what would technically be "coenzyme C." Eventually, "a mutation took place that now prevents humans from making it," he said. "However, evolution chose not to mutate out CoQ10."

If one doesn't get vitamin C, the consequences can be dire. "It's essential for several cellular processes. For example, everyone knows about scurvy," Lipshutz said. "You can last 30 days, maybe 60 days, as your cells deteriorate."

On the other hand, CoQ10 – much of which is in the mitochondria of our cells – is essential for cellular respiration and ATP (adenosine triphosphate) production. "You wouldn't last 30 minutes without CoQ10," he said. "Thus, evolution teaches us that CoQ10 is as important as vitamin C. But who's teaching this to our aging population? Nobody."

Lipshutz has a history of CoQ10 research at UCSB. Initially, he retooled the chemistry that would produce the supplement via synthesis instead of fermentation, which is what Japan used to become the world leader in CoQ10 production. But China's entry into the CoQ10 market only a few years ago changed everything.

"The price of CoQ for over 30 years was about $1,600 per kilo as produced by the Japanese," Lipshutz said. "The Chinese came along and, for the time being, have dramatically altered the market by deciding at the government level that they were going to own this important area of dietary supplements. CoQ10 can now be purchased for as little as $400 a kilo, which in principle is great news for consumers."

When the supply of CoQ10 grew faster than demand, Lipshutz went into the lab to study what else could be done with this life-enriching compound. After all, CoQ is now readily available. At Costco or drug stores, you can buy CoQ10 formulated into softgels that deliver the nutrient in various strengths. It's marketed as helping to provide a boost in energy as well as a healthy heart. But, Lipshutz notes, you absorb only10-15 percent of CoQ10 in the softgel form. How, he asked, could this become more available and bioefficient?

"The future is not about access to CoQ10 anymore," he said. "It's not about, ‘Do we have the best synthesis?' or ‘Can we compete with the Chinese?' It's about getting it into water, so that we can get it into our mitochondria."

Quite a challenge since CoQ10 is water insoluble. The answer? Go nano.

"We do it with nano-micelle-forming technology," Lipshutz said. He starts by putting a known, inexpensive molecule called PTS into water, which spontaneously forms a nanosphere about 25 nanometers (one nanometer is equal to one billionth of a meter) in diameter. This sphere has a lipophilic portion tied to a hydrophilic portion through a linker. The lipophilic portion, which is actually vitamin E, goes to the center. "The vitamin E portion associates in the middle with itself because it doesn't have any solubility, any energy-lowering interactions, with the water around it," Lipshutz said. "But the external or hydrophilic portion associates with water.

"So, on the outside is the water-loving portion, while the lipophilic, or grease-loving portion, is on the inside. When you add the CoQ, it says, ‘Where would I rather be?' Since like dissolves like, the CoQ10 goes inside the micelle. It's 25 nanometers and it's crystal clear. And, it's stable at room temperature."

That's nanotechnology. It delivers twice the amount of the compound into the bloodstream, and the concentration in water can be adjusted, he said. This approach can be applied to a broad range of nutraceuticals, including omega-3s, carotenoids like lutein and beta-carotene, and resveratrol. "We can also take pharmaceuticals, like Taxol, an anti-tumor agent, and put them into just water or saline using this PTS," he said.

By taking advantage of this micellar technology, synthetic chemistry can also be done inside the nano-containers. That translates into doing chemistry in pure water, and at room temperature. "That's green chemistry," Lipshutz said.

The amount of heat usually needed in reactions, and the waste created by organic solvents, are dramatically reduced. Lipshutz hopes that when his processes are looked at on a much larger scale, a savings of metric tons of solvent, currently released into the environment, will be realized.

"We aim to get organic solvents out of organic reactions," he said. "And we're already looking into next-generation possibilities. All of our green chemistry has come out of being able to put CoQ10 and other dietary supplements into water."

Lipshutz sees this as his most significant contribution to an already illustrious career as an organic chemist.

"It's an opportunity to affect every person on the planet," he says proudly.

Source

Nanotube Circuits - Carbon nanotubes combine high performance and flexibility for electronics.

