Chitosan Coated, Chemotherapy Packed Nanoparticles may Target Cancer Stem Cells


Phenformin Nano Cancer Delivery id39449Chitosan coated, chemotherapy packed nanoparticles may target cancer stem cells

COLUMBUS, Ohio – Nanoparticles packed with a clinically used chemotherapy drug and coated with an oligosaccharide derived from the carapace of crustaceans might effectively target and kill cancer stem-like cells, according to a recent study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James). Cancer stem-like cells have characteristics of stem cells and are present in very low numbers in tumors. They are highly resistant to chemotherapy and radiation and are believed to play an important role in tumor recurrence. This laboratory and animal study showed that nanoparticles coated with the oligosaccharide called chitosan and encapsulating the chemotherapy drug doxorubicin can target and kill cancer stem-like cells six times more effectively than free doxorubicin.

The study is reported in the journal ACS Nano.

“Our findings indicate that this nanoparticle delivery system increases the cytotoxicity of doxorubicin with no evidence of systemic toxic side effects in our animal model,” says principal investigator Xiaoming (Shawn) He, PhD, associate professor of Biomedical Engineering and a member of the OSUCCC – James Translational Therapeutics Program.

“We believe that chitosan-decorated nanoparticles could also encapsulate other types of chemotherapy and be used to treat many types of cancer.”

This study showed that chitosan binds with a receptor on cancer stem-like cells called CD44, enabling the nanoparticles to target the malignant stem-like cells in a tumor.

The nanoparticles were engineered to shrink, break open, and release the anticancer drug under the acidic conditions of the tumor microenvironment and in tumor-cell endosomes and lysosomes, which cells use to digest nutrients acquired from their microenvironment.vnDpjc0OLw.JPG

He and his colleagues conducted the study using models called 3D mammary tumor spheroids (i.e., mammospheres) and an animal model of human breast cancer.

The study also found that although the drug-carrying nanoparticles could bind to the variant CD44 receptors on cancerous mammosphere cells, they did not bind well to the CD44 receptors that were overexpressed on noncancerous stem cells.

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Funding from an American Cancer Society Research Scholar Grant (No. 120936-RSG- 11-109-01-CDD) and a Pelotonia postdoctoral fellowship supported this research.

Other researchers involved in this study were Wei Rao, Hai Wang, Jianfeng Han, Shuting Zhao, Jenna Dumbleton, Pranay Agarwal, Jianhua Yu and Debra L. Zynger of Ohio State; Wujie Zhang of Milwaukee School of Engineering; Gang Zhao of University of Science and Technology of China; and Xiongbin Lu of The University of Texas MD Anderson Cancer Center.

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only four centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State’s cancer program as “exceptional,” the highest rating given by NCI survey teams. As the cancer program’s 306-bed adult patient-care component, The James is a “Top Hospital” as named by the Leapfrog Group and one of the top cancer hospitals in the nation as ranked by U.S.News & World Report.

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


WORLD WAR CANCER

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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:

http://www.youtube.com/watch?feature=player_detailpage&v=kxSX6YJTS2I&list=PL9C30814198614279

 

 

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.

SOURCE

http://www.newyorker.com/online/blogs/elements/2013/07/world-war-cancer.html

Researchers can deliver RNA, proteins and nanoparticles for many applications


QDOTS imagesCAKXSY1K 8How to squeeze large molecules into cells

By deforming cells, researchers can deliver RNA, proteins and nanoparticles for many applications
January 28, 2013

As cells squeeze through a narrow channel, tiny holes open in their membranes, allowing large molecules such as RNA to pass through (credit: Armon Sharei and Emily Jackson)

Living cells are surrounded by a membrane that tightly regulates what gets in and out of the cell. This barrier is necessary for cells to control their internal environment, but it makes it more difficult for scientists to deliver large molecules such as nanoparticles for imaging, or proteins that can reprogram them into pluripotent stem cells.squeezed_cells

Researchers from MIT have now found a safe and efficient way to get large molecules through the cell membrane, by squeezing the cells through a narrow constriction that opens up tiny, temporary holes in the membrane. Any large molecules floating outside the cell — such as RNA, proteins or nanoparticles — can slide through the membrane during this disruption.

Using this technique, the researchers were able to deliver reprogramming proteins and generate induced pluripotent stem cells with a success rate 10 to 100 times better than any existing method. They also used it to deliver nanoparticles, including carbon nanotubes and quantum dots, which can be used to image cells and monitor what’s happening inside them.

“It’s very useful to be able to get large molecules into cells. We thought it might be interesting if you could have a relatively simple system that could deliver many different compounds,” says Klavs Jensen, the Warren K. Lewis Professor of Chemical Engineering, professor of materials science and engineering, and a senior author of a paper describing the new device in the Proceedings of the National Academy of Sciences.

