Unique nano-capsules promise the targeted drug delivery


Nano Capsule Target Drug Delivery 050416 160504121448_1_540x360

A method of manufacturing of containers and their nano-structure depending on the temperature.
Credit: Igor Potemkin/Scientific Reports
Scientists created unique nano-capsules for the targeted drug delivery

By now, the research is quite fundamental. However, one of the authors, Igor Potemkin (Professor of the Chair of Polymer and Crystal Physics, Physics Department, the Lomonosov Moscow State University) argues that the creation of the perfect nano-capsules for targeted drug delivery would be possible on the basis of the reported system in the nearest years, and the production will be relatively cheap.

Scientists have been engaged with drug delivery systems for a long time. Many laboratories in the world are working on their creation, as the promise of this approach is enormous. A lot of “nano-carriages” for drug delivery to the right address were created, but the scientists still faced many challenges. The major among them is considered the problem of how not to let the medicine act before it gets to the right place in a body.

‘Many existing carriers encapsulate drugs through the long-range electrostatic interactions — the carrier attracts oppositely charged medicine. Our method does not deal with the electrostatics at all. Filling in the nanogel by the guest molecules, locking them in the cavity and further release arecontrolled by the temperature. Therefore, the medicines themselves can be both charged and neutral,’ says one of the Russian co-authors of the article, Professor Igor Potemkin.

According to the authors, there are other tools to trigger the release of drugs, for example, an external magnetic field and pH. But in each case researchers face the problem of efficiency of the drug release.

The scientists decided to use the gel nano-capsules that were previously undervalued as the carrier systems. Their main problem, which held back the interest towards them, was that the capsules stuck together with their neighbors (lost colloidal stability) when trying to “upload” drugs. Such behavior made the delivery impossible (or ineffective). The scientists managed to solve this problem by creating a carrier, the inner cavity of which, like an egg with two shells, is surrounded by two “membranes” of different chemical structures.

The outer porous shell plays a protective (stabilizing) role and hinders aggregation of the nano-capsules, while the pores of the inner shell can open and close depending on the temperature due to the variable interactions between its monomeric units.

At the time of filling, the pores of both shells are open and the nanogel absorbs the drug molecules as a sponge.Then the temperature changes and the pores of the inner shell close, and locked in the cavity, the drug is ready for the delivery. Subsequently, the pores will open again and the guest molecules will be releasedonly in the places where the temperature allows.

The way of the nanogel design was reduced to the synthesis of two nanogel shells of different chemical structuresaround the silica core. At the end of the synthesis the core was chemically dissolved, leaving only the “empty space” (cavity).

The major difficulty of this work was the fact that researchers have largely gone blindly, not knowing for sure how the nano-capsule is going to behave, whether its cavity remains stable after removal of the silicon core or it collapses, whether the size of the pore is sufficient to absorb the transported substance and then release it, and whether it is locked reliably during transportation. Fortunately, these fears proved groundless — in response to the temperature changes, the pores opened and closed. “On the road” (in the experiment, there was no actual “road”- the researchers studied the loss from the cavity with the time passing), the contents of the capsules were almost completely safe, and the inner cavity was not only stable in the shape: it became even larger than the initial size of the silicacore.

Synthesis of the nanogel capsules and the related measurements were conducted in Europe, mainly in Germany, and Russian scientists from the Lomonosov Moscow State University, Igor Potemkin and his colleague Andrey Rudov, worked on the computer modeling that allowed researchers to study the dependence of the nano-capsules’ structure on the temperature. Also, the Lomonosov Moscow State University physicists simulated a way of encapsulation and release of the transported molecules under temperature variation.

At this stage, the work was purely fundamental and was intended primarily to demonstrate the effectiveness of the concept. Experiments were carried out in the temperature range of 32-42°C. It is slightly more than the temperature range favorable for a human, although in the future this range can be easily narrowed, states Igor Potemkin.