Wednesday, July 23, 2008

By Lauren Rugani

Fast and flexible: An integrated circuit on a thin plastic sheet incorporates transistors made from single-walled carbon-nanotube networks. The carbon-based networks rival the performance of single-crystal silicon, but they can be easily printed onto the plastic from solution and have good mechanical properties that are useful for flexible electronics. Credit: Beckman Institute, University of Illinois

New research suggests that networks of single-walled carbon nanotubes printed onto bendable plastic perform well as semiconductors in integrated circuits. Researchers from the University of Illinois at Urbana-Champaign (UIUC) and Purdue University, whose work appears this week in Nature, say that these nanotube networks could replace organic semiconductors in applications such as flexible displays.

Development of flexible electronics has recently focused on organic molecules because, unlike silicon, they are compatible with bendable plastic substrates. Flexible electronics have potential in such applications as low-power electronic newspapers or PDAs that roll up into the size and shape of a pen. The problem with existing organic-electronic devices, however, is that "they aren't well developed for long-term reliability, and they perform far worse than silicon," says John A. Rogers, an engineering professor at UIUC and co-author of the Nature paper.

Carbon-nanotube networks, on the other hand, combine the performance of silicon with the flexibility of organic films on plastic. Rogers says that the speed of the nanotube device compares favorably with the speed of commercially used single-crystal silicon circuits. The transistors can also switch between on and off states in the range of several kilohertz, which is similar to the range of those used for liquid crystal displays and radio frequency identification (RFID) sensors. However, the on-off current ratio for carbon nanotubes is still a few orders of magnitude lower than that for silicon transistors.

The researchers made the networks by depositing nanotubes onto plastic by standard printing methods, which could lead to low-cost, large-scale fabrication. And the printed circuits can bend to a radius of about five millimeters without compromising the electrical performance of the device. "This method is good for flexible electronics that need to be printed over a large area," says Ali Javey, an assistant professor of electrical engineering at the University of California, Berkeley.

Using a technique called transfer printing, the researchers deposited randomly aligned carbon nanotubes onto a 50-micrometer-thick sheet of plastic, and then patterned gold electrodes and other circuit components onto the substrate. Because about one-third of the nanotubes in any network are metallic, which can short out the transistors, the researchers then etched narrow parallel lines through the network with soft lithography. By cutting the nanotubes, they can effectively eliminate the possibility of a purely metallic pathway connecting two electrodes while preserving the performance of the device.

Several challenges still remain before the nanotubes networks are ready for actual products. Devices need to be made in which the performance from device to device doesn't vary; billions of individual nanotubes have to be made with high purity and the right dimensions for optimal performance. The printing process also needs development, says George Gruner, a professor of physics at the University of California, Los Angeles. Gruner suggests that nanotubes could be dissolved into ink and then printed onto plastic. "These devices have to be cheap and disposable," especially for devices like RFID tags in food packaging, he adds.

Rogers's group's immediate goals are to work toward lower power and higher speed in the devices. "We want to push the limits to see how far we can go," he says.

Source

Printable Thin-Film Transistor for Flexible Electronics

United States Patent Application	20080173865
Kind Code	A1
Fink; Richard Lee ; et al.	July 24, 2008

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Abstract

Fabrication of thin-film transistor devices on polymer substrate films that is low-temperature and fully compatible with polymer substrate materials. The process produces micron-sized gate length structures that can be fabricated using inkjet and other standard printing techniques. The process is based on microcrack technology developed for surface conduction emitter configurations for field emission devices.

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Inventors:	Fink; Richard Lee; (Austin, TX) ; Yaniv; Zvi; (Austin, TX)
Assignee Name and Adress:	NANO-PROPRIETARY, INC. Austin TX Claims 1. A thin film transistor (TFT) comprising:a substrate;a source electrode on the substrate;a drain electrode on the substrate positioned a distance from the source electrode;a layer of metal oxide deposited on the substrate between the source and drain electrodes, wherein the layer of metal oxide is reduced to metal to form a microcrack in the layer between the source and drain electrodes, wherein the microcrack separates a first portion of the metal layer contacting the source electrode from a second portion of the metal layer contacting the drain electrode;an active semiconductor material deposited so that it bridges the microcrack, contacting both the first and second portions of the metal layer;a gate dielectric material deposited over the active semiconductor material; anda gate electrode deposited on the gate dielectric material and not contacting the metal layer or the active semiconductor material. 9. A method of manufacturing a TFT comprising:inkjet printing conductive ink on a substrate to form source and drain electrodes spaced apart from each other;inkjet printing a PdO layer on the substrate between the source and drain electrodes;reducing the PdO layer to Pd metal resulting in formation of a microcrack in the Pd metal layer;inkjet printing an active semiconductor on the reduced PdO layer across the microcrack;inkjet printing a gate dielectric over the active semiconductor; andinkjet printing a gate electrode over the gate dielectric.