Robert Langer, the David H. Koch Institute Professor at MIT, is also a senior author of the paper. Lead authors are chemical engineering graduate student Armon Sharei, Koch Institute research scientist Janet Zoldan, and chemical engineering research associate Andrea Adamo.

The new MIT system appears to work for many cell types — so far, the researchers have successfully tested it with more than a dozen types, including both human and mouse cells. It also works in cells taken directly from human patients, which are usually much more difficult to manipulate than human cell lines grown specifically for lab research.

The new device builds on previous work by Jensen and Langer’s labs, in which they used microinjection to force large molecules into cells as they flowed through a microfluidic device. This wasn’t as fast as the researchers would have liked, but during these studies, they discovered that when a cell is squeezed through a narrow tube, small holes open in the cell membrane, allowing nearby molecules to diffuse into the cell.

To take advantage of that, the researchers built rectangular microfluidic chips, about the size of a quarter, with 40 to 70 parallel channels. Cells are suspended in a solution with the material to be delivered and flowed through the channel at high speed — about one meter per second. Halfway through the channel, the cells pass through a constriction about 30 to 80 percent smaller than the cells’ diameter. The cells don’t suffer any irreparable damage, and they maintain their normal functions after the treatment.

Special delivery

The research team is now further pursuing stem cell manipulation, which holds promise for treating a wide range of diseases. They have already shown that they can transform human fibroblast cells into pluripotent stem cells, and now plan to start working on delivering the proteins needed to differentiate stem cells into specialized tissues.

Another promising application is delivering quantum dots — nanoparticles made of semiconducting metals that fluoresce. These dots hold promise for labeling individual proteins or other molecules inside cells, but scientists have had trouble getting them through the cell membrane without getting trapped in endosomes.

In a paper published in November, working with MIT graduate student Jungmin Lee and chemistry professor Moungi Bawendi, the researchers showed that they could get quantum dots inside human cells grown in the lab, without the particles becoming confined in endosomes or clumping together. They are now working on getting the dots to tag specific proteins inside the cells.

The researchers are also exploring the possibility of using the new system for vaccination. In theory, scientists could remove immune cells from a patient, run them through the microfluidic device and expose them to a viral protein, and then put them back in the patient. Once inside, the cells could provoke an immune response that would confer immunity against the target viral protein.

The research was funded by the National Institutes of Health and the National Cancer Institute.

MIT-Harvard Center of Cancer Nanotechnology Excellence:


QDOTS imagesCAKXSY1K 8First-of-its-kind self-assembled nanoparticle for targeted and triggered  thermo-chemotherapy

 

(Nanowerk News) Research from investigators at the MIT-Harvard Center of Cancer Nanotechnology Excellence has  succeeded in designing and demonstrating the effectiveness of a  first-of-its-kind, self assembled, multi-functional, near-infrared (NIR)  responsive gold nanorods that can deliver a chemotherapy drug specifically  targeted to cancer cells and selectively release the drug in response to an  external beam of light while creating heat for synergistic thermo-chemo mediated  anti-tumor efficacy. NIR is minimally absorbed by skin and tissue, has the  ability to penetrate deep tissue in a noninvasive way, and can be converted to  heat by gold nanomaterials for effective thermal ablation of diseased tissue.  The results of this study were published by Omid Farokhzad and his colleagues in  the journal Angewandte Chemie International Edition (“DNA Self-Assembly of Targeted Near-Infrared-Responsive Gold  Nanoparticles for Cancer Thermo-Chemotherapy”).
“The design of this gold nanorod and its self-assembly was  inspired by nature and the ability of complimentary strands of DNA to hybridize  on their own without imposing complicated chemical processes on them,” explained  Dr. Farokhzad, director of the Laboratory of Nanomedicine and Biomaterials at  Brigham and Women’s Hospital. “Each functionalized DNA strand individually, and  the self assembled components as a system, play a distinct yet integrative role  resulting in synergistic targeted and triggered thermo-chemotherapy capable of  eradicating tumors in our pre-clinical models.”
One DNA strand is attached to the gold nanorod and the  complementary strand is attached to a stealth layer and a homing molecule that  keeps the system under the radar of the immune system while targeting it  directly to cancer cells. When the DNA strands come together, the targeted gold  nanorod is formed and the double stranded DNA serves as the scaffold for binding  the chemotherapy drug, doxorubicin, which can be released in response to NIR  light that concurrently results in generation of heat by the gold nanorods. Each  of the three distinct functional components plays a role in contributing to the  triple punch of triggered thermotherapy, controlled doxorubicin release, and  cancer cell targeting.
To demonstrate the robust capability of this nanorod system, Dr.  Farokhzad and his collaborators used a pre-clinical model to evaluate the in  vivo anti-tumor efficacy in two different tumor models and four different groups  with different drug regiments, each group varying in weight and tumor size.  Researchers administrated an injection of the novel, self-assembled nanoparticle  and then 10 minutes post-injection, the tumors were irradiated using NIR light  that activated the nanoparticle using the gold nanorod and created heat. The  results showed that this platform successfully delivered heat and anti-cancer  drugs to synergistically eradicate tumors.
Thermal ablation is already commonly used in cancer treatment,” said Dr. Farokhzad. “What is extremely exciting about this platform is that we  are able to selectively target cancer cells and then hit the tumor twice: first  with a controlled release of a chemotherapy drug and then secondly with  triggered induction of heat from the activation of the gold nanorod. And all  this can be done noninvasively.”
Source: National Cancer  Institute

