Purdue University: Nanowire Implants offer Remote-Controlled Drug Delivery: Applications: Spinal Cord Injuries; Chemotherapy

Purdue-signatureA team of researchers has created a new implantable drug-delivery system using nanowires that can be wirelessly controlled.

The nanowires respond to an electromagnetic field generated by a separate device, which can be used to control the release of a preloaded drug. The system eliminates tubes and wires required by other implantable devices that can lead to infection and other complications, said team leader Richard Borgens, Purdue University’s Mari Hulman George Professor of Applied Neuroscience and director of Purdue’s Center for Paralysis Research.

“This tool allows us to apply drugs as needed directly to the site of injury, which could have broad medical applications,” Borgens said. “The technology is in the early stages of testing, but it is our hope that this could one day be used to deliver drugs directly to spinal cord injuries, ulcerations, deep bone injuries or tumors, and avoid the terrible side effects of systemic treatment with steroids or chemotherapy.”

The team tested the drug-delivery system in mice with compression injuries to their spinal cords and administered the corticosteroid dexamethasone. The study measured a molecular marker of inflammation and scar formation in the central nervous system and found that it was reduced after one week of treatment. A paper detailing the results will be published in an upcoming issue of the Journal of Controlled Release and is currently available online.

Purdue U Nano Wire 94283_web

IMAGE: An image of a field of polypyrrole nanowires captured by a scanning electron microscope is shown. A team of Purdue University researchers developed a new implantable drug-delivery system using the… view more

Credit: (Purdue University image/courtesy of Richard Borgens)

The nanowires are made of polypyrrole, a conductive polymer material that responds to electromagnetic fields. Wen Gao, a postdoctoral researcher in the Center for Paralysis Research who worked on the project with Borgens, grew the nanowires vertically over a thin gold base, like tiny fibers making up a piece of shag carpet hundreds of times smaller than a human cell. The nanowires can be loaded with a drug and, when the correct electromagnetic field is applied, the nanowires release small amounts of the payload. This process can be started and stopped at will, like flipping a switch, by using the corresponding electromagnetic field stimulating device, Borgens said.

The researchers captured and transported a patch of the nanowire carpet on water droplets that were used used to deliver it to the site of injury. The nanowire patches adhere to the site of injury through surface tension, Gao said.

The magnitude and wave form of the electromagnetic field must be tuned to obtain the optimum release of the drug, and the precise mechanisms that release the drug are not yet well understood, she said. The team is investigating the release process.

The electromagnetic field is likely affecting the interaction between the nanomaterial and the drug molecules, Borgens said.

“We think it is a combination of charge effects and the shape change of the polymer that allows it to store and release drugs,” he said. “It is a reversible process. Once the electromagnetic field is removed, the polymer snaps back to the initial architecture and retains the remaining drug molecules.”

For each different drug the team would need to find the corresponding optimal electromagnetic field for its release, Gao said.

This study builds on previous work by Borgens and Gao. Gao first had to figure out how to grow polypyrrole in a long vertical architecture, which allows it to hold larger amounts of a drug and extends the potential treatment period. The team then demonstrated it could be manipulated to release dexamethasone on demand. A paper detailing the work, titled “Action at a Distance: Functional Drug Delivery Using Electromagnetic-Field-Responsive Polypyrrole Nanowires,” was published in the journal Langmuir.

Other team members involved in the research include John Cirillo, who designed and constructed the electromagnetic field stimulating system; Youngnam Cho, a former faculty member at Purdue’s Center for Paralysis Research; and Jianming Li, a research assistant professor at the center.

For the most recent study the team used mice that had been genetically modified such that the protein Glial Fibrillary Acidic Protein, or GFAP, is luminescent. GFAP is expressed in cells called astrocytes that gather in high numbers at central nervous system injuries. Astrocytes are a part of the inflammatory process and form a scar tissue, Borgens said.

A 1-2 millimeter patch of the nanowires doped with dexamethasone was placed onto spinal cord lesions that had been surgically exposed, Borgens said. The lesions were then closed and an electromagnetic field was applied for two hours a day for one week. By the end of the week the treated mice had a weaker GFAP signal than the control groups, which included mice that were not treated and those that received a nanowire patch but were not exposed to the electromagnetic field. In some cases, treated mice had no detectable GFAP signal.

Whether the reduction in astrocytes had any significant impact on spinal cord healing or functional outcomes was not studied. In addition, the concentration of drug maintained during treatment is not known because it is below the limits of systemic detection, Borgens said.

“This method allows a very, very small dose of a drug to effectively serve as a big dose right where you need it,” Borgens said. “By the time the drug diffuses from the site out into the rest of the body it is in amounts that are undetectable in the usual tests to monitor the concentration of drugs in the bloodstream.”

Polypyrrole is an inert and biocompatable material, but the team is working to create a biodegradeable form that would dissolve after the treatment period ended, he said.

The team also is trying to increase the depth at which the drug delivery device will work. The current system appears to be limited to a depth in tissue of less than 3 centimeters, Gao said.

Story Source:

The above post is reprinted from materials provided by Purdue University. The original item was written by Elizabeth K. Gardner. Note: Materials may be edited for content and length.