Advantages of this approach are:

[0041]1. Low cost: All-printing technologies are used to form feedlines and TFT components. Inkjet printing and other printing approaches may he used. Printing is an additive approach and not subtractive, thus in general, the materials cost will be less. In addition, the capital investment for printing equipment is much lower than CVD or vapor deposition equipment needed for a-Si TFT technology or high-performance pentacene transistors.

[0042]2. Low temperature; The fabrication processes are below 200.degree. C.

[0043]3. Compatible with flexible substrates: The fabrication processes are completely compatible with PEN substrates.

[0044]4. Scalable to large area: Ink-jet printers are used now to print billboard signage. 100'' diagonal will be no problem. The fact that Canon, is using this microcrack approach for their SED 36'' diagonal (and larger) displays also demonstrates that arrays of submicron channel TFTs can be fabricated over large areas reliably.

[0045]5. Performance specifications for emissive technologies: The driving currents from this TFT structure are sufficient to drive OLEDs.

Source

Pearly whites

24 July 2008

Chinese scientists have found a new route to the perfect smile, using nanoparticles to repair tooth enamel.

Ruikang Tang at Zhejiang University and his team found that nanoparticles made from hydroxyapatite (HAP), a mineral which is the major component of dental enamel, adsorb very strongly onto the surface of the natural enamel - potentially enabling decayed teeth to be repaired and strengthened.

Dentists have found it hard to understand why synthetic hydroxyapatite has not been a good candidate for enamel repair, but they could now have the answer.

Tang explains that up to now dentists have found it hard to understand why synthetic hydroxyapatite has not been a good candidate for enamel repair, but they could now have the answer.

In contrast to previous studies, Tang's group have used much smaller particles, which they say are similar to the size of the building blocks of dental enamel. The features of these 20 nm sized HAP nanoparticles may be more similar to the features of natural hydroxyapatite than those of the larger HAP particles that are usually used he explains.

George Nancollas, professor of oral biology at the University of Buffalo in the US, explains that the team's work with HAP nanoparticles has revealed some exciting possibilities for the remineralisation of decayed enamel. 'The apparent restoration of enamel hardness using an in vitro method is particularly significant. The challenge will be to control the kinetics of the process and to achieve a degree of reproducibility.'

In order to confirm the effects seen with the HAP nanoparticles in vitro, Tang says they need to extend their work to in vivo studies. 'We are also interested in using these nanoparticles to repair other apatite hard tissue like bone' he says.

Klaus Jandt, an expert in biomaterials research at Friedrich Schiller University of Jena in Germany, agrees. 'Enamel repair studies are important and of high relevance. In the future, it will be especially important to demonstrate the enamel repair potential in vivo and that the repaired enamel is mechanically stable'.

Katherine Davies

Repair of enamel by using hydroxyapatite nanoparticles as the building blocks
Li Li, Haihua Pan, Jinhui Tao, Xurong Xu, Caiyun Mao, Xinhua Gu and Ruikang Tang, J. Mater. Chem., 2008
DOI: 10.1039/b806090h

Source

Article citation: Li Li, J. Mater. Chem., 2008, DOI: 10.1039/b806090h

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Repair of enamel by using hydroxyapatite nanoparticles as the building blocks

Li Li, Haihua Pan, Jinhui Tao, Xurong Xu, Caiyun Mao, Xinhua Gu and Ruikang Tang

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The application of calcium phosphates and their nanoparticles have been received great attention. However, hydroxyapatite (HAP) is not suggested in dental therapy to repair the damaged enamel directly although this compound has a similar chemical composition to enamel. We note that the size-effects of HAP are not taken into account in the previous studies as these artificial particles frequently have sizes of hundreds of nanometres. It has recently been revealed that the basic building blocks of enamel are 20–40 nm HAP nanoparticles. We suggest that the repair effect of HAP can be greatly improved if its dimensions can be reduced to the scale of the natural building blocks. Compared with conventional HAP and nano amorphous calcium phosphate (ACP), our in vitro experimental results demonstrate the advantages of 20 nm HAP in enamel repairs. The results of scanning electron microscopy, confocal laser scanning microscopy, quantitative measurement of the adsorption, dissolution kinetics, and nanoindentation, show the strong affinity, excellent biocompatibility, mechanical improvement, and the enhancement of erosion-free by using 20 nm particles as the repairing agent. However, these excellent in vitro repair effects cannot be observed when conventional HAP and ACP are applied. Clearly, nano HAP with a size of 20 nm shares similar characteristics to the natural building blocks of enamel so that it may be used as an effective repair material and anticaries agent. Our current study highlights the analogues of nano building blocks of biominerals during biomedical applications, which provide a novel pathway for biomimetic repair.