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Stanford scientists develop new technique for visualizing blood flow


Stanford scientists have developed a new technique for watching blood flow in living animals. It involves carbon nanotubes and lasers, and will allow researchers to better study arterial diseases and therapies.

By Bjorn Carey

These images of a mouse’s blood vessels show the difference in resolution between traditional near-infrared fluorescence imaging (top) and Stanford’s new NIR-II technique (bottom).
These images of a mouse's blood vessels show the difference in resolution between traditional near-infrared fluorescence imaging (top) and Stanford's new NIR-II technique (bottom).

Stanford scientists have developed a fluorescence imaging technique that allows them to view the pulsing blood vessels of living animals with unprecedented clarity. Compared with conventional imaging techniques, the increase in sharpness is akin to wiping fog off your glasses.

The technique, called near infrared-II imaging, or NIR-II, involves first injecting water-soluble carbon nanotubes into the living subject’s bloodstream.

The researchers then shine a laser (its light is in the near-infrared range, a wavelength of about 0.8 micron) over the subject; in this case, a mouse.

The light causes the specially designed nanotubes to fluoresce at a longer wavelength of 1-1.4 microns, which is then detected to determine the blood vessels’ structure.

That the nanotubes fluoresce at substantially longer wavelengths than conventional imaging techniques is critical in achieving the stunningly clear images of the tiny blood vessels: longer wavelength light scatters less, and thus creates sharper images of the vessels. Another benefit of detecting such long wavelength light is that the detector registers less background noise since the body does not does not produce autofluorescence in this wavelength range.

In addition to providing fine details, the technique – developed by Stanford scientists Hongjie Dai, professor of chemistry; John Cooke, professor of cardiovascular medicine; and Ngan Huang, acting assistant professor of cardiothoracic surgery – has a fast image acquisition rate, allowing researchers to measure blood flow in near real time.

The ability to obtain both blood flow information and blood vessel clarity was not previously possible, and will be particularly useful in studying animal models of arterial disease, such as how blood flow is affected by the arterial blockages and constrictions that cause, among other things, strokes and heart attacks.

L.A. CiceroGraduate student Guosong Hong, left, and chemistry Professor Hongjie Dai look at the vascular structures in a mouse model of peripheral arterial disease. Graduate student Guosong Hong, left, and chemistry Professor Hongjie Dai look at the vascular structures in a mouse model of peripheral arterial disease with blood vessels shown in great detail using their new imaging technique called near-infrared II fluorescence imaging.

“For medical research, it’s a very nice tool for looking at features in small animals,” Dai said. “It will help us better understand some vasculature diseases and how they respond to therapy, and how we might devise better treatments.”

Because NIR-II can only penetrate a centimeter, at most, into the body, it won’t replace other imaging techniques for humans, but it will be a powerful method for studying animal models by replacing or complementing X-ray, CT, MRI and laser Doppler techniques.

The next step for the research, and one that will make the technology more easily accepted for use in humans, is to explore alternative fluorescent molecules, Dai said. “We’d like to find something smaller than the carbon nanotubes but that emit light at the same long wavelength, so that they can be easily excreted from the body and we can eliminate any toxicity concerns.”

The lead authors of the study are graduate student Guosong Hong of the Department of Chemistry and research assistant Jerry Lee of the School of Medicine. Other co-authors include graduate student Joshua Robinson and postdoctoral scholars Uwe Raaz and Liming Xie. The work was supported by the National Cancer Institute, the National Heart, Lung and Blood Institute and a Stanford Graduate Fellowship. The work was published online in Nature Medicine.

Media Contact

Hongjie Dai, Chemistry:  (650) 723-4518 , hdai1@stanford.eduThese images of a mouse's blood vessels show the difference in resolution between traditional near-infrared fluorescence imaging (top) and Stanford's new NIR-II technique (bottom).