Journal Reference:

  1. Wen Gao, Richard Ben Borgens. Remote-controlled eradication of astrogliosis in spinal cord injury via electromagnetically-induced dexamethasone release from “smart” nanowires. Journal of Controlled Release, 2015; 211: 22 DOI: 10.1016/j.jconrel.2015.05.266

New unique nanostructure to target drug-delivery treatment of cancer cells

Human BodyA unique nanostructure developed by a team of international researchers, including those at the University of Cincinnati, promises improved all-in-one detection, diagnoses and drug-delivery treatment of cancer cells.


The first-of-its-kind nanostructure is unusual because it can carry a variety of cancer-fighting materials on its double-sided (Janus) surface and within its porous interior. Because of its unique structure, the nano carrier can do all of the following:

  • Transport cancer-specific detection nanoparticles and biomarkers to a site within the body, e.g., the breast or the prostate. This promises earlier diagnosis than is possible with today’s tools.
  • Attach fluorescent marker materials to illuminate specific cancer cells, so that they are easier to locate and find for treatment, whether drug delivery or surgery.
  • Deliver anti-cancer drugs for pinpoint targeted treatment of cancer cells, which should result in few drug side effects. Currently, a cancer treatment like chemotherapy affects not only cancer cells but healthy cells as well, leading to serious and often debilitating side effects.

This research, titled “Dual Surface Functionalized Janus Nanocomposites of Polystyrene//Fe304@Si02 for Simultaneous Tumor Cell Targeting and pH-Triggered Drug Release,” will be presented as an invited talk on Oct. 30, 2013, at the annual Materials Science & Technology Conference in Montreal, Canada. Researchers are Feng Wang, a former UC doctoral student and now a postdoc at the University of Houston; Donglu Shi, professor of materials science and engineering at UC’s College of Engineering and Applied Science (CEAS); Yilong Wang of Tongji University, Shanghai, China; Giovanni Pauletti, UC associate professor of pharmacy; Juntao Wang of Tongji University, China; Jiaming Zhang of Stanford University; and Rodney Ewing of Stanford University.

This recently developed Janus nanostructure is unusual in that, normally, these super-small structures (that are much smaller than a single cell) have limited surface. This makes is difficult to carry multiple components, e.g., both cancer detection and drug-delivery materials. The Janus nanocomponent, on the other hand, has functionally and chemically distinct surfaces to allow it to carry multiple components in a single assembly and function in an intelligent manner.

“In this effort, we’re using existing basic nano systems, such as carbon nanotubes, graphene, iron oxides, silica, quantum dots and polymeric nano materials in order to create an all-in-one, multidimensional and stable nano carrier that will provide imaging, cell targeting, drug storage and intelligent, controlled drug release,” said UC’s Shi, adding that the nano carrier’s promise is currently greatest for cancers that are close to the body’s surface, such as breast and prostate cancer.

If such nano technology can someday become the norm for cancer detection, it promises earlier, faster and more accurate diagnosis at lower cost than today’s technology. (Currently, the most common methods used in cancer diagnosis are magnetic resonance imaging or MRI; Positron Emission Tomography or PET; and Computed Tomography or CT imaging, however, they are costly and time consuming to use.)

In addition, when it comes to drug delivery, nano technology like this Janus structure, would better control the drug dose, since that dose would be targeted to cancer cells. In this way, anticancer drugs could be used much more efficiently, which would, in turn, lower the total amount of drug administered.

Source: University of Cincinnati

New theranostic nanoparticle delivers, tracks cancer drugs

201306047919620(Nanowerk News) University of New South Wales (UNSW)  chemical engineers have synthesised a new iron oxide nanoparticle that delivers  cancer drugs to cells while simultaneously monitoring the drug release in real  time.
The result, published online in the journal ACS Nano (“Using Fluorescence Lifetime Imaging Microscopy to  Monitor Theranostic Nanoparticle Uptake and Intracellular Doxorubicin  Release”), represents an important development for the emerging field of  theranostics – a term that refers to nanoparticles that can treat and diagnose  disease.
Iron oxide nanoparticles that can track drug delivery will  provide the possibility to adapt treatments for individual patients,” says  Associate Professor Cyrille Boyer from the UNSW School of Chemical Engineering.
By understanding how the cancer drug is released and its effect  on the cells and surrounding tissue, doctors can adjust doses to achieve the  best result.
Importantly, Boyer and his team demonstrated for the first time  the use of a technique called fluorescence lifetime imaging to monitor the drug  release inside a line of lung cancer cells.
“Usually, the drug release is determined using model experiments  on the lab bench, but not in the cells,” says Boyer. “This is significant as it  allows us to determine the kinetic movement of drug release in a true biological  environment.”
Magnetic iron oxide nanoparticles have been studied widely  because of their applications as contrast agents in magnetic resonance imaging,  or MRI. Several recent studies have explored the possibility of equipping these  contrast agents with drugs.
However, there are limited studies describing how to load  chemotherapy drugs onto the surface of magnetic iron oxide nanoparticles, and no  studies that have effectively proven that these drugs can be delivered inside  the cell. This has only been inferred.
With this latest study, the UNSW researchers engineered a new  way of loading the drugs onto the nanoparticle’s polymer surface, and  demonstrated for the first time that the particles are delivering their drug  inside the cells.
“This is very important because it shows that bench chemistry is  working inside the cells,” says Boyer. “The next step in the research is to move  to in-vivo applications.”
Source: University of New South Wales

