20091209-6

Science-Wired Blogspot.com, December 8, 2009  —  Nanoparticles that deliver two or more drugs simultaneously can significantly shrink pancreatic cancer tumors and also reduce its spread, say researchers at Massachusetts General Hospital. Tayyaba Hasan, who is also a professor of dermatology at Harvard Medical School, led the development and testing of two “nanocells.” These nanocells combine light-based therapy with molecules that inhibit the growth of cancer cells or of the blood vessels that feed them.

Though the particles have only been studied in mice so far, the cancer-research community is excited. Pancreatic cancer remains one of the deadliest and hardest cancers to treat; mortality rates have changed very little in the last 30 years. After diagnosis, patients tend to live only six months, and less than 5 percent survive for five years. “In terms of a patient population, there is very little we can do for them once we find the cancer,” says Craig Thompson, director of the Abramson Cancer Center at the University of Pennsylvania.

Hasan and two research fellows in her lab, Prakash Rai and Lei Z. Zheng, presented their initial results on November 17 at the International Conference on Molecular Targets and Cancer Therapeutics, held jointly by the American Association for Cancer Research, the U.S. National Cancer Institute (NCI), and the European Organization for Research and Treatment of Cancer.

The team’s first type of nanocell is designed to effectively starve tumors by cutting off their blood supply. They trapped a photosensitive drug called verteporfin, which creates toxic oxygen radicals when exposed to specific wavelengths of light, inside solid polymer nanoparticles. Those nanoparticles were then encapsulated in lipid particles along with bevacizumab, an antibody that specifically inhibits the growth of new blood vessels by blocking a protein called VEGF. Both verteporfin and bevacizumab are already approved by the U.S. Food and Drug Administration. Bevacizumab is approved for the treatment of advanced cancers of the colon, breast, lung, and kidney; it’s marketed by Genentech as Avastin. Verteporfin is used to eliminate abnormal blood vessels in wet-form macular degeneration. It’s sold as Visudyne by Novartis.

In a previous small-scale clinical trial, verteporfin alone increased the median survival of pancreatic cancer patients from six months to nine months. Adding Avastin, however, did not increase survival time–possibly because the Avastin killed off the tumor’s blood vessels, making it difficult to get enough of the photosensitive drug to the cancer.

In contrast, when the nanocells are injected intravenously, they deliver both drugs directly to the inside of cancer cells. Blood vessels in normal tissue are impermeable to the nanoparticles, but blood vessels in tumors are “leakier,” with much larger pores that allow the nanoparticles to pass through. As a result, the nanoparticles accumulate inside tumors and deliver more of their payload to the cancer cells than to healthy cells. The nanocells provide a higher effective dose of drug to the tumors as well as fewer side effects because the researchers used a lower dose of both drugs than usual.

The team implanted human pancreatic cancer cells in mice and allowed tumors to grow. They then injected the mice with a single dose of the nanocells and exposed the tumor to long-wavelength light. Mice given this single treatment showed a greater reduction in their tumor size than mice treated with either drug alone. The mice treated with the nanocells also had at least two times fewer metastases to the liver, lungs, and lymph nodes. “Injecting these things as separate entities is not as effective as combining them into one construct,” says Hasan.

Hasan believes that’s because the nanocells actually fuse with the tumor cells and deliver the Avastin inside the cell, instead of just to the outside. And though Hasan’s lab has not done any toxicity studies, she hopes that the nanocells’ preferential accumulation inside of tumors may decrease the drug’s side effects, which can be quite dangerous. As many as 30 percent of patients receiving Avastin suffer cardiovascular side effects, including dangerously high blood pressure, stroke, and heart failure.

Shiladitya Sengupta, an assistant professor of medicine and health sciences and technology at Harvard Medical School, calls the results of Hasan’s mouse experiments “dramatic.” He says, “In the context of pancreatic cancer, [the results are] outstanding, because there’s no therapy.”

Sengupta did not participate in Hasan’s research, but he originated the idea of drug delivery using nanocells. Technology Review recognized him for this idea with a 2005 TR35 award. He cofounded Cerulean Pharma to commercialize the nanocell platform and other nanopharmaceutical delivery methods. But one tricky aspect of the technology is that it must be individually optimized for every new combination of drugs, he notes.

Hasan’s team has already developed a second nanocell designed to prevent pancreatic cancers from developing resistance to chemotherapy, a very common problem. Other researchers have identified two proteins, EGFR and MET, as particularly important in the development and growth of pancreatic cancer. In fact, in cancer cell lines in the lab, when biologists block EGFR, the cells increase their production of MET, and vice versa. So to better control the tumors, Hasan’s team set out to target EGFR and MET simultaneously, while again hitting the tumor with light to increase the effectiveness of the treatment.

