Stabilizing entangled spaghetti-like materials: Controling forces between oppositely charged polymers opens new route for gene therapy vectors

Gene therapy can only be effective if delivered by a stable complex molecule. Now, scientists have determined the conditions that would stabilise complex molecular structures that are subject to inherent attractions and repulsions triggered by electric charges at the surfaces of the molecules, in a study about to be published in the European Physical Journal E, by Valentina Mengarelli and her colleagues from the Solid State Physics Laboratory at the Paris-Sud University in Orsay, France, in collaboration with Paris 7 and Évry Universities scientists.

The authors studied soluble complexes made of negatively charged DNA or another negatively charged polymer -- polystyrene-sulfonate (PSSNa) -- and a so-called condensation agent, which is a negatively charged polymer, known as linear polyethyleneimine (PEI). PEI participates in the condensation process by tying onto a molecule such as DNA, like tangled hair, to form an overall positively charged DNA/polymer complex structure. Previous research focused mainly on non-soluble complexes, while the few attempts at focusing on soluble complexes dealt either with smaller polymers or those with a weaker electric charge, which may therefore be easier to stabilise.

The French team thus confirmed experimentally that the complexation process does not depend on the rigidity of the original molecule, be it DNA or PSSNa, but on the positive/negative electric charge ratio and on the polymer concentrations. It is the interactions between electrically charged parts within the complex that govern its properties. When the condensation agent is in excess, the positively charged complex is then attracted to negatively charged biological cell membranes. This could be used to deliver the DNA into a targeted cell nucleus as part of gene therapy treatment.Future work will focus on using long DNA molecules and novel polymers to form complexes of controlled size and electric charge for gene therapy.

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Journal Reference:

Mengarelli V, Auvray L, Pastré D, and Zeghal M,. Charge inversion, condensation and decondensation of DNA and Polystyrene sulfonate by polyethylenimine. European Physical Journal E (EPJE), 2011; 34, 127 DOI: 10.1140/epje/i2011/11127-3

Engineered botulism toxins could have broader role in medicine

Edwin Chapman and colleagues explain that toxins, or poisons, produced by Clostridium botulinum bacteria, cause of a rare but severe form of food poisoning, are the most powerful toxins known to science. Doctors can inject small doses, however, to block the release of the neurotransmitters, or chemical messengers, that transmit signals from one nerve cell to another. The toxins break down a protein in nerve cells that mediates the release of neurotransmitters, disrupting nerve signals that cause pain, muscle spasms and other symptoms in certain diseases. That protein exists not just in nerve cells, but in other cells in the human body. However, these non-nerve cells lack the receptors needed for the botulinum toxins to enter and work. Chapman's group sought to expand the potential use of the botulinum toxins by hooking it to a molecule that can attach to receptors on other cells.

Their laboratory experiments showed that these engineered botulinum toxins do work in non-nerve cells, blocking the release of a protein from immune cells linked to inflammation, which is the underlying driving force behind a range of diseases. Such botulinum toxin therapy holds potential in a range of chronic inflammatory diseases and perhaps other conditions, which could expand the role of these materials in medicine.

More information: “Retargeted Clostridial Neurotoxins as Novel Agents for Treating Chronic Diseases” Biochemistry, 2011, 50 (48), pp 10419–10421. DOI: 10.1021/bi201490t

Provided by American Chemical Society (news : web)

'Left-handed iron corkscrews' point the way to new weapon in battle against superbugs like MRSA

Researchers have created a new synthetic class of helix-shaped molecules which they believe could be a key tool in the worldwide battle against antibiotic resistance.

By twisting molecules around iron atoms they have created what they term 'flexicates' which are active against MRSA and E-coli - but which also appear to have low toxicity, reducing the potential for side effects if used in treatment.

The work is published in Nature Chemistry.

The new structures harness the phenomenon of 'chirality' or 'handedness' whereby the corkscrew molecules could be left-handed or right-handed.

By making the most effective 'hand' to attack a specific disease, the University of Warwick research paves the way towards a more targeted approach to killing pathogens.

In the case of E-coli and MRSA, it is the left 'hand' which is most effective.

Professor Peter Scott of the University of Warwick's chemistry department said although this particular study concentrated on flexicates' activity against MRSA and E-coli, the new method of assembly could also result in new treatments for other diseases.

"It's a whole new area of chemistry that really opens up the landscape to other practical uses.

"These new molecules are synthetically flexible, which means that with a bit of tweaking they can be put to use against a whole host of different diseases, not just bugs like MRSA which are rapidly developing resistance to traditional antibiotics.

"Flexicates are also easier to make and produce less waste than many current antibiotics."

Scientists have long been able to copy nature's corkscrew-shaped molecules in man-made structures known as helicates – but they have thus far not been able to use them in fighting diseases.

One of the key issues is the problem of handedness.

Sometimes 'left-handed' molecules in drugs are the most effective at combating some disease, while sometimes the 'right-handed' version works best.

Until now, scientists working with helicates have found it difficult to make samples containing just one type of corkscrew; either the right- or left-handed twist.