The scientific collaboration is going to be prolonged for another four years. ‘There are still many questions,’ the scientist says. ‘For example, we have “caught” a structure in which a cavity does not collapse as the pores are closed. Now we need to understandwhy it happens, how does the density of the layers’ crosslink effect, i.e., what is the minimum amount of crosslinker that does not lead to a collapse of the cavity, and so on. ”

Potemkin is sure that in any case the created nano-containers are the ideal carriers for targeted drug delivery. Moreover, their synthesis is neither complex nor really expensive. Although at current stage of research it is difficult to pronounce the precise cost, the collaboration’s plans already include the creation of the large-scale,commercially acceptable production of nanogels.


Story Source:

The above post is reprinted from materials provided byLomonosov Moscow State University. Note: Materials may be edited for content and length.

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New cancer therapy uses nanoparticles to reprogram immune cells


Electronics-research-001(Nanowerk News) Researchers at the University of  Georgia are developing a new treatment technique that uses nanoparticles to  reprogram immune cells so they are able to recognize and attack cancer. The  findings were published recently in the early online edition of ACS  Nano (“Ex Vivo Programming of Dendritic Cells by  Mitochondria-Targeted Nanoparticles to Produce Interferon-Gamma for Cancer  Immunotherapy”).
The human body operates under a constant state of martial law.  Chief among the enforcers charged with maintaining order is the immune system, a  complex network that seeks out and destroys the hordes of invading bacteria and  viruses that threaten the organic society as it goes about its work.
The immune system is good at its job, but it’s not perfect. Most  cancerous cells, for example, are able to avoid detection by the immune system  because they so closely resemble normal cells, leaving the cancerous cells free  to multiply and grow into life-threatening tumors while the body’s only  protectors remain unaware.
“What we are working on is specifically geared toward breast  cancer,” said Dhar, the study’s co-author and an assistant professor of  chemistry in the UGA Franklin College of Arts and Sciences. “Our paper reports  for the first time that we can stimulate the immune system against breast cancer  cells using mitochondria-targeted nanoparticles and light using a novel  pathway.”
In their experiments, Dhar and her colleagues exposed cancer  cells in a petri dish to specially designed nanoparticles 1,000 times finer than  the width of a human hair. The nanoparticles invade the cell and penetrate the  mitochondria?the organelles responsible for producing the energy a cell needs to  grow and replicate.
They then activated the nanoparticles inside the cancer cells by  exposing them to a tissue-penetrating long wavelength laser light. Once  activated, the nanoparticles disrupt the cancer cell’s normal processes,  eventually leading to its death.
The dead cancer cells were collected and exposed to dendritic  cells, one of the core components of the human immune system. What the  researchers saw was remarkable.
“We are able to potentially overcome some of the traditional  drawbacks to today’s dendritic cell immunotherapy,” said Sean Marrache, a  graduate student in Dhar’s lab. “By targeting nanoparticles to the mitochondria  of cancer cells and exposing dendritic cells to these activated cancer cells, we  found that the dendritic cells produced a high concentration of chemical signals  that they normally don’t produce, and these signals have traditionally been  integral to producing effective immune stimulation.”
Dhar added that the “dendritic cells recognized the cancer as  something foreign and began to produce high levels of interferon-gamma, which  alerts the rest of the immune system to a foreign presence and signals it to  attack. We basically used the cancer against itself.”
She cautions that the results are preliminary, and the approach  works only with certain forms of breast cancer. But if researchers can refine  the process, this technology may one day serve as the foundation for a new  cancer vaccine used to both prevent and treat disease.
“We particularly hope this technique could help patients with  advanced metastatic disease that has spread to other parts of the body,” said  Dhar, who also is a member of the UGA Nanoscale Science and Engineering Center,  Cancer Center and Center for Drug Discovery.
If the process were to become a treatment, doctors could biopsy  a tumor from the patient and kill the cancerous cells with nanoparticles. They  could then produce activated dendritic cells in bulk quantities in the lab under  controlled conditions before the cells were injected into the patient.
Once in the bloodstream, the newly activated cells would alert  the immune system to the cancer’s presence and destroy it.
“These are the things we can now do with nanotechnology,” Dhar  said. “If we can refine the process further, we may be able to use similar  techniques against other forms of cancer as well.”
Source: University of Georgia