This second nanocell required a more sophisticated design. Rai started with a small molecule called PHA-66572, which inhibits the MET protein, and confined it in the same sort of solid polymer nanoparticle used in the first nanocell. He then surrounded those nanoparticles with cetuximab, an antibody that blocks EGFR. Finally, he incorporated Visudyne into a lipid sphere that he used to encapsulate these two layers.

Zheng says that tumors shrank dramatically in mice that had been implanted with pancreatic cancers and then given a single injection of the nanocells followed by light therapy. He is still measuring the effects on metastasis, but since the MET protein is active in most cancers that have metastasized (not just pancreatic cancer), the researchers are optimistic that the growth-factor nanocells will significantly decrease the number and size of metastases as well.

Zheng says that these results are particularly encouraging because of the apparent reduction in toxicity of the drugs. Pfizer developed PHA-66572 specifically to block MET in cancer cells, but it proved so toxic that the company abandoned the drug. In contrast, Zheng says that the animals that he gave the nanocell maintained normal activity levels and didn’t lose weight.

Hasan hopes that both nanocells will be tested in pancreatic cancer patients within just a few years. Because Avastin and Visudyne are already FDA-approved, their two-part nanocell will likely be the first tested, probably in about two years, but perhaps as soon as a year from now, she says.

The NCI is already conducting toxicology tests of the Avastin-Visudyne nanocell as part of a new drug application to the FDA. The growth factor nanocell should enter the clinic “soon after,” Hasan says. The key is finding the best MET inhibitor, and Hasan says that other researchers are already testing several promising candidates.    By Erika Jonietz

(Nanowerk Spotlight) A number of applications in nanomedicine – imaging, drug delivery or photo therapy for instance – utilize phenomena called two-photon absorption (TPA). In TPA, the simultaneous absorption of two photons excite a molecule from one state to a higher energy electronic state. TPA initially was used only as a spectroscopic tool but new applications emerged over time.

“Currently approved two-photon absorption-induced excitation is one of the most promising approaches in photo therapies as it increases light penetration,” Dong-Hwang Chen tells Nanowerk.”It enables the use of light in the tissue-transparent window (750-1000 nm), allowing deeper light penetration and reduced risk of laser hyperthermia. An uphill energy conversion through the use of two-photon absorbing chromophores and subsequent energy transfer is a promising scientific frontier.”

Chen, a Distinguished Professor in the Department of Chemical Engineering at National Cheng Kung University in Tainan, Taiwan, continues to explain that fluorescence resonant energy transfer (FRET)-based semiconductor nanocrystal sensors and nanoformulation for photodynamic therapy have emerged over the past few years as promising nanoscales for analyte detection and light-activated treatment for cancer and other diseases.

Drug release triggered by two-photon excitation in near infrared (NIR) using the FRET technique have not yet been developed despite much progress in photo-triggered drug release.

“One of the promising approaches to obtain large intrinsic two-photon absorption cross sections in the near-infrared region is to exploit the energy-transferring combination of existing photosensitive linkers with two-photon absorption dyes,” he says. “Here, the photosensitive linker (energy acceptor) is indirectly excited through fluorescence resonance energy from the two-photon absorption dye unit (energy donor).”

This previous work has motivated Chen and his group to design a new class of drug nanocarriers capable of on demand drug release by efficient up-converting energy of NIR light to higher energy and intraparticle energy transfer for drug release.

The result is a multifunctional nanoparticle that can efficiently absorb the energy of NIR light and emit light of higher energy for triggering drug release by cleavage of a photosensitive linker.

20091209-5

Photo-triggered release of Dexa by up-converting energy of NIR light to higher energy and indirect energy transfer from RDB grafted gum arabic bound Fe3O4 nanoparticle to the linker. (Reprinted with permission from IOP Publishing)

Chen, together with his first author Shashwat S Banerjee, reports these findings in the April 14, 2009 online edition of Nanotechnology (“A multifunctional magnetic nanocarrier bearing fluorescent dye for targeted drug delivery by enhanced two-photon triggered release”).

Chen points out that, although the use of a fluorophore to cleave a linker molecule has been reported, in all the cases UV light has been utilized to cleave the linker. “The concept of energy harvesting by uphill energy conversions through the use of two-photon absorption and the phenomenon of FRET has never been utilized.”

This approach involves an energy-transferring magnetic nanoscopic co-assembly fabricated of rhodamine B fluorescent dye grafted gum arabic modified Fe3O4 magnetic nanoparticle (GAMNP) and photosensitive linker by which dexamethasone (a corticosteroid drug that acts as an anti-inflammatory and immunosuppressant and is used in cancer therapies of brain tumors) is conjugated to the magnetic nano-assembly.