Read more: http://www.nanowerk.com/news2/newsid=32972.php#ixzz2j9WI0HAR

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

Tumor Targeting platform with Nanoghosts

By Marcelle Machluf, Associate Professor, The  Faculty of Biotechnology & Food Engineering, Technion – Israel Institute of  Technology, Haifa, Israel.


nanomanufacturing-2(Nanowerk Spotlight) The field of drug discovery is  growing at a remarkable pace, leading to the development of many new drugs, most  of which are generally more potent than their predecessors, yet suffer from poor  solubility and/or high toxicities.

Targeted drug-delivery vehicles (e.g.,  liposomes, nano-particles) have often been proposed in an effort to reduce the  side effects of such drugs and improve their overall efficacy for treating  genetic, viral and malignant diseases.   Three main considerations must be addressed when designing any  such delivery system: It should be biocompatible; bioavailable; and highly  selective to its specific target.

Targeting may be improved by conjugating drug carrying vehicles  with targeting moieties that substantially improve their selectivity. For  example, antibodies, proteins etc. have been incorporated into nano-sized  drug-carriers made from polymeric particles, micelles or liposomes, yet their  relatively short circulation time and the complexity of their production render  them too costly and inefficient.

The need for drug delivery vehicles is particularly stressed in  cancer treatment, where high doses of toxic drugs are often required.  Passively-targeted drug-loaded vehicles are still the predominantly used  delivery systems for cancer therapy. Because of their nano-size and physical  properties, such systems were shown to achieve extended circulation times, and  retention in the tumor microenvironment—owing to the Enhanced Permeability and  Retention (EPR) effect of tumor vasculature and microenvironment.

These systems,  nonetheless, are limited by tumor vascularization and permeability that are  largely dependent on the stage of the malignancy and tumor type. Consequently,  active targeting vehicles, once a promising therapeutic approach, have almost  exhausted their potential, particularly in the area of cancer therapy where such  solutions are desperately needed.

In our recent paper (“Reconstructed Stem Cell Nanoghosts: A Natural Tumor  Targeting Platform”) we report on a novel targeted drug-delivery vehicle for  cancer therapy, which can selectively target the tumor niche while delivering an  array of therapeutic agents.   This targeting platform is based on unique vesicles  (‘nanoghosts’) that are produced, for the first time, from intact cell membranes  of stem cells with inherent homing abilities, and which may be loaded with  different therapeutics.

     Binding of nanoghosts to cells Binding of nanoghosts (white arrow) to PC3 cells; cell, green (GFP);  nucleolus, blue (DAPI) evaluated using confocal microscopy over short (3 h)  incubation times. (Reprinted with permission from American Chemical Society)  

We have shown that such vesicles, encompassing the cell surface  molecules and preserving the targeting mechanism of the cells from which they  were made, can outperform conventional delivery systems based on liposomes or  nanoparticles.   These vesicles leverage the benefits related to the size, and  chemical and physical properties of nano-liposomes, allowing them to efficiently  entrap various hydrophilic and hydrophobic drugs, and be administered through  different routes while exhibiting versatile and controllable release profiles.

The prior art pertaining to the design of this unique and novel drug-delivery  platform is drawn from and associated with the production and utilization of  cell-derived vesicles, and the inherent tumor-targeting abilities of mesenchymal  stem cells (MSCs).   A similar therapeutic effect, to what we have achieved, was  previously demonstrated for prostate cancer, using monoclonal antibodies against  N-cadherin, which is highly expressed in castration-resistant prostate cancer;  however, it requires more frequent and higher dosing.

Our therapeutic outcome is comparable to that demonstrated by De  Marra et al. (“New self-assembly nanoparticles and stealth  liposomes for the delivery of zoledronic acid: a comparative study”) who  used no less than three administrations per week of liposomes encapsulating  Zoledronic acid and exceeded the effect achieved by a weekly administration of  an imatinib–mitoxantrone liposomal formulation.

The efficiency of our delivery system is even more compelling in  light of the results reported by Srivastava et al. (“Effects of sequential treatments with chemotherapeutic drugs  followed by TRAIL on prostate cancer in vitro and in vivo”), which  demonstrated no inhibition of tumor growth after two weeks and as many as four  IV administrations of similar quantities of free sTRAIL. The efficacy of our  system also exceeded that of previously reported liposomal formulations  containing sTRAIL tested on glioblastoma and lung cancer.

Till now, nanoghosts made from mammalian cells have been used to  study cell membranes and were utilized for cancer immunotherapy but have never  been tested as targeted drug-delivery vehicles. Recently, we reported a novel  concept describing a targeted drug-delivery system based on nanoghosts, which  were prepared from the outer cell membranes of a non-human cells engineered to  express the human receptor (CCR5) of a viral ligand (gp120) found on the surface  of HIV-infected cells (“Cell derived liposomes expressing CCR5 as a new  targeted drug-delivery system for HIV infected cells”).