Read more: http://www.nanowerk.com/news2/newsid=31827.php#ixzz2jKmxve36

Nanotech system, cellular heating may improve treatment of ovarian cancer


Oct 17, 2013 
    

       Nanotech system, cellular heating may improve treatment of ovarian cancerEnlarge        

 A new drug delivery system that incorporates heat, nanotechnology and chemotherapy shows promise in improving the treatment of ovarian cancer. Credit: Oregon State University

The combination of heat, chemotherapeutic drugs and an innovative delivery system based on nanotechnology may significantly improve the treatment of ovarian cancer while reducing side effects from toxic drugs, researchers at Oregon State University report in a n

The findings, so far done only in a laboratory setting, show that this one-two punch of mild hyperthermia and chemotherapy can kill 95 percent of ovarian cells, and scientists say they expect to improve on those results in continued research.

The work is important, they say, because – one of the leading causes of cancer-related deaths in women – often develops resistance to if it returns after an initial remission. It kills more than 150,000 women around the world every year.

“Ovarian cancer is rarely detected early, and because of that chemotherapy is often needed in addition to surgery,” said Oleh Taratula, an assistant professor in the OSU College of Pharmacy. “It’s essential for the chemotherapy to be as effective as possible the first time it’s used, and we believe this new approach should help with that.”

It’s known that elevated temperatures can help kill , but heating just the cancer cells is problematic. The new system incorporates the use of  nanoparticles that can be coated with a cancer-killing drug and then heated once they are imbedded in the cancer cell.

Other features have also been developed to optimize the new system, in an unusual collaboration between engineers, material science experts and pharmaceutical researchers.

A peptide is used that helps guide the nanoparticle specifically to cancer cells, and the nanoparticle is just the right size – neither too big nor too small – so the immune system will not reject it. A special polyethylene glycol coating further adds to the “stealth” effect of the nanoparticles and keeps them from clumping up. And the interaction between the cancer drug and a polymer on the nanoparticles gets weaker in the acidic environment of cancer cells, aiding release of the drug at the right place.

“The hyperthermia, or heating of cells, is done by subjecting the magnetic nanoparticles to an oscillating, or alternating magnetic field,” said Pallavi Dhagat, an associate professor in the OSU School of Electrical Engineering and Computer Science, and co-author on the study. “The absorb energy from the oscillating field and heat up.”

The result, in laboratory tests with , was that a modest dose of the chemotherapeutic drug, combined with heating the cells to about 104 degrees, killed almost all the cells and was far more effective than either the drug or heat treatment would have been by itself.

Doxorubicin, the cancer drug, by itself at the level used in these experiments would leave about 70 percent of the cancer cells alive. With the new approach, only 5 percent were still viable.

The work was published in the International Journal of Pharmaceutics, as a collaboration of researchers in the OSU College of Pharmacy, College of Engineering, and Ocean NanoTech of Springdale, Ark. It was supported by the Medical Research Foundation of Oregon, the PhRMA Foundation and the OSU College of Pharmacy.

“I’m very excited about this delivery system,” Taratula said. “Cancer is always difficult to treat, and this should allow us to use lower levels of the toxic chemotherapeutic drugs, minimize side effects and the development of drug resistance, and still improve the efficacy of the treatment. We’re not trying to kill the cell with heat, but using it to improve the function of the drug.”

Iron oxide particles had been used before in some medical treatments, researchers said, but not with the complete system developed at OSU. Animal tests, and ultimately human trials, will be necessary before the new system is available for use.

Drug delivery systems such as this may later be applied to other forms of cancer, such as prostate or pancreatic cancer, to help improve the efficacy of  in those conditions, Taratula said.

Explore further:     New ovarian cancer treatment succeeds in the lab

Read more at: http://phys.org/news/2013-10-nanotech-cellular-treatment-ovarian-cancer.html#jCp

Read more at: http://phys.org/news/2013-10-nanotech-cellular-treatment-ovarian-cancer.html#jCp

Super Science: Nanotechnology


Published on Jun 17, 2013

http://youtu.be/a8FM9umJXvo

nanomanufacturing-2Imagine a tiny robot the size of a human cell, injected by the millions into your bloodstream on a search and destroy mission: to locate cancer cells, and kill them. Welcome to the scientific frontier of nanotechnology

Nanoparticles Enable Earlier Cancer Diagnosis


QDOTS imagesCAKXSY1K 8 From Science Daily, Dec. 17, 2012 — Finding ways to diagnose cancer earlier could greatly improve the chances of survival for many patients. One way to do this is to look for specific proteins secreted by cancer cells, which circulate in the bloodstream. However, the quantity of these biomarkers is so low that detecting them has proven difficult.


