Treating triple-negative breast cancer gets new immunotherapy option without side effects

Smaller than a grain of rice, this tiny device, invented by a Houston Methodist nanoscientist, delivers immunotherapy straight into a tumor, eliminating both side effects and the need for multiple IV treatments.

Single Direct-to-tumor Drug-delivery Device Offers Hope for Treating Triple-negative Breast Cancer

Houston Methodist scientists have developed a nanodevice to deliver immunotherapy without side effects to treat triple-negative breast cancer. Inserted straight into a tumor, this nanofluidic seed makes it possible to deliver a one-time, sustained-release dose that would eliminate the need for patients to undergo several IV treatments over time.

Invented by Alessandro Grattoni, Ph.D., chairman of the Department of Nanomedicine at the Houston Methodist Research Institute, this tiny device is smaller than a grain of rice and, once inserted inside a tumor, can deliver the medication little by little, gradually releasing the drug from its reservoir.

“With this research we are trying to establish a novel strategy to deliver immunotherapy straight into a tumor instead of delivering it to the whole body of a patient,” Grattoni said. “And we’re trying to understand whether delivering it this way would actually be more effective and have less side effects as compared to conventional immunotherapy, which today is given to the entire body of the patient.”

Grattoni and team are not alone in studying ways to administer immunotherapeutics intratumorally. What distinguishes his approach from others is the use of the implantable nanodevice that can be placed inside the tumor very accurately, with just one, simple procedure and with the ability to sustain the delivery of the immunotherapy over a prolonged period of time.

“Timing of the release may be extremely important,” said E. Brian Butler, M.D., chair of the Department of Radiation Oncology at Houston Methodist and Grattoni’s co-senior author on a recent paper in the Journal of Controlled Release. “These immunotherapy payloads Dr. Grattoni created come in a little metal device with nanochannels that release the medication at a constant rate in a controlled way.”

Grattoni, who also is the corresponding author, says that by providing sustained doses, their implant maintains an active level of the drug for extended periods of time. This would reduce the need for continual clinic visits, which are usually required for immunotherapy and other cancer treatments.

By contrast, most other methods currently under preclinical and clinical trials require multiple injections into the tumor and, in many instances, necessitate repeated invasive procedures to access it. Additionally, injecting drugs straight into a tumor as a single dose may not be very effective, as only a part of it will stay, with the rest being rapidly eliminated due to the high-pressure nature of a tumor’s microenvironment. Grattoni’s intratumoral sustained-delivery method prevents this from happening.

“We’re in the middle of an exciting time in medicine, because if we can get it to work, you decrease the toxicities to the patient,” Butler said. “This offers the opportunity of treating locally and getting the systemic response without all the side effects.”

Grattoni likens their device to an hourglass.

“Our implant releases the drug in a constant manner until the entire amount is completely gone from the reservoir,” Grattoni said. “Since it can deliver the immunotherapy by itself for weeks to potentially months, we would only need to place the device inside the tumor once and then the drug would be released autonomously for that long period of time.”

While this platform technology can be applied to many different types of cancer, they chose to work on triple-negative breast cancer, since there’s not currently a good therapeutic approach for treating patients that are affected by the disease.

Breast cancer is traditionally not considered immunogenic, which means it may not respond well to immunotherapy, but triple-negative breast cancer (TNBC) is more immunogenic than other breast cancer subtypes. This is another reason why the researchers chose to focus on it. They are trying to make TNBC more responsive to the treatment with their implant.

“In this study we demonstrated in mice that our intratumoral delivery of immunotherapy was equally effective compared to systemic immunotherapy treatment,” Grattoni said. “The difference was that the systemic immunotherapy showed significant side effects, while our device delivered the same effective treatment without side effects. We were, in fact, able to completely eliminate side effects, which was very surprising to us.”

The next phase of their research, also in mice, will be to combine the device with radiation therapy to see if this approach can improve on the effectiveness currently achieved through systemic delivery of immunotherapy and not just equal it.

“Using Dr. Grattoni’s nanodevice in conjunction with our clinic, we hope to create a very robust immunological response, by putting the immunotherapy directly into the tumor, which is where all the information is,” Butler said. “This will allow us to possibly harness the full power of a person’s immune system to destroy the cancer, offering the opportunity to get the systemic response, while treating locally, without all the side effects.”