Cancer drug delivery research at Case Western Reserve University cuts time from days to hours

7/22/2008 4:46:05 PM

Researchers at Case Western Reserve University have developed a technique that has the potential to deliver cancer-fighting drugs to diseased areas within hours, as opposed to the two days it currently takes for existing delivery systems.

Using laboratory mice, drug delivery time from injection to the cancer cells was reduced from two days to mere hours. Using this as a model for potential human use, cancer patients may someday soon receive the benefits of cancer-fighting drugs within hours of injection.

Findings are discussed in a paper, co-authored by Clemens Burda, associate professor of chemistry and director of the Center for Chemical Dynamics and Nanomaterials Research at Case Western Reserve University and graduate student Yu Cheng, appearing in the current edition of the Journal of the American Chemical Society.

The system uses gold nanoparticle vectors to deliver photodynamic therapy (PDT) drugs through the bloodstream to cancerous sites.

"Gold nanoparticles are usually not used for the PDT drug vector," said Cheng. "However, gold is chemically inert and nontoxic."

Photodynamic therapy utilizes light-sensitive drugs that, when exposed to light of a certain wavelength, will energize and burn away cancer cells.

Because exposure to light activates these drugs, PDT patients must keep out of bright lights for days while the drugs make their way through the bloodstream to the cancer site. At that time, they are activated by a light focused on the specific area of the body.

"By shortening the waiting time from drug injection to activation, PDT patients are much less inconvenienced and tend to have a more normal lifestyle," said Burda.

Looks like a "Hairy Ball"

The drug delivery system uses a gold nanoparticle (Au NP) as its hub. Gold is non-toxic to the human body, and has a versatile surface chemistry, large surface-to-volume ratio and variable size and shape.

Each Au NP is coated with polyethylene glycol (PEG) ligands, giving it the appearance of a hairy ball, said Burda. These PEG molecules offer several advantages over other materials: they are soluble in fats and water, don't interact with proteins in the bloodstream and help protect the drug, keeping it safe and stable until delivery to the cancer site.

Between each PEG ligand, molecules of a photodynamic chemotherapy drug (Pc 4) are attached to the Au NP. The Pc 4 drug (a phthalocyanine compound) was developed at Case Western Reserve by Malcolm Kenney, professor of chemistry.

When the nanoparticle reaches the cancerous tissue the drug molecules are released and uploaded to the diseased area. Focused red light is used to energize the drug in the patient once it has been delivered to the tumor.

Burda says that a potential future research project would look at providing a time-release administration of the drug rather than a more all-at-once release. In the long term, Burda hopes to make the Au NP delivery system applicable to a broad range of diseases.

The Au NP has a diameter of 5 nm. The addition of PEG ligands expands the total diameter to 32 nm, larger than some other nanoparticles currently in use, but still small enough to pass unencumbered through the bloodstream.

A single 1/4-mL injection holds approximately 100 million Au NPs, each carrying approximately 100 drug molecules.

Tail to Tumor in Two Minutes

In the laboratory of Baowei Fei, assistant professor of radiology and biomedical engineering at Case Western Reserve, these Au NPs have been used to treat mice with cancerous tumors. Once the Au NPs have been injected into the tail, the Pc 4 is uploading into the diseased area within minutes. The accelerated speed of drug administration in mice is due in part to the much more efficient dispersion of the NP delivered drug.

When tested on human cells called HeLa – a line of laboratory-grown human cells used in testing – most of the drug is uploaded within one hour.

Testing on human beings may not begin for some time. Commercialization will take even longer due to Food and Drug Administration (FDA) testing and approval. However, all of the components – Au Nps, PEG ligands and Pc 4 – have already received FDA approval.

What's Next

Burda says that as Au NP testing continues, short-term goals include minimizing the amount of material and drug load needed for effective interaction with cancer cells; optimizing potential targeting systems on the PEG ligands for faster, even more specific placement in diseased areas; and increasing the overall effectiveness of nanoparticle enhanced therapy.