Drug-loaded  nanoghosts selectively targeted HIV-infected cells in vitro, achieving  over 60% reduction in their viability compared to empty nanoghosts, free drug,  or nanoghosts applied on control uninfected cells that were not affected at all.   This intrinsically-targeted system, which does not entail the  elaborate production of targeting molecules and their incorporation into passive  vehicles, represents a simpler and more clinically relevant approach than  existing particulate drug-delivery vehicles.

Our success in using nanoghosts to target HIV-infected cells has  prompted us to devise a more sophisticated universal and non-immunogenic  delivery platform, in which the nanoghosts will be produced from stem cells that  are known to naturally target various tumors.   Insights gained from this work may pave the way for new research  utilizing nanoghosts’ inherent targeting to treat not only tumors but also sites  of inflammations, wound healing, and trauma.

The knowledge accumulated on the entrapment of diverse drugs can  facilitate the loading of nanoghosts with nucleic acid (DNA, siRNA etc.) for  gene therapy.   Nanoghosts loaded with MRI contrast agents (Indocyanine or  magnetite nano-crystals) can open unique research avenues in imaging and  diagnosis. Their small size and specific targeting abilities may enable the  nanoghosts to freely travel in the body possibly detecting small and  sub-metastatic cancer nuclei and lesions, which are otherwise undetectable using  conventional methodologies.

Owing to MSCs natural role in regenerative medicine, nanoghosts  can be also investigated in tissue engineering applications for delivering  growth factors for regenerating tissues.   Finally, MSCs can be engineered to express additional targeting  molecules and used to treat other diseases manifested by the expression of  unique targetable ligands.

This work was conducted by PhD students Naama Ester  Toledano-Furman, Yael Lupu-Haber, Limor Kaneti, and the Lab manager Dr. Tomer  Bronshtein.

By Marcelle Machluf, Associate Professor, The  Faculty of Biotechnology & Food Engineering, Technion – Israel Institute of  Technology, Haifa, Israel.

Read more: http://www.nanowerk.com/spotlight/spotid=31548.php#ixzz2apeCNQzx

Cancer nanotechnology: Nanoparticles with protein ‘passports’ evade immune system (w/video)