 A new technology developed at MIT may help to make biomarker detection much easier. The researchers, led by Sangeeta Bhatia, have developed nanoparticles that can home to a tumor and interact with cancer proteins to produce thousands of biomarkers, which can then be easily detected in the patient’s urine.

This biomarker amplification system could also be used to monitor disease progression and track how tumors respond to treatment, says Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science at MIT.

“There’s a desperate search for biomarkers, for early detection or disease prognosis, or looking at how the body responds to therapy,” says Bhatia, who is also a member of MIT’s David H. Koch Institute for Integrative Cancer Research. She adds that the search has been complicated because genomic studies have revealed that many cancers, such as breast cancer, are actually groups of several diseases with different genetic signatures.

The MIT team, working with researchers from Beth Israel Deaconess Medical Center, described the new technology in a paper appearing in Nature Biotechnology on Dec. 16. Lead author of the paper is Gabriel Kwong, a postdoc in MIT’s Institute for Medical Engineering and Science and the Koch Institute.

Amplifying cancer signals

Cancer cells produce many proteins not found in healthy cells. However, these proteins are often so diluted in the bloodstream that they are nearly impossible to identify. A recent study from Stanford University researchers found that even using the best existing biomarkers for ovarian cancer, and the best technology to detect them, an ovarian tumor would not be found until eight to 10 years after it formed.

“The cell is making biomarkers, but it has limited production capacity,” Bhatia says. “That’s when we had this ‘aha’ moment: What if you could deliver something that could amplify that signal?”

Serendipitously, Bhatia’s lab was already working on nanoparticles that could be put to use detecting cancer biomarkers. Originally intended as imaging agents for tumors, the particles interact with enzymes known as proteases, which cleave proteins into smaller fragments.

Cancer cells often produce large quantities of proteases known as MMPs. These proteases help cancer cells escape their original locations and spread uncontrollably by cutting through proteins of the extracellular matrix, which normally holds cells in place.

The researchers coated their nanoparticles with peptides (short protein fragments) targeted by several of the MMP proteases. The treated nanoparticles accumulate at tumor sites, making their way through the leaky blood vessels that typically surround tumors. There, the proteases cleave hundreds of peptides from the nanoparticles, releasing them into the bloodstream.

The peptides rapidly accumulate in the kidneys and are excreted in the urine, where they can be detected using mass spectrometry.

This new system is an exciting approach to overcoming the problem of biomarker scarcity in the body, says Sanjiv Gambhir, chairman of the Department of Radiology at Stanford University School of Medicine. “Instead of being dependent on the body to naturally shed biomarkers, you’re sampling the site of interest and causing biomarkers that you engineered to be released,” says Gambhir, who was not part of the research team.

Distinctive signatures

To make the biomarker readings as precise as possible, the researchers designed their particles to express 10 different peptides, each of which is cleaved by a different one of the dozens of MMP proteases. Each of these peptides is a different size, making it possible to distinguish them with mass spectrometry. This should allow researchers to identify distinct signatures associated with different types of tumors.

In this study, the researchers tested their nanoparticles’ ability to detect the early stages of colorectal cancer in mice, and to monitor the progression of liver fibrosis.

Liver fibrosis is an accumulation of scarring in response to liver injury or chronic liver disease. Patients with this condition have to be regularly monitored by biopsy, which is expensive and invasive, to make sure they are getting the right treatment. In mice, the researchers found that the nanoparticles could offer much more rapid feedback than biopsies.

They also found that the nanoparticles could accurately reveal the early formation of colorectal tumors. In ongoing studies, the team is studying the particles’ ability to measure tumor response to chemotherapy and to detect metastasis.

The research was funded by the National Institutes of Health and the Kathy and Curt Marble Cancer Research Fund.