But with flexicates, the University of Warwick scientists have succeeded in making samples containing just one type of twist – resulting in a more targeted approach which would allow the drug dosage to be halved.

And flexicates solve other problems encountered by helicates, as they are easier to optimise for specific purposes, are better absorbed by the body and are also easier to mass-produce synthetically.

Professor Scott said: "Drugs often have this property of handedness - their molecules can exist in both right and left handed versions but the body prefers to use only one of them."

"For this reason, drug companies have to go to the trouble of making many traditional molecules as one hand only.

"What we have done is solve the 'handedness' problem for this new type of drug molecule.

"By getting the correct hand we can halve the drug dose, which has the benefits of minimising side effects and reducing waste.

"For patients, it's safer to swallow half the amount of a drug.

"Our work means that we can now make whichever hand of the corkscrew we want, depending on the job we require it to do."

More information: The study, entitled Optically pure, water-stable metallo-helical 'flexicate' assemblies with antibiotic activity, is published in Nature Chemistry. http://dx.doi.org/ … 8/NCHEM.1206

Provided by University of Warwick (news : web)

Graphene lights up with new possibilities: Two-step technique makes graphene suitable for organic chemistry

 The future brightened for organic chemistry when researchers at Rice University found a highly controllable way to attach organic molecules to pristine graphene, making the miracle material suitable for a range of new applications.

The Rice lab of chemist James Tour, building upon a set of previous finds in the manipulation of graphene, discovered a two-step method that turned what was a single-atom-thick sheet of carbon into a superlattice for use in organic chemistry. The work could lead to advances in graphene-based chemical sensors, thermoelectric devices and metamaterials.

The work appears in the online journal Nature Communications.

Graphene alone is inert to many organic reactions and, as a semimetal, has no band gap; this limits its usefulness in electronics. But the project led by the Tour Lab's Zhengzong Sun and Rice graduate Cary Pint, now a researcher at Intel, demonstrated that graphene, the strongest material there is because of the robust nature of carbon-carbon bonds, can be made suitable for novel types of chemistry.

Until now there was no way to attach molecules to the basal plane of a sheet of graphene, said Tour, Rice's T.T. and W.F. Chao Chair in Chemistry as well as a professor of mechanical engineering and materials science and of computer science. "They would mostly go to the edges, not the interior," he said. "But with this two-step technique, we can hydrogenate graphene to make a particular pattern and then attach molecules to where those hydrogens were.

"This is useful to make, for example, chemical sensors in which you want peptides, DNA nucleotides or saccharides projected upward in discrete places along a device. The reactivity at those sites is very fast relative to placing molecules just at the edges. Now we get to choose where they go."

The first step in the process involved creating a lithographic pattern to induce the attachment of hydrogen atoms to specific domains of graphene's honeycomb matrix; this restructure turned it into a two-dimensional, semiconducting superlattice called graphane. The hydrogen atoms were generated by a hot filament using an approach developed by Robert Hauge, a distinguished faculty fellow in chemistry at Rice and co-author of the paper.

The lab showed its ability to dot graphene with finely wrought graphane islands when it dropped microscopic text and an image of Rice's classic Owl mascot, about three times the width of a human hair, onto a tiny sheet and then spin-coated it with a fluorophore. Graphene naturally quenches fluorescent molecules, but graphane does not, so the Owl literally lit up when viewed with a new technique called fluorescence quenching microscopy (FQM).

FQM allowed the researchers to see patterns with a resolution as small as one micron, the limit of conventional lithography available to them. Finer patterning is possible with the right equipment, they reasoned.

In the next step, the lab exposed the material to diazonium salts that spontaneously attacked the islands' carbon-hydrogen bonds. The salts had the interesting effect of eliminating the hydrogen atoms, leaving a structure of carbon-carbon sp3 bonds that are more amenable to further functionalization with other organics.

"What we do with this paper is go from the graphene-graphane superlattice to a hybrid, a more complicated superlattice," said Sun, who recently earned his doctorate at Rice. "We want to make functional changes to materials where we can control the position, the bond types, the functional groups and the concentrations.

"In the future -- and it might be years -- you should be able to make a device with one kind of functional growth in one area and another functional growth in another area. They will work differently but still be part of one compact, cheap device," he said. "In the beginning, there was very little organic chemistry you could do with graphene. Now we can do almost all of it. This opens up a lot of possibilities."

The paper's co-authors are graduate students Daniela Marcano, Gedeng Ruan and Zheng Yan, former graduate student Jun Yao, postdoctoral researcher Yu Zhu and visiting student Chenguang Zhang, all of Rice.

The work was supported by the Air Force Office of Scientific Research, Sandia National Laboratory, the Nanoscale Science and Engineering Initiative of the National Science Foundation and the Office of Naval Research MURI graphene program.

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The above story is reprinted from materials provided by Rice University.

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Journal Reference:

Zhengzong Sun, Cary L. Pint, Daniela C. Marcano, Chenguang Zhang, Jun Yao, Gedeng Ruan, Zheng Yan, Yu Zhu, Robert H. Hauge, James M. Tour. Towards hybrid superlattices in graphene. Nature Communications, 2011; 2: 559 DOI: 10.1038/ncomms1577