One issue that the researchers found with their nanocarrier is that rhodamine, which acts as energy acceptor, showed slow degradation on prolong exposure to NIR. But they are confident that this problem can be resolved by using semiconductor nanocrystals in place of fluorescent dyes like rhodamine B.

Generally, this kind of multifunctional nanocarriers will provide targeted and on demand drug release that will lead to more effective therapies, eliminating the potential for both under and overdosing; the need for fewer administrations; optimal use of the drug in question; and increased patient compliance.

These nanocarriers will revolutionize especially cancer chemotherapies. Most chemotherapeutic compounds are nonspecific and are taken up by all types of cells – and this nonselective nature of the agents usually causes severe toxicity. The drug nanocarriers currently under development will dramatically improve the treatment of cancer by selectively providing the optimum dosage of the drug at the tumor site, ultimately even the individual tumor cell.

According to Chen, the type of nanocarrier designed by his group provides several advantages such as

“1) magnetic guiding to the desired target area and fixing them at the local site while the medication is released and acts locally;

2) surface functionalization by gum arabic provides an opportunity to allow directing the therapeutic agent to selected cells away from other cells and, in doing so, provides a method for targeting a therapeutic agent into selected cells;

3) the combined properties of fluorescence and magnetism associated with nanoparticles offer new opportunities for in vitro and in vivo imaging; and

4) indirect photo-triggering-on-demand drug release by efficient up-converting energy of the near-IR (NIR) light to higher energy and intraparticle energy transfer from the dye-grafted magnetic nanoparticle to the linker for photo-cleavage.”

The approach of two-photon induced intraparticles FRET for drug release, based on the use of two-photon fluorescent nanoassembly as a donor and a photosensitive linker as an acceptor, offers a novel design for developing formulations of smart drug-carrier nanoassemblies for more superior control over the location and the onset of drug release.

By Michael Berger. Copyright 2009 Nanowerk LLC

 

Nano Lett. 2009 Nov 11. [Epub ahead of print]

20091209-4

Dvir T, Banghart MR, Timko BP, Langer R, Kohane DS.

Department of Chemical Engineering, Massachusetts Institute of Technology, 45 Carleton Street, Cambridge, Massachusetts 02142, Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Children’s Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave, Boston, Massachusetts 02115, and Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, Massachusetts 02139.

We report a novel and simple proof-of-concept of a nanoparticulate system that targets any tissue selectively upon illumination. Nanoparticles were covalently functionalized with the amino acid sequence YIGSR, which adheres to the beta1 integrins present on most cell surfaces. This peptide was masked with a caging group, rendering it biologically inert. Illumination with UV light released the caging group from the YIGSR, allowing binding to cells.

PMID: 19904979 [PubMed – as supplied by publisher]

20091209-2

In this image, targeted nanoparticles–each about 1/100th the size of a human cell and engineered to be stealthy within the body–deliver high doses of chemotherapy to cancer cells. A team of researchers led by Omid Farokhzad at Brigham and Women’s Hospital and MIT Institute Professor Robert Langer has demonstrated the precision required to engineer a nanoparticle that is effective in targeted drug delivery. Details of their work were published in the Proceedings of the National Academy of Science. Image / Nicolle Rager Fuller, Sayo-Art

20091209-3

A team of researchers from NIMS, supported by the JST, has managed to create platinum nanoparticles whose shape is reminiscent of Japanese confectionery kompeitô (candy with the aspect of an embossed ball). Their surface (55m2/g) are found significantly higher than those of nanoparticles, nanofibers or nanotubes previously created (30m2/g).

Platinum is widely used, particularly as a catalyst (catalytic converter of a car) or electrode in batteries. Increasing the contact area of these nanoparticles will reduce the quantities, and thus the costs of these different applications.

Researchers explain that by adding a reducing agent in a solution containing a surfactant (a chain of polypropylene oxide), platinum ions and solvent is obtained in about ten minutes of nanoparticles with this shape. The yield of the chemical reaction is 100%. It may also, by playing on the strengths of the gearbox,  to obtain a solution containing of the quite distinct nanoparticules, with regular diameters. It can also vary the size of crystals obtained. These have a face-centered cubic. Such as providing a high resistance to high temperatures (250 °).

20091209-1

By TARA PARKER-POPE

The New York Times, Published: December 8, 2009

Can you give your muscles a better workout simply by changing your shoes?

The athletic shoe giant Reebok claims you can. The new EasyTone walking shoe, a provocative new marketing campaign says, leaves leg and buttock muscles better toned than regular walking shoes.