"The system is very modular," says Burda. "We can change the size and shape of the Au core NPs and we can change the functionality of the PEG ligands. This should lead to optimization of the drug targeting and therapy. If our research is successful, other researchers might adapt this drug delivery system to other diseases and applications."

Funding support came from the National Science Foundation, National Institute of Health/National Cancer Institute and the Biomedical Research Technology Transfer Center under the leadership of Pamela Davis, dean of the Case Western Reserve School of Medicine and vice president for medical affairs.

Case Western Reserve University is among the nation's leading research institutions. Founded in 1826 and shaped by the unique merger of the Case Institute of Technology and Western Reserve University, Case is distinguished by its strengths in education, research, service, and experiential learning. Located in Cleveland, Case offers nationally recognized programs in the Arts and Sciences, Dental Medicine, Engineering, Law, Management, Medicine, Nursing, and Social Work. http://www.case.edu.

Source

Carbon Nanotubes with Nanoscopic Paraffin Coating Form Self-Cleaning Surfaces

Never wash your car again? Never clean your windows? These may well become reality if it becomes possible to produce the right coatings—coatings that imitate the self-cleaning effect of the lotus blossom. A research team led by Ayyappanpillai Ajayaghosh at the National Institute for Interdisciplinary Science and Technology (Trivandrum, India) has made significant progress toward this goal. As they report in the journal Angewandte Chemie, these scientists have successfully produced a superhydrophobic, self-cleaning surface. Their success results from carbon nanotubes having a nanometer-thick paraffin coating with the help of a rigid aromatic molecule called para-phenylenevinylene.

The lotus plant has given its name to a natural self-cleaning mechanism: The extremely water-repellent (superhydrophobic) surface of its leaves causes drops of water to form spheres, which roll off the leaf, sweeping any dirt away. The lotus leaf is equipped with 3 to 10 µm “bumps” that are in turn coated with a nanoscopic water-repellent coating. The bumpy structure minimizes the area with which the water can come into contact and the water-repellent coating keeps water from getting into the valleys between the bumps. The water cannot coat the leaf and simply rolls off.

The researchers started with carbon nanotubes—long, hollow fibers made of carbon atoms in a honeycomb-like arrangement. Using a self-assembly process, they attached organic molecules to the exterior of the tubes. These molecules consist of a short backbone of aromatic six-membered carbon rings that supports several long hydrocarbon chains. The aromatic rings attach themselves firmly to the honeycomb structure of the nanotubes; the hydrocarbon chains act like a paraffin-like coating. The research team applied a dispersion of these adducts to glass, metal, and mica surfaces. Once dry, the result was a water-repellent coating with stable self-cleaning properties.

Electron microscopic images show that the coating does not have a regular structure like the leaves of the lotus, but does have comparable nanoscale roughness. Water has as much trouble coating these artificial surfaces as the lotus leaf. A tilt angle of 2° is sufficient to cause water droplets to roll off. Like the lotus, any dust is removed from the surface by the water droplets.

Posted July 23rd, 2008

Source

Heat May Harbour Testicular Cancer Cure

By: ANI


Boffins at Johns Hopkins Medical Institutions have found that heat sensitivity may be the key behind why testicular cancer patients like, seven-time Tour de France winner Lance Armstrong, survive far better than patients with other advanced cancers.

Researchers suggest that heat sensitivity may make testicular cancer cells more susceptible to standard treatments and die off more readily.

Armstrong's tumour, like those of all primary testicular cancer, began in the testes, which are a few degrees cooler than the rest of the body to keep heat-sensitive sperm safe.

Hopkins scientists believe the temperature boost may weaken protein scaffolding within the cancer cell's nucleus, making the nuclear DNA more vulnerable to chemotherapy and radiation when the cancer cells spread into warmer regions of the body.

	Heat is at the centre of many cellular changes.

Robert Getzenberg, Ph.D., professor and director of urology research at Johns Hopkins said that testicular cancer patients have a much better chances of surviving the disease than those patients suffering from other types of cancer.

"More than 80 percent of men with widespread testicular cancer can achieve a cure. In other cancers, the cure rate is far less," he said.

Dr Getzenberg feels that heat also may offer a strategy against other malignancies as well.

"If we understand how heat may naturally help kill testicular cancer cells, then perhaps we can make it happen in other solid tumours," he said.