In addition to the sustained release system, Grattoni’s nanodevice serves as a fiducial marker to facilitate precise delivery for image-guided radiation. Their hope is that in combination with radiation therapy, this device would not only provide an alternative, but also help improve upon current immunotherapeutic approaches.

“We are hoping to go to patients within three years,” Grattoni said. “We would definitely improve on what is out there currently and what other groups are already studying.”




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Injectable soft biomaterial could be used to manipulate organ behavior

A transmission X-ray microscopy 3-D data set of one region of a mesostructured silicon particle, suggesting spongy structures. The purple square measures 8.28 microns along the top edges, which is much less than the width of a human hair.Courtesy ofTian Lab

A transmission X-ray microscopy 3-D data set of one region of a mesostructured silicon particle, suggesting spongy structures. The purple square measures 8.28 microns along the top edges, which is much less than the width of a human hair.Courtesy of Tian Lab

Silicon-based invention is tiny, soft, wirelessly functional

In the campy 1966 science fiction movie “Fantastic Voyage,” scientists miniaturize a submarine with themselves inside and travel through the body of a colleague to break up a potentially fatal blood clot. Micro-humans aside, imagine the inflammation that metal sub would cause.

Ideally, injectable or implantable medical devices should not only be small and electrically functional, they should be soft, like the body tissues with which they interact. Scientists from two UChicago labs set out to see if they could design a material with all three of those properties.

The material they came up with, the subject of a study published June 27 in Nature Materials, forms the basis of an ingenious light-activated injectable device that could eventually be used to stimulate nerve cells and manipulate the behavior of muscles and organs.

“Most traditional materials for implants are very rigid and bulky, especially if you want to do electrical stimulation,” said Bozhi Tian, an assistant professor in chemistry whose lab collaborated with that of neuroscientist Francisco Bezanilla, the Lillian Eichelberger Cannon Professor of Biochemistry and Molecular Biology.

The new material, in contrast, is soft and tiny, composed of particles just a few micrometers in diameter—far less than the width of a human hair—that disperse easily in a saline solution so they can be injected. The particles also degrade naturally inside the body after a few months, so no surgery would be needed to remove them.

Nanoscale ‘sponge’

Each particle is built of two types of silicon that together form a structure full of nano-scale pores, like a tiny sponge. And like a sponge, it is also squishy—a hundred to a thousand times less rigid than the familiar crystalline silicon used in transistors and solar cells. “It is comparable to the rigidity of the collagen fibers in our bodies,” said Yuanwen Jiang, Tian’s graduate student. “So we’re creating a material that matches the rigidity of real tissue.”

The material constitutes half of an electrical device that creates itself spontaneously when one of the silicon particles is injected into a cell culture, or, eventually, a human body. The particle attaches to a cell, making an interface with the cell’s plasma membrane. Those two elements together—cell membrane plus particle—form a unit that generates current when light is shined on the silicon particle.

“You don’t need to inject the entire device; you just need to inject one component,” said João L. Carvalho-de-Souza, a postdoctoral scholar in Bezanilla’s lab. “This single particle connection with the cell membrane allows sufficient generation of current that could be used to stimulate the cell and change its activity. After you achieve your therapeutic goal, the material degrades naturally. And if you want to do therapy again, you do another injection.“

The scientists built the particles using a process they call nano-casting. They fabricate a silicon dioxide mold composed of tiny channels, or “nano-wires,” about seven nanometers in diameter and connected by much smaller “micro-bridges.” Into the mold they inject silane gas, which fills the pores and channels and decomposes into silicon.

And this is where things get particularly cunning. The scientists exploit the fact the smaller an object is, the more the atoms on its surface dominate its reactions to what is around it. The micro-bridges are minute, so most of their atoms are on the surface. These interact with oxygen that is present in the silicon dioxide mold, creating micro-bridges made of oxidized silicon gleaned from materials at hand. The much larger nano-wires have proportionately fewer surface atoms, are much less interactive and remain mostly pure silicon.

“This is the beauty of nanoscience,” Jiang said. “It allows you to engineer chemical compositions just by manipulating the size of things.”

Web-like nanostructure

Finally, the mold is dissolved. What remains is a web-like structure of silicon nano-wires connected by micro-bridges of oxidized silicon that can absorb water and help increase the structure’s softness. The pure silicon retains its ability to absorb light.

The scientists have added the particles onto neurons in culture in the lab, shone light on the particles, and seen current flow into the neurons which activates the cells. The next step is to see what happens in living animals. They are particularly interested in stimulating nerves in the peripheral nervous system that connect to organs. These nerves are relatively close to the surface of the body, so near-infra-red wavelength light can reach them through the skin.