QDOTS imagesCAKXSY1K 8(Nanowerk News) Scientists have found a way to sneak  nanoparticles carrying tumor-fighting drugs past cells of the immune system,  which would normally engulf the particles, preventing them from reaching their  target. The technique takes advantage of the fact that all cells in the human  body display a protein on their membranes that functions as a specific  ‘passport’ in instructing immune cells not to attack them. By attaching a small  piece of this protein to nanoparticles, scientists were able to fool immune  cells in mice into recognizing the particles as ‘self’ rather than foreign,  thereby increasing the amount of medication delivered to tumors (“Minimal “Self” Peptides That Inhibit Phagocytic Clearance and  Enhance Delivery of Nanoparticles”).
peptide attached to nanoparticle
A  minimal peptide ‘passport’ (yellow) can be attached to therapeutic nanoparticles  so that it binds to an immune cell receptor (grey) and prevents engulfment.  
Cancer Nanotechnology
Current approaches to chemotherapy leave patients with severe  side effects because anti-cancer drugs meant to destroy tumors inadvertently  kill healthy cells in the body. But scientists have recently developed  nanoparticles that can ferry toxic medications directly to tumors while sparing  healthy tissue. Because of their small size, nanoparticles escape from leaky  blood vessels that are characteristic of tumors and accumulate in the cancerous  tissue. Tumor cells take up the particles which release their toxic contents  once inside. This localized delivery system allows doctors to give patients  higher doses of medications than would normally be tolerated.
Previous attempts have been made to ward off attack by the  immune system by coating nanoparticles densely with polyethylene glycol (PEG)  “brushes” that physically block the adhesion of proteins that normally deposit  onto foreign bodies to attract macrophages. While these brushes delay the onset  of the immune response, they don’t prevent it.
The inspiration for Discher’s breakthrough work dates back  thirteen years when a group of researchers showed with genetically engineered  mice that a protein called CD47—which is found in the cell membranes of nearly  all mammals—interacts with a receptor on macrophages called SIRPa, and, in doing  so, signals that the cell is native and shouldn’t be destroyed. The findings  hinged on deleting mouse CD47 and raised many questions, including how such mice  survive and whether there was relevance to humans.
Discher, who was engineering nanoparticles that self-assemble  into various shapes at the time of the discovery, realized that the CD47-SIRPa  mechanism for self-recognition could, in principle, be exploited to help  nanoparticles sneak past the immune system. But it was also clear that human  versions of purified proteins needed to be studied for any translation to  humans.
In 2008, Discher’s lab demonstrated that human CD47 acts  similarly to mouse CD47 as a “marker of self” via signaling through the SIRPa  receptor. Shortly thereafter, a group of researchers elucidated the combined  structure of human CD47 and SIRPa in atomic detail. Discher’s lab used this  information to conduct computer simulations and identify the smallest portion of  CD47 that could still bind to SIRPa. The result was a short peptide that  Discher’s lab chemically synthesized and attached to standard nanoparticles.
“Reducing CD47 to an essential peptide was a key step,” said  Discher. “Sequencing of thousands of human genomes around the world has recently  revealed many variations in the sequences of CD47 and SIRPa. We needed to  engineer a ‘universal’ peptide that could bind SIRPa and function in all humans  despite these differences.”
Stealth nanoparticles avoid immune response
To test whether their peptide could help nanoparticles evade the  immune system, Discher’s team injected both peptide-bound nanoparticles and  nanoparticles lacking CD47 into mice. Both types of nanoparticles contained a  fluorescent dye that allowed the scientists to track the particles. In an  article published on February 22, 2013 in Science, the researchers reported that  in just thirty minutes post-injection of the particles, the mice’s blood  contained four times as many nanoparticles containing CD47 peptide as particles  without the peptide, suggesting that CD47-bound particles were being viewed by  macrophages as being similar to cells that belonged in the body.
Encouraged by these initial results, the team next filled their  CD47-bound nanoparticles, as well as PEG-coated nanoparticles without CD47, with  the anticancer drug paclitaxel plus a tumor-targeting antibody. The team  separately injected both types of nanoparticles as well as Cremophore—the  standard carrier for paclitaxel—into mice with human-like tumors. After just one  day, the tumors in mice injected with CD47-bound nanoparticles were 70% the size  of those injected with the PEG-coated nanoparticles. Additionally, CD47-bound  nanoparticles were just as good or better at shrinking the tumors as Cremophore  without causing any side effects. The team went on to document the molecular  changes that occur inside macrophages when CD47 inhibits engulfment, suggesting  additional medications might be used to inhibit clearance.
Macrophage engulfs foreign cells
“Clinical trials using nanoparticles to deliver anticancer drugs  are currently underway, but clearance by the immune system remains a significant  hurdle,” said Karen Peterson, Ph.D., Senior Advisor of Extramural Programs at  NIBIB. “Discher’s work is an elegant approach, which could enable other  nanotherapeutics to be effective in clinical trials by providing a molecular  “authentication” that the body does not recognize as foreign.”
Peterson also noted the combination of bioengineering and  computer modeling that went into generating the peptide; Discher’s ability to  test the function of differently sized peptides via computer simulation first,  and then produce a man-made peptide based on these simulations allowed him to  eliminate some of the guessing game, saving time and money in the long-run.
Future applications
Discher speculates that his CD47 peptide could be similarly used  to prevent immune clearance of viruses used to deliver genes for gene-therapy  treatment or to enhance biocompatibility and durability of larger foreign  objects such as pacemakers and implants, whose parts can degrade over time due  to attacks by the immune system.
Source: By Margot Kern, National Institute of Biomedical  Imaging and Bioengineering

Read more: http://www.nanowerk.com/news2/newsid=31360.php#ixzz2ZK4s8IkA

2013 Perspective on “War on Cancer” on from December 23, 1971 to ‘Where Are We Now’?



SciSource_9M9229-580.jpg201306047919620Richard Nixon launched the so-called War on Cancer on December 23, 1971, in what was supposed to be a “moonshot” effort to cure the disease. Two years later, a Time magazine cover read, “Toward Control of Cancer.” Two decades after that, it announced, in bold red letters, “Hope in the War Against Cancer,” surmising that “a turning point” may have been reached. In 2001, its cover asked if the blood cancer drug Gleevec “is the breakthrough we’ve been waiting for.” And this past April, the newsweekly pronounced “How to Cure Cancer.” Yet roughly one hundred and forty thousand Americans have died from the disease in the last three months.

Outrage over our paltry victories against cancer informs the forthcoming book, “The Truth in Small Doses: Why We’re Losing the War on Cancer—and How to Win It,” by Clifton Leaf, who wrote a much-discussed essay on the same topic for Fortune in 2004. The title comes from a 1959 pamphlet that tells doctors to trickle out information to cancer-stricken patients, since most of them “couldn’t stand” to know the truth: the disease would kill them and there was little that could be done about it. Today, draped in ribbons of every hue, blinded by the promises of targeted therapies and antioxidants, we have, according to Leaf, neglected a basic truth: “‘the cancer problem’ is, in reality, as formidable a challenge as ever.” (Jerome Groopman discussed the progress in cancer cures, particularly immune therapy, in the magazine last year.)

Leaf is not an oncologist, but he became acquainted with the profession at an early age; he was diagnosed with Hodgkin’s disease at fifteen years old. In the book’s most poignant moment, Leaf orders his father into the corner of his hospital room to atone for having dozed off while sitting bedside. When Leaf woke up the next morning, “the biggest man I had ever known” was still standing in the corner.