Donald Coffey, Ph.D., the Catherine Iola & J. Smith Michael Distinguished Professor of Urology, Oncology, Pathology, and Pharmacology and Molecular Sciences at Johns Hopkins, said that scientist were now working on ways to harness heat to fight other types of cancer as well.

"Heat is at the centre of many cellular changes. It drives everything from reproduction to fighting infection, and now we'd like to harness its power to fight cancer. Scientists haven't connected precisely how heat affects the scaffolding and might be one of the reasons treatment can cure tumors such as Lance Armstrong's," he said.

Providing scientific evidence for the theory was unrelated study by researchers at the Robert Wood Johnson Medical School of men with undescended testes, a fairly common birth defect in which the genitals remain stuck in the pelvis after birth instead of descending into the scrotum.

Theodore DeWeese, M.D., professor and director of the Department of Radiation Oncology and Molecular Radiation Sciences, and colleagues state that an examination of the men's sperm showed that the sperm cells' nuclear protein scaffolding, known technically as the nuclear matrix, was also wrecked.

"The warmer region of the pelvis made the nuclear matrix in the cells that make sperm unstable and prone to death, and cancer cells already have unstable nuclear matrices. If we give a cancer cell more heat to completely disrupt its matrix, and then add toxic drugs and radiation, the cancer cell may be so disabled that it won't be able to replicate and will die."

"Once we've devised the best way to deliver heat to cancer cells, we will test the technique in animal models to help define the right temperature and doses of chemo and radiation therapy," he added.

To direct heat only to cancer cells, the researchers are investigating the use of nanoparticles that have an affinity for surface proteins carried by cancer cells. The Hopkins scientists believe that, if injected through the bloodstream, magnetic nanoparticles may be able to reach tumours throughout most of the body. And as long as the nanoparticles penetrate most of the cells in the tumour, the temperature increase will spread to the entire mass.

The report is published in the July 26 issue of the Journal of the American Medical Association

Source

Reminds me of Kanzius and his radio wave machine heating nanoparticles attached to cancer cells to kill them.

The Sensor Network Design Tool (SNDT), developed by Applied Nanotech, Inc.

By Donald R. Schropp, Jr.
July/August 2008

Software for predictive modeling of toxin migration and lethality within building structures to optimize the placement of CB sensors in buildings, transportation hubs, and other public venues

A software tool for designing and implementing an optimized sensor network is needed to monitor and respond to unsafe environmental conditions within buildings. The Sensor Network Design Tool (SNDT), developed by Applied Nanotech, Inc., incorporates building-air transport models and selectable probability distribution models integrated with databases of gas sensors and their properties, as well as detects a broad spectrum of hazardous contaminants including toxic chemicals and chemical and biological (CB) attack agents.

This SNDT was originally developed with funding from the Department of Homeland Security (DHS), which was seeking a system to designate where to install CB sensors in buildings, transportation hubs, and public venues with the goal of obtaining the shortest time to detection and the most comprehensive coverage for a given number of sensors. Deciding where to place a network of sensors in a sizable structure is a daunting task compounded by a current lack of standardization on methodology for evaluating system performance. Despite the DHS requirement that the SNDT provide for rapid and verifiable deployment in a wide spectrum of CB threat scenarios, it has to be accessible to non-expert users.

These inherent capabilities of SNDT make it directly applicable to the design of sensor networks for industrial and commercial settings, where toxic chemicals are handled and leaks or spills can occur, such as: semiconductor fabrication, pharmaceutical, chemical, petroleum, building construction, nuclear, or defense facilities. In additional to accidental release scenarios, SNDT can be applied in indoor air quality, contaminant migration, or ventilation system performance assessment to provide automated capability for the quantitative evaluation of airflow and contaminant movement in complex situations.

Figure 1 shows the operational structure of the SNDT. Through a series of design steps and menus, a system operator is guided through the design and verification protocol. Beneath its graphical interface the SNDT contains a processing algorithm combining a multi-zonal air transport engine with constrained non-linear optimization. This software generates and analyzes a multitude of possible sensor networks and toxin release scenarios and searches for optimal sensor placement. The output is a visual representation where the sensors should be located, along with numerical data comparing the networks and scenarios analyzed.