Tian imagines using the light-activated devices to engineer human tissue and create artificial organs to replace damaged ones. Currently, scientists can make engineered organs with the correct form but not the ideal function.

To get a lab-built organ to function properly, they will need to be able to manipulate individual cells in the engineered tissue. The injectable device would allow a scientist to do that, tweaking an individual cell using a tightly focused beam of light like a mechanic reaching into an engine and turning a single bolt. The possibility of doing this kind of synthetic biology without genetic engineering is enticing.

“No one wants their genetics to be altered,” Tian said. “It can be risky. There’s a need for a non-genetic system that can still manipulate cell behavior. This could be that kind of system.”

Jiang did the material development and characterization on the project, while Carvalho-de-Souza did the biological component of the collaboration in Bezanilla’s lab. They were, said Tian, the “heroes” of the work.

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Scientists develop self-constructing nanodevices for diagnosing diseases



Motor vehicles were created in the 19th century as an efficient mode of transportation. As useful as they’ve proven to be, cars do not manufacture themselves, nor is it inexpensive to build one.  Scientists working at the Henderson lab at Iowa State University have successfully designed machines at the nanoscale that do just that — construct itself with regard to a difficult task at hand.

The scientists responsible for the development are Eric Henderson, a professor of genetics, development and cell biology at Iowa State University, and his former graduate student, Divita Mathur.

“These nanodevices have all these good qualities,” Mathur said. “[They] work a lot like normal-sized machines.”

The nanodevice is called OPTIMuS, and it works as a sensor to detect molecules at the nanoscale.

“In this case, these nanodevices can detect Ebola-mock DNA, which means that it can tell us if a sample has DNA sequences that are similar to the Ebola virus genome,” Mathur said.

Upon capturing a target molecule, OPTIMuS changes its shape. The shape change leads to a change in a fluorescent light signal received from the nanodevice. The fluorescence is then recorded by the lab. From there, the lab can analyze whether the target molecule is present or not.

“Like any machine, OPTIMuS takes input from the environment and releases a user-observable output,” Mathur said.

About 40 billion individual machines fit in a single drop of water, Professor Henderson said in a release, and the trick to creating the machines lies in understanding the rules that govern how DNA works.

OPTIMuS was constructed using DNA. DNA naturally lends itself programmable self-assembly, Mathur said.

When hundreds of DNA strands are heated and cooled, after being placed in a tube of water, millions of DNA nanostructures will form, making the construction of nanodevices inexpensive and simple.

“What you see here is a culmination of 5 years of research,” Mathur said. “It was only me and Eric who invested our time and energy on the work but we had some help for imaging the nanodevices from experts.”

Mathur said that her initial reason for joining Henderson’s lab was research, but after a few weeks in the lab, she found the environment to be extremely friendly, and she also enjoyed the independent aspect of the lab.

“Eric’s a great mentor for learning about science and research,” Mathur said. “If [students] run into any problems, Eric is always there to nudge them in the right direction.”

Mathur is a native of India, and she is currently a postdoctoral research fellow at the US Naval Research Laboratory in Washington, D.C. Mathur believes that she has a real passion for problem solving.

“I enjoy working with DNA to engineer nanoscale devices because it is a way of solving larger problems using a great nanosized building material,” Mathur said. “Doing research is a very deliberate and meticulous way of reaching solutions, so here I am!”

Mathur has five contributory published articles under her belt, as well as two first author publications, which includes the article describing her and Henderson’s nanodevice designs. The article can be found in the peer- reviewed journal “Scientific Reports.”

The next step for these nanodevices is to test them for detecting other target molecules, which will include real viral samples.

“We have achieved the first step in a process of engineering a fully functional diagnostic tool – we have demonstrated a working prototype,” Mathur said. “The end goal, truly, is to see this doing its magic as a point-of-care diagnostic tool for everybody’s use.”

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Scientists engineer tunable DNA for electronics applications

Over short distances, electrons flow across DNA and spread fast like waves across a pond. Across longer distances, they behave more like particles and hopping takes effect. “Think of trying to get across a river,” explained Limin Xiang, a postdoctoral researcher in Biodesign Institute researcher Nongjian Tao’s lab. “You can either walk across quickly on a bridge or try to hop from one rock to another.”