The nanomechanical signature of breast cancer


Using ARTIDIS to feel the tissue structure of a tumor biopsy by a nanometer-sized atomic force microscope tip. Image: Martin Oeggerli

 

 

 

 

 

 

Using ARTIDIS to feel the tissue structure of a tumor biopsy by a nanometer-sized atomic force microscope tip. Image: Martin Oeggerli

The spread of cancer cells from primary tumors to other parts of the body remains the leading cause of cancer-related deaths. The research groups of Roderick Lim and Cora-Ann Schoenenberger from the Biozentrum of the University of Basel, reveal in the journal Nature Nanotechnology how the unique nanomechanical properties of breast cancer cells are fundamental to the process of metastasis. The discovery of specific breast cancer “fingerprints” was made using breakthrough nanotechnology known as ARTIDIS. Lim’s team has now been awarded about 1.2 million Swiss francs from the Commission for Technology and Innovation (CTI) to further develop ARTIDIS.
Breast cancer is the most common form of cancer in women with 5,500 patients being diagnosed with the disease in Switzerland each year. Despite major scientific advancements in our understanding of the disease, breast cancer diagnostics remains slow and subjective. Here, the real danger lies in the lack of knowing whether metastasis, the spread of cancer, has already occurred. Nevertheless, important clues may be hidden in how metastasis is linked to specific structural alterations in both cancer cells and the surrounding extracellular matrix. This forms the motivation behind ARTIDIS (“Automated and Reliable Tissue Diagnostics”), which was conceived by Dr. med. Marko Loparic, Dr. Marija Plodinec and Prof. Roderick Lim to measure the local nanomechanical properties of tissue biopsies.

Fingerprintingbreast tumors
At the heart of ARTIDIS lies an ultra-sharp atomic force microscope tip of several nanometers in size that is used as a local mechanical probe to “feel” the cells and extracellular structures within a tumor biopsy. In this way, a nanomechanical “fingerprint” of the tissue is obtained by systematically acquiring tens of thousands of force measurements over an entire biopsy.

Subsequent analysis of over one hundred patient biopsies could confirm that the fingerprint of malignant breast tumors is markedly different as compared to healthy tissue and benign tumors. This was validated by histological analyses carried out by clinicians at the University Hospital Basel, which showed a complete agreement with ARTIDIS. Moreover, the same nanomechanical fingerprints were found in animal studies initiated at the Friedrich Miescher Institute.

Plodinec, first author of the study, explains: “This unique fingerprint reflects the heterogeneous make-up of malignant tissue whereas healthy tissue and benign tumors are more homogenous.” Strikingly, malignant tissue also featured a marked predominance of “soft” regions that is a characteristic of cancer cells and the altered microenvironment at the tumor core. The significance of these findings lies in reconciling the notion that soft cancer cells can more easily deform and “squeeze” through their surroundings. Indeed, the presence of the same type of “soft” phenotype in secondary lung tumors of mice reinforces the close correlation between the physical properties of cancer cells and their metastatic potential.

ARTIDIS in the clinics
“Resolving such basic scientific aspects of cancer further underscores the use of nanomechanical fingerprints as quantitative markers for cancer diagnostics with the potential to prognose metastasis,” states Loparic, who is project manager for ARTIDIS. On an important practical note, a complete biopsy analysis by ARTIDIS currently takes four hours in comparison to conventional diagnostics, which can take one week. Based on the potential societal impact of ARTIDIS to revolutionize breast cancer diagnostics, Lim’s team and the Swiss company Nanosurf AG have now been awarded about 1.2 million Swiss francs by the Commission for Technology and Innovation (CTI) to further develop ARTIDIS into a state-of-the-art device for disease diagnostics with further applications in nanomedicine.

Over the next two years, Lim and colleagues will engage and work closely with clinicians to develop ARTIDIS into an easy-to-use “push-button” application to fingerprint diseases across a wide range of biological tissues. As a historical starting point, the first ARTIDIS demo-lab has already been established at the University Hospital Eye Clinic to collect data on retinal diseases with the goal of improving treatment strategies.

The nanomechanical signature of breast cancer

Source: University of Basel