The major software components comprise:

1. Front end interface where the operator is interrogated and inputs desired agents for the network to sense along with a building model.
2. Multi-zone building airflow and contaminant migration engine to calculate agent transportation yielding concentration densities as a function of time and space.
3. Sensor network design module that generates candidate sensor networks by selecting appropriate sensors from the database and distributes them about the building, then evaluates possible release scenarios using the multi-zone building airflow and contaminant migration engine to determine time to fi rst detection, or if detection occurs at all.
4. Sensor database is a database of sensors for various threat agents or toxic industrial compounds and includes agent properties (molecular weight, spore size, lethal dose, incapacitating dose, etc.), and sensor sensitivity, response time, cost and associated engineering data.

Multi-Zone Building Airflow and Contaminant Migration Engine
ANI collaborated with Lagus Applied Technology, Inc. (LAT, http://www.tracergas.com) on the predictive modeling of toxin migration and lethality effects within building structures. Prior to SNDT development the company had extensive expertise in CB sensor technologies; LAT performs modeling and measurement of contaminant migration and building air transport, and had already developed CB-Protect, a software tool that became the foundation of the SNDT.

CB-Protect is a multi-zone building airflow and contaminant migration engine. Zonal models treat the building as a set of volume zones, typically being rooms, hallways, stairwells and HVAC ducting, and employ coefficients linking each zone to all others, which physically represent air flow rates. The flow rate matrix has discreet variants representing for example, HVAC blowers being on or off , doors open or closed, etc., and can have continuously variable time dependent matrix coefficients. Each unique matrix defines a building state. The coupled rate equations are then solved using standard numerical integration and matrix techniques to provide the temporal and zonal evolution of the agent concentration throughout the building.

Zonal models require an initial building description to be input. Though the actual flow rate matrix can be established experimentally by tracer gas studies, the SNDT employs CAD style building models to minimize equipment requirements, using tabulated ASHRE data of leakage rates through the various construction materials (sheet-rock, cinder-block, concrete, etc.) and HVAC blower/ducting throughputs. The flow rate matrix values and volume zone description completely specifies the building and its air flow properties. Then, with the building and fl ow rate values established, the airflow and contaminant migration engine is used to analyze simulated toxin release within the building.

Sensor Network Design Module
The SNDT and CB sensor database software modules are integrated with CB-Protect. The Sensor Network Design Module (SNDM) is the core of the SNDT. It generates candidate networks by selecting sensors from the database responding to the desired agents. The permutations of m unique sensors distributed throughout the n building zones are then successively examined for detection performance. The number of sensors m ranges from 1 to a maximum generally determined by budget constraints. The definition of optimal network is objectively cast in terms of a time score. Initial development has focused on the averaged least time to detection T_d squared as the criteria to minimize,

where the index i runs over all possible unique sets of conditions and P_i is the probability that those specific set of conditions will exist. Specific facts must be speculated regarding an agent release: the type of agent employed, the quantity and duration of release and the release zone. The probability P_i can be considered as the product of the probabilities for each variable:

With this the full expression for the value of the minimization functional is:

The value of the functional f using equation (3) is now evaluated for all the candidate sensor networks. The sensor network with the minimum value of f is then considered the optimal network.

Choices for the probability distributions for the elements comprising equation (2) must be made, and each has unique considerations. In practical implementations, identifying all building states is infeasible and fortunately unnecessary; using a small number of representative building states yield results comparable to very detailed methods. The distribution for agent type should include all known agents in order to be comprehensive, but is simplifi ed because all gases are transported equivalently in the zone model. Therefore the distribution need only incorporate a single gas calculation weighted over the agent type and sensor properties.

The distribution for agent quantity is unknown but reasonable maximum quantities for terrorist attacks are what an individual or a vehicle, depending on release zone, can carry. In practice, an optimal sensor network for one specific quantity of an agent release will also be the optimal sensor network for a larger quantity of the same agent because the spatial and temporal transport profiles scale with the quantity, so the particular sensor that fi rst detects in one situation will also be the first to detect in the second situation, only with a shorter time to detection. What is required to be confirmed by the optimization algorithm is what the minimum release quantity that can be detected by the network under evaluation is, and does that minimum detectable quantity allow concentration levels above the lethal or incapacitating concentration.