Over short distances, electrons flow across DNA and spread fast like waves across a pond. Across longer distances, they behave more like particles and hopping takes effect. “Think of trying to get across a river,” explained Limin Xiang, a postdoctoral researcher in Biodesign Institute researcher Nongjian Tao’s lab. “You can either walk across quickly on a bridge or try to hop from one rock to another.”

DNA may be the blueprint of life, but it’s also a molecule made from just a few simple chemical building blocks. Among its properties is the ability to conduct an electrical charge, fueling an engineering race to develop novel, low-cost nanoelectronic devices.

Now, a team led by ASU Biodesign Institute researcher Nongjian “N.J.” Tao and Duke theorist David Beratan has been able to understand and manipulate DNA to more finely tune the flow of electricity through it. The key findings, which can make DNA behave in different ways — cajoling electrons to smoothly flow like electricity through a metal wire, or hopping electrons about like the semiconductors materials that power our computers and cellphones — pave the way for an exciting new avenue of research advancements.

The results, published in the online edition of Nature Chemistry, may provide a framework for engineering more stable and efficient DNA nanowires, and for understanding how DNA conductivity might be used to identify gene damage.

Building on a series of recent works, the team has been able to better understand the physical forces behind DNA’s affinity for electrons.

“We’ve been able to show theoretically and experimentally that we can make DNA tunable by changing the sequence of the ‘A, T, C, or G’ chemical bases, by varying its length, by stacking them in different ways and directions, or by bathing it in different watery environments,” said Tao, who directs the Biodesign Center for Biolectronics and Biosensors and is a professor in the Ira A. Fulton Schools of Engineering.

Along with Tao, the research team consisted of ASU colleagues, including lead co-author Limin Xiang and Yueqi Li, and Duke University’s Chaoren Liu, Peng Zheng and David Beratan.

Untapped potential

Every molecule or substance has its own unique attraction for electrons — the negatively charged particles that dance around every atom. Some molecules are selfish and hold onto or gain electrons at all costs, while others are far more generous, donating them more freely to others in need.

But in the chemistry of life, it takes two to tango. For every electron donor there is an acceptor. These different electron dance partners drive so-called redox reactions, providing energy for the majority of the basic chemical processes in our bodies.

For example, when we eat food, a single sugar molecule gets broken down to generate 24 electrons that go on to fuel our bodies. Every DNA molecule contains energy, known as a redox potential, measured in tenths of electron volts. This electrical potential is similarly generated in the outer membrane of every nerve cell, where neurotransmitters trigger electronic communication between the 100 trillion neurons that form our thoughts.

But here’s where the ability of DNA to conduct an electrical charge gets complicated. And it’s all because of the special properties of electrons — where they can behave like waves or particles due to the inherent weirdness of quantum mechanics.

Scientists have long disagreed over exactly how electrons travel along strands of DNA, said David N. Beratan, professor of chemistry at Duke University and leader of the Duke team.

“Think of trying to get across a river,” explained Limin Xiang, a postdoctoral researcher in Tao’s lab. “You can either walk across quickly on a bridge or try to hop from one rock to another. The electrons in DNA behave in similar ways as trying to get across the river, depending on the chemical information contained within the DNA.”

Previous findings by Tao (pictured left) showed that over short distances, the electrons flow across DNA by quantum tunneling that spread fast like waves across a pond. Across longer distances, they behave more like particles and the hopping takes effect.

This result was intriguing, said Duke graduate student and co-lead author Chaoren Liu, because electrons that travel in waves are essentially entering the “fast lane,” moving with more organization and efficiency than those that hop.

“In our studies, we first wanted to confirm that this wave-like behavior actually existed over longer distances,” Liu said. “And second, we wanted to understand the mechanism so that we could make this wave-like behavior stronger or extend it to longer distances.“

Flick of the switch

DNA strands are built like chains, with each link comprising one of four molecular bases whose sequence codes the genetic instructions for our cells. Like metal chains, DNA strands can easily change shape, bending, curling and wiggling around as they collide with other molecules around them.

All of this bending and wiggling can disrupt the ability of the electrons to travel like waves. Previously, it was believed that the electrons could only be shared over at most three bases.

Using computer simulations, the Beratan team found that certain sequences of bases could enhance the electron sharing, leading to wave-like behavior over long distances. In particular, they found that stacking alternating series of five guanine (G) bases created the best electrical conductivity.

The team theorizes that creating these blocks of G bases causes them to all “lock” together so the wave-like behavior of the electrons is less likely to be disrupted by the random motions of the DNA strand.