As an editor at Fortune, Leaf became enthralled by the promise of Gleevec, an enzyme inhibitor that, since its release in 2001, has proven highly effective at battling chronic myeloid leukemia. Many thought a new age was coming, in which the chaotic spread of cancer would be hindered by drugs that would be precision-targeted to block the replication of rogue cells. It seemed far better than indiscriminately killing both cancerous and healthy cells, as chemotherapy had been doing for the past half-century.

But Gleevec is the exception, not the rule—and C.M.L. is a relatively simple cancer compared to solid-state tumors of the lung, colon, pancreas, or breast. Once they metastasize, most cannot be cured. Those, like Leaf, who have faced cancer have good reason for their impatience: it takes an average of thirteen years to bring a new cancer drug to market. Many of these drugs are pellets fired into cancer’s flank. A recent article in the New York Times titled “Promising New Cancer Drugs Empower the Body’s Own Defense” hailed a new melanoma drug whose median survival rate was 16.8 months. An editorial this winter in The Lancet, the august British medical journal, put the matter even more bluntly: “Has cancer medicine failed patients? In the words of cancer experts, the answer is yes.”

Watch this video from “Nanobiotix” on the use of nanotechnology for treating Cancer using established treatment methods here:




Leaf argues we should be closer to an all-out cure, considering our investment in the effort. The National Cancer Institute receives roughly five billion dollars per year from the federal government. If both public and private investments are to be accounted for, then Leaf estimates the United States spends about sixteen billion dollars a year on cancer research. Nor is there a lack of political will to eradicate cancer, as there is to, say, reducing carbon emissions. Leaf calls it a “bipartisan disease” that a Republican from Alabama would want defeated as much as a Democrat from Illinois. President Barack Obama said in 2009 that he would “launch a new effort to conquer a disease that has touched the life of nearly every American, including me, by seeking a cure for cancer in our time.”

In Leaf’s telling, oncology is a hidebound field averse to risk, a culture that “has grown progressively less hospitable to new voices and ideas over the past four decades.” He yearns for the likes of Sidney Farber, the unorthodox pathologist who invented chemotherapy in the late nineteen forties at Boston Children’s Hospital by injecting children stricken with acute lymphoblastic leukemia with aminopterin, which prevents cancer cells from replicating. A hero in Siddhartha Mukherjee’s “The Emperor of All Maladies,” Farber is largely responsible for the fact that childhood A.L.L. is a manageable disease today. But his methods had a high cost: he disobeyed superiors, conducted his own trial-and-error studies, and foisted unproven drugs on sick, vulnerable children.

What made Farber an iconoclast is that he wanted to cure cancer even more than he wanted to understand it. As he would come to argue, “The three hundred and twenty-five thousand patients with cancer who are going to die this year cannot wait; nor is it necessary, in order to make great progress in the cure for cancer, for us to have the full solution of all the problems of basic research…the history of Medicine is replete with examples of cures obtained years, decades, and even centuries before the mechanism of action was understood for these cures.”

Few new bold projects are being funded now, writes Leaf, noting that in 2010, the N.C.I. used the bulk of its two billion dollars in research grants on existing projects. He is as incensed that the same institutions get most of the money, writing that “in 2011, the top 43 research centers got more funding ($12 billion) than did the bottom 2,574 institutions receiving any kind of NIH support.” To some, this is the price of science that is both sound and safe. To others, it is a culture of scientific inefficiency, an I.B.M. mindset in a field that desperately yearns for Apple.

Oncologists in the field with whom I spoke agreed with this overall assessment of the War on Cancer. Andrea Hayes-Jordan, a pediatric surgical oncologist at the M. D. Anderson Cancer Center in Houston, told me that “Our strategic attacks are improving, and we are winning some battles, but not the war yet.” Silvia Formenti, who chairs the radiation oncology department at New York University’s Langone Medical Center, was even more negative in her assessment of the War on Cancer. She wrote to me in an e-mail, “We have managed to make cancer a huge business, and a national ‘terror,’ but the progress in reducing mortality is quite questionable.”

The book suggests some remedies, foremost among them preventing cancer before it strikes. At Stage 0, a cancerous growth can be detected and removed before it has diversified and spread. By the time a tumor is the size of a grape, it has as many as a billion cells. Those cells become increasingly heterogeneous, and once they break through the basement membrane that acts as a final barrier between organs and tissues, they are free to metastasize throughout the body via the bloodstream or the lymphatic system.

The book finds great promise in the chemoprevention pioneered by Dartmouth researcher Michael Sporn, who wants to treat pre-invasive lesions as seriously as full-blown cancers. This seems to fly in the face of the cautious watch-and-wait philosophy popular with many oncologists, who have become convinced (not without reason) that the cure—toxic chemotherapy, high doses of radiation—could be worse than the disease.

However, other than the breast cancer drug tamoxifen and the H.P.V. vaccine—both of which can reduce the risk of getting cancer, not cure the disease—the promise of chemoprevention remains largely unrealized. A recent paper by two preventative oncologists concluded, “There have been numerous chemoprevention trials in the past 10 years, but the number of approved chemoprevention drugs is still quite small.” Another recent study on older men with prostate cancer suggested that “watchful waiting” was often the best route, noting that many patients opted for expensive treatments they didn’t need, thus leading to impotence and incontinence. And a federal task force ruled four years ago that women should delay getting mammograms until age fifty (ten years later than the previous recommendation) because of the procedure’s own potential dangers.