The probability distribution for agent release duration is also unknown, but reasonable values are in the minutes to tens of- minutes time scales. The issue for this particular probability distribution is that a very short release duration can lead to lethal concentration levels unless the first to-detect sensor is in the release zone. On the other hand, a very long release duration will keep concentration levels low, but they could still be above lethal thresholds unless the detection sensor is in the release zone and has a sensitivity threshold above the ambient concentration level. The release zone distribution has several models to choose from. Candidates considered and evaluated include:

• Flat Distribution: where each zone is equally likely for a release with probability inversely proportional to the number of zones, or n-¹.
• Area Weighted Distribution: where the probability for release in a zone is equal to that zone’s area divided by the sum of all zone areas.
• Security Weighted Distribution: where zones that are secure or have limited accessibility can be assigned a small to zero probability for a release.
• Casualty Weighted Distribution: where the probability for release in a zone is proportional to the likely resulting casualties.

Probability distributions that incorporate compound strategies can also be considered; an easily accessible zone and likely large amount of casualties is a more desirable target.

Chemical and Biological Sensor Database
Reliably sensing the presence of a CB or toxic industrial agent with unattended sensors requires a diverse array of devices, as no single sensor can detect all possible chemical and biological entities. Sensors range from the simple, inexpensive metal-oxide devices used for gas detection to expensive analytical instruments such as gas chromatographs and mass spectrometers. Inexpensive sensors tend to have poor selectivity, low sensitivity and correspondingly high limits-of-detection. Instruments that will unequivocally identify the substance present will be sophisticated and expensive, and may require technicians to operate, monitor and interpret the data.

The Chemical and Biological Sensor Database (CBSD) database contains existing and available sensors and their properties. The database holds fields for the sensor type, manufacturer, detectable analytes, limits-of detection, sensitivity to cross-contaminants, maintenance requirements/lifetimes, and cost per unit. The CBSD is accessible from the SNDM software module and completes the input information required to allow design of the permanent sensor network.

Figure 3. The probability-weighted time
score value for networks of 1 to 5 sensors.

Typical Program Output and Sensor Network Evaluation
Figure 2 shows example results from the SNDT. The icons indicate where the network of four sensors should be placed for optimal detection of a release. Figure 3 shows the probability weighted time score value for networks of 1 to 5 sensors. Increasing the number of sensors decreases the average detection time until a point of diminishing returns is reached. Ancillary data produced by the SNDT include the time score, the number of scenarios evaluated where no detection occurs, the total probability of no detection occurring, and maximum time to detection.

The SNDT has been evaluated in experimental trials. Gas concentration levels throughout each zone of a building were accurately calculated as a function of time. Probability distributions were devised for which zone the release would occur in, which CB agent was released, and its quantity. The algorithm then generated a subset of all possible sensor networks, ran the building modeling program to calculate concentrations for CB releases based on the probability distributions, then calculated the time to first detection. The network configuration with the probability-weighted least time to first detection was selected as the optimal network. The candidate networks were generated from sensors chosen from a database containing the sensor parameters (analyte sensitivity, time response, cost, etc.).

Conclusion
A new software tool is being developed to assist in the design of optimized sensor networks. ANI’s SNDT can greatly facilitate optimal sensor network design implementation via open and verifiable optimization algorithms, and is useful for commercial facilities where toxic gases and chemicals are handled.

Fitted with appropriate sensors, “smart buildings” have the ability to detect a release, determine where it originated and predict where and how it will travel, taking into account HVAC and building status. “Smart buildings” can even be fitted with actuators to close off ventilation or direct personnel to the safest escape routes. With a priori planning and the required infrastructure in place, SNDT offers the potential for reduced exposure hazard.

DONALD R. SCHROPP, JR. IS A SENIOR SCIENTIST AT APPLIED NANOTECH, INC., 3006 LONGHORN BLVD., SUITE 107, AUSTIN, TX 78758. HE PERFORMS PHYSICAL MODELING, AND DEVELOPS MEASUREMENT METHODS AND APPLICATION SPECIFIC DATA ANALYSIS ALGORITHMS ESPECIALLY TARGETED TOWARD THE RESEARCH AND DEVELOPMENT ENVIRONMENT OF CUSTOMIZED EXPERIMENTAL SETUPS AND INSTRUMENTATION. HE HAS WORKED IN THE FIELDS OF ATOMIC PHYSICS, SPACE SCIENCE, AND MOST RECENTLY AS SENIOR SCIENTIST AT CANDESCENT TECHNOLOGIES, INC., A LARGE SILICON VALLEY VENTURE TO PRODUCE FIELD EMISSION DISPLAYS. HE RECEIVED HIS PH.D. IN PHYSICS FROM YALE UNIVERSITY. HE CAN BE CONTACTED AT 512-339-5020 X129 OR DSCHROPP@ APPLIEDNANOTECH.NET.

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