Consumers are buying it – literally. Officials from Reebok, a unit of Adidas, say the EasyTone is the company’s most successful new product in at least five years.

Other companies have marketed shoes that promise a physiological benefit. Masai Group International, of Switzerland, sells the MBT, a “rocker” shoe with a curved sole, said to ease arthritis and back pain. Shape-Ups from Skechers USA are designed to improve posture and muscle tone and promote weight loss. The FitFlop brand has been engineered to increase leg, calf and gluteal muscle activity, giving the wearer “a workout while you walk.”

While most athletic shoes offer support and cushioning, the new muscle-activating shoes are engineered to create a sense of instability. Design elements like curved soles and Reebok’s “balance pods” are said to force the wearer to engage stabilizing muscles further, resulting in additional toning for calf, hamstring and gluteal muscles.

That sounds great, but do they really work? To support the claims, the shoemakers each offer company-financed exercise studies suggesting that the shoes produce a higher level of muscle engagement, at least in a controlled research setting.

But the studies don’t show whether more engagement leads to meaningful changes in muscle tone or appearance over time. Nor is it clear whether the high level of engagement continues once the walker becomes accustomed to the shoe.

Reebok’s EasyTone has made the biggest splash in the muscle-shoe market, especially with its advertising. In one commercial, the camera drifts away from the woman’s face and zooms in on her backside. Another advertisement claims that the leg and butt-toning effects of EasyTone will “make your boobs jealous.”

The advertisements, aimed at younger women, have appeared in magazines and online, and a big television campaign is under way: 3,000 commercial slots have been scheduled on network and cable in November and December.

But the claim that the shoes offer muscle toning is backed by a single study involving just five people, not published in a peer-reviewed academic journal. In that study, done at the University of Delaware, five women walked on a treadmill for 500 steps wearing either the EasyTone or another Reebok walking shoe, and while barefoot. Using sensors that measure muscle activity, the researchers showed that wearing the EasyTone worked gluteal muscles an average of 28 percent more than regular walking shoes. Hamstring and calf muscles worked 11 percent harder.

Reebok’s head of advanced innovation, Bill McInnis, said the size of the study was adequate to determine the effect of the shoe and added that exercise studies of this nature commonly used small numbers of participants.

The EasyTone is the brainchild of Mr. McInnis, a former NASA engineer, who said he was interested in the stability balls used in gym workouts and wanted to translate the technology to a shoe. In particular, he was intrigued by the Bosu ball, a small half-sphere that exercisers stand on during workouts as a way to engage leg and core muscles better.

In designing the EasyTone, Mr. McInnis and his team sought to mimic that concept by adding “balance pods” to the toe and heel of the shoe. As the person walks, the air pushes back and forth between toe and heel, and the person sinks into the shoe. The effect is similar to that of walking on a sandy beach – which requires more work, balance and muscle engagement than walking on a flat surface.

John Lynch, head of United States brand marketing for Reebok, said the company’s market research showed that four out of five women were especially interested in products that toned their leg and gluteal muscles. Mr. Lynch added that retailers were reporting brisk sales of the shoe; one Los Angeles sporting goods store reported that its Reebok sales more than doubled in November.

Reebok says it has collected 15,000 hours’ worth of wear-test data from shoe users who say they notice the difference. “They definitely feel something in their muscles after they’ve walked in the product,” Mr. McInnis said.

One of them is Carol Vanner, 51, an executive assistant in Atlanta who had tried the larger-soled FitFlop shoe and was skeptical she would notice much difference with the EasyTone.

“I thought there was no way they would work, but I tried them and I felt like I had worked out,” she said. “Do I look like I’m 20? No, but I feel like when I wear them for periods of time that I have exercised and worked those muscles.”

Shay Gipson, 31, an apparel product manager in New York City, said she tried the shoes after hearing a friend rave about them. She immediately felt the balancing effect, she said, and she likes walking in the shoe.

“I can definitely feel the muscle groups in my legs working more than I would in regular shoes,” she said. “I feel more toned.”

But it remains to be seen whether such effects will make a difference over time. In a July 2008 study of instability boards and balls, Canadian researchers found that among experienced exercisers, moderate instability balls like the Bosu had little effect on muscle activation.

The shoes are designed only for walking, and because of the instability design, wearers are discouraged from running, jumping and engaging in other athletic activities while wearing them. So the real effect may come from simple awareness that they are wearing a muscle-activating shoe, causing them to walk more briskly and with purpose.

“I think buying them with this in mind is likely to increase mindfulness, which is good for health,” said Ellen J. Langer, a Harvard psychologist who has studied the connections between mindfulness, exercise and health. “It will probably result in even more walking, with the implicit and explicit virtues endemic to exercise.”