Leaf acknowledges these dangers, and also points out an even more serious problem with chemoprevention: biomarkers that would signal carcinogenesis in its earliest stages have not been found. So while he is correct to highlight the potential promise of a prophylactic approach, Leaf’s own description of “the failed biomarker hunt” is, indirectly, a defense of why oncologists today are left with no choice but to wait until the disease develops.

The desire for an accelerated approach to cancer has antecedents in the AIDS activism of the nineteen-eighties. As Mukherjee describes in his book, organizations like ACT UP “made the FDA out to be a woolly bureaucratic grandfather—exacting but maddeningly slow.” That had repercussions in cancer medicine, where patients also demanded quicker access to potentially life-saving therapies. Especially en vogue by the early nineties was “megadose chemotherapy” for breast cancer, complemented by a bone marrow transplant. (The original marrow would have been destroyed by the high toxicity of the purported cure.) Yet as Mukherjee notes, by early 2000, the procedure was discovered to have been supported by fictional studies. One of its main proponents, a South African oncologist named Werner Bezwoda, had charmed his fellow practitioners with astounding results that masked the true, fatal dangers of this excessive approach. Mukherjee calls Bezwoda’s influential drug trials “a fraud, an invention, a sham,” yet he was hardly the lone cheerleader for megadose chemotherapy. Any urge to hasten the War on Cancer—however justified that urge may be—must grapple with the risk of promising anecdotes curdling into hideous truths.

Of course, some approaches are neither terribly controversial nor difficult, at least from a medical standpoint: Debu Tripathy of the University of Southern California’s Norris Cancer Center told me that he believes that ninety per cent of all lung cancers could be eliminated through the cessation of cigarette smoking. Studies have shown a link between red meat consumption and an elevated risk of cancer. Here, then, may be cancer prevention in its simplest form.

On the whole, Leaf is much less optimistic than Mukherjee. Surveying the state of cancer medicine as it was in 2005, Mukherjee concludes, “The empire of cancer was still indubitably vast…but it was losing power, fraying at its borders.” Surveying some three thousand years of humanity’s battle with cancer, Mukherjee’s is the more meditative work. Leaf’s book is more urgent, more insistent—the voice of a frightened patient who yearns for a cure, rather than of the sober oncologist concerned with getting the science right. “Emperor” is a story; “Truth” is an argument.

Earlier in June, researchers discovered a tumor of the rib bone of a Neanderthal believed to be a hundred and twenty thousand years old. What plagued him then still plagues us today, much as it plagued Atossa, the ancient Persian queen who is believed to have suffered from breast cancer, as well as the London chimney sweeps stricken with scrotal malignancies. This war has been a long one.

Alexander Nazaryan is a writer living in Brooklyn.

Photograph by Biophoto Associates/Science Source.



Nanoparticle Drug Delivery in Cancer Therapy

Published on Mar  3, 2013




Follow our channel on Twitterhttps://twitter.com/Nanobotmodels
Read more in article: http://www.nanobotmodels.com/node/69
Nanobotmodels Company presents vision of modern drug delivery methods using  DNA-origami nanoparticles. In animation you can see cancer therapy using doxorubicin, delivered  by nanomedicine methods.

Nanoparticles for Controlled Drug Release

QDOTS imagesCAKXSY1K 8Scientists at CIC bioGUNE and the Laboratoire de Chimie des Polymères Organiques (LCPO) in Bordeaux have undertaken a project for developing ‘intelligent’ nanoparticles. These polymeric particles act as ‘nanomissiles’ against determined targets and enable the controlled release in space and time of pharmaceutical drugs, releasing their ‘load’ only when and where required. This release of medication is controlled by applying a local magnetic field.

Chemists at the LCPO are in charge of generating the nanoparticles, which have approximately the size of a virus, while the CIC bioGUNE researchers are responsible for evaluating the efficacy of a model of cell cultures. The research has been published recently in the online version of the Journal of Controlled Release.

The technique developed increases the effectiveness of the treatment, as it deposits the medication directly on the affected organ, thus avoiding side effects. Side effects of all chemotherapy treatment are, in general, a consequence of the toxicity of the drugs on healthy tissue (for example, hair loss), in many cases the dosage used not being the optimum and excessively toxic for the patient.

The system developed by the joint LCPO and CIC bioGUNE team will enable the controlled release to an organ of a pharmaceutical drug. The nanoparticles that transport the medicine are made of polymer and contain iron oxide. On applying a magnetic field, making use of the presence of iron oxide, ‘pores’ are opened at the surface of the polymer and through which the drug is released.

The localised release of the medication will reduce the effect on the healthy tissue and, at the same time, the dosage used on the cancerous tissue can be made greater. The benefits of this method are, thus, the reduction of side effects and the increase in the effectiveness of the treatment. In the words of the CIC bioGUNE researcher, Ms.Edurne Berra, “the local application of the magnetic field facilitates the release of the pharmaceutical drug and increases its cytotoxic effect on the cancer cells”.