“We can think of the bases being effectively linked together so they all move as one. This helps the electron be shared within the blocks,” Liu said.

Next, the Tao group carried out conductivity experiments on short, six to 16 base strands of DNA, carrying alternating blocks of three to eight guanine bases. By tethering their test DNA between a pair of two gold electrodes, the team could flip on and control a small current to measure the amount of electrical charge flowing through the molecule.

They found that by varying a simple repeating “CxGx” pattern of DNA letters (x is the odd- or even-numbered G or C letters), there was an odd-even pattern in the ability of DNA to transport electrons. With an odd number, there was less resistance, and the electrons flowed faster and more freely (more wave-like) to blaze a path across the DNA.

They were able to exert precise molecular-level control and make the electrons hop (known as incoherent transport, the type found in most semiconductors) or flow faster (coherent transport, the type found in metals) based on variations in the DNA sequence pattern.

The experimental work confirmed the predictions of the theory.

Information charge

The results shed light on a long-standing controversy over the exact nature of electron transport in DNA and might provide insight into the design of DNA nanoelectrics and the role of electron transport in biological systems, Beratan said.

In addition to practical DNA-based electronic applications (for which the group has filed several patents), one of the more intriguing aspects is relating their work — done with short simple stretches of DNA — back to the complex biology of DNA thriving inside of every cell.

Of upmost importance to survival is maintaining the fidelity of DNA to pass along an exact copy of the DNA sequence every time a cell divides. Despite many redundant protection mechanisms in the cell, sometimes things go awry, causing disease. For example, absorbing too much UV light can mutate DNA and trigger skin cancer.

One of the DNA chemical letters, “G,” is the most susceptible to oxidative damage by losing an electron (think of rusting iron — a result of a similar oxidation process). Xiang points out that long stretches of Gs are also found on the ends of every chromosome, maintained by a special enzyme known as telomerase. Shortening of these G stretches has been associated with aging.

But for now, the research team has solved the riddle of how the DNA information influences the electrical charge.

“This theoretical framework shows us that the exact sequence of the DNA helps dictate whether electrons might travel like particles, and when they might travel like waves,” Beratan said. “You could say we are engineering the wave-like personality of the electron.”

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Stretchable nano-devices towards smart contact lenses



Researchers at RMIT University and the University of Adelaide have joined forces to create a stretchable nano-scale device to manipulate light

The device manipulates light to such an extent that it can filter specific colours while still being transparent and could be used in the future to make smart contact lenses.

Using the technology, high-tech lenses could one day filter harmful optical radiation without interfering with vision – or in a more advanced version, transmit data and gather live vital information or even show information like a head-up display.

The light manipulation relies on creating tiny artificial crystals termed  “dielectric resonators”, which are a fraction of the wavelength of light – 100-200 nanometers, or over 500 times thinner than a human hair.

The research combined the University of Adelaide researchers’ expertise in interaction of light with artificial materials with the materials science and nanofabrication expertise at RMIT University.

Dr Withawat Withayachumnankul, from the University of Adelaide’s School of Electrical and Electronic Engineering, said: “Manipulation of light using these artificial crystals uses precise engineering.

“With advanced techniques to control the properties of surfaces, we can dynamically control their filter properties, which allow us to potentially create devices for high data-rate optical communication or smart contact lenses.

“The current challenge is that dielectric resonators only work for specific colours, but with our flexible surface we can adjust the operation range simply by stretching it.”

Associate Professor Madhu Bhaskaran, Co-Leader of the Functional Materials and Microsystems Research Group at RMIT, said the devices were made on a rubber-like material used for contact lenses.

“We embed precisely-controlled crystals of titanium oxide, a material that is usually found in sunscreen, in these soft and pliable materials,” she said.

“Both materials are proven to be bio-compatible, forming an ideal platform for wearable optical devices.

“By engineering the shape of these common materials, we can create a device that changes properties when stretched. This modifies the way the light interacts with and travels through the device, which holds promise of making smart contact lenses and stretchable colour changing surfaces.”

Lead author and RMIT researcher Dr. Philipp Gutruf said the major scientific hurdle overcome by the team was combining high temperature processed titanium dioxide with the rubber-like material, and achieving nanoscale features.

“With this technology, we now have the ability to develop light weight wearable optical components which also allow for the creation of futuristic devices such as smart contact lenses or flexible ultrathin smartphone cameras,” Gutruf said.

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