Used as a model in this research was doxorubicin, a pharmaceutical drug widely used in chemotherapy against cancer. Moreover, the conclusions of this research could be he launching platform for developing new, intelligent systems for the release of other pharmaceutical drugs.

As Ms. Berra added, “the system studied not only enables encapsulating other types of pharmaceutical drugs other than doxorubicin, but it will also be able to incorporate molecules that recognize particular types of cancer cells. Moreover, it can be used for diagnosing the cancer with magnetic resonance and even in theragnosis, i.e. simultaneous diagnosis and drug therapy”.

Liposomes Disguise Chemotherapy Drug Packed into Trojan Horse Nanobins

QDOTS imagesCAKXSY1K 8A new gentler chemotherapy drug in the form of nanoparticles has been designed by Northwestern Medicine® scientists to be less toxic to a young woman’s fertility but extra tough on cancer. This is the first cancer drug tested while in development for its effect on fertility using a novel in vitro test.

The scientists designed a quick new in vitro test that predicts the toxicity of a chemotherapy drug to fertility and can be easily used to test other cancer drugs in development as well as existing ones. Currently the testing of cancer drugs for fertility toxicity is a time and resource intensive process.

“Our overall goal is to create smart drugs that kill the cancer but don’t cause sterility in young women,” said Teresa Woodruff, a co-principal investigator of the study and chief of fertility preservation at Northwestern University Feinberg School of Medicine. The paper was published March 20 in in the journal PLOS ONE.

The scientists hope their integration of drug development and reproductive toxicity testing is the beginning of a new era in which chemotherapy drugs are developed with an eye on their fertotoxity (fertility toxicity). As cancer survival rates increase, the effect of cancer treatments on fertility is critically important to many young patients.

Woodruff and Thomas O’Halloran, also a co-principal investigator and director of the Chemistry of Life Processes Institute at Northwestern, are a wife and husband team who developed and tested the drug. Their intersecting interests — hers in fertility preservation, his in cancer drug development — percolated over dinner conversations and sparked the collaboration.

O’Halloran also is the associate director for basic sciences research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and Woodruff is the Thomas J. Watkins Memorial Professor of Obstetrics and Gynecology at Feinberg. Richard Ahn, now a fourth-year medical student at Feinberg in the M.D.-PhD program and the study’s lead author, coordinated the preclinical testing of the nanobins as a graduate student in O’Halloran’s lab.

A Tiny Trojan Horse

The chemotherapy drug, arsenic trioxide, is packed into a very tiny Trojan horse called a nanobin. The nanobin consists of nano-size crystalline arsenic particles densely packed and encapsulated in a fat bubble. The fat bubble, a liposome, disguises the deadly cargo — half a million drug molecules.

“You have to wallop the tumor with a significant dose of arsenic but at the same time prevent exposure to normal tissue from the drug,” said O’Halloran. The fat bubble is hundreds of times smaller than the average human cell. It is the perfect size to stealthily slip through holes in the leaky blood vessels that rapidly grow to feed tumors. The local environment of the tumor is often slightly acid; it is this acid that causes the nanobin to release its drug cargo and deliver a highly effective dose of arsenic where it is needed.

The scientists show this approach to packaging and delivering the active drug has the desired effect on the tumor cells but prevents damage to ovarian tissue, follicles or eggs.

While the drug is gentle on fertility, it is ferocious on cancer. When tested against lymphoma, it was more potent than the drug in its traditional free form.

“The drug was designed to maximize its effectiveness but reduce fertotoxicity,” said O’Halloran, also the Morrison Professor of Chemistry in the Weinberg College of Arts and Sciences at Northwestern. “Many cancer drugs cause sterilization, that’s why the reproductive tract is really important to focus on in the new stages of drug design. Other body systems get better when people stop taking the drug, but fertility you can’t recover.”

Arsenic trioxide was approved a few years ago for treating some types of blood cancers such as leukemia in humans, but O’Halloran thinks the arsenic trioxide nanobins can be used against breast cancer and other solid tumors. In his previously published preclinical research, nanobins were effective in reducing tumor growth in triple-negative breast cancer, which often doesn’t respond well to traditional chemotherapy and has a poor survival rate.

Quick Test For Fertility Toxicity

Woodruff was able to show early effects of the drug on fertility by using an in vitro follicle culture and a quick, simple new test she developed. She compared the fertotoxicity of the nanobin and free drug and found the nanobin was much less toxic to female fertility than the free drug in the experimental model.

“The system can be adapted very easily for any cancer drug under development to get an early peek under the tent,”said Woodruff, also the Thomas J. Watkins Memorial Professor of Obstetrics and Gynecology at Feinberg. “As this new drug goes forward in development, we can say this is a good drug for young female cancer patients who are concerned about fertility.”

The information gained from the toxicity test will help inform the treatment decisions of oncologists and their young female cancer patients to improve their chances of creating a future family.

“They may prescribe less toxic drug regimens or refer them to specialists in fertility preservation,” Woodruff said.

Source: http://www.northwestern.edu/