Defeat Osteosarcoma » NanoTechnology

Nanoparticles home in on brain tumors, boost accuracy of surgical removal

James Street — Sun, 15 Apr 2012 19:09:52 +0000

Posted: Apr 15th, 2012

(Nanowerk News) Like special-forces troops laser-tagging targets for a bomber pilot, tiny particles that can be imaged three different ways at once have enabled Stanford University School of Medicine scientists to remove brain tumors from mice with unprecedented accuracy.
In a study to be published online April 15 in Nature Medicine, a team led by Sam Gambhir, MD, PhD, professor and chair of radiology, showed that the minuscule nanoparticles engineered in his lab homed in on and highlighted brain tumors, precisely delineating their boundaries and greatly easing their complete removal. The new technique could someday help improve the prognosis of patients with deadly brain cancers.
About 14,000 people are diagnosed annually with brain cancer in the United States. Of those cases, about 3,000 are glioblastomas, the most aggressive form of brain tumor. The prognosis for glioblastoma is bleak: the median survival time without treatment is three months. Surgical removal of such tumors — a virtual imperative whenever possible — prolongs the typical patient’s survival by less than a year. One big reason for this is that it is almost impossible for even the most skilled neurosurgeon to remove the entire tumor while sparing normal brain.
“With brain tumors, surgeons don’t have the luxury of removing large amounts of surrounding normal brain tissue to be sure no cancer cells are left,” said Gambhir, who is the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research and director of the Molecular Imaging Program at Stanford. “You clearly have to leave as much of the healthy brain intact as you possibly can.”
This is a real problem for glioblastomas, which are particularly rough-edged tumors. In these tumors, tiny fingerlike projections commonly infiltrate healthy tissues, following the paths of blood vessels and nerve tracts. An additional challenge is posed by micrometastases: minuscule tumor patches caused by the migration and replication of cells from the primary tumor. Micrometastases dotting otherwise healthy nearby tissue but invisible to the surgeon’s naked eye can burgeon into new tumors.
Although brain surgery today tends to be guided by the surgeon’s naked eye, new molecular imaging methods could change that, and this study demonstrates the potential of using high-technology nanoparticles to highlight tumor tissue before and during brain surgery.
The nanoparticles used in the study are essentially tiny gold balls coated with imaging reagents. Each nanoparticle measures less than five one-millionths of an inch in diameter — about one-sixtieth that of a human red blood cell.
“We hypothesized that these particles, injected intravenously, would preferentially home in on tumors but not healthy brain tissue,” said Gambhir, who is also a member of the Stanford Cancer Institute. “The tiny blood vessels that feed a brain tumor are leaky, so we hoped that the spheres would bleed out of these vessels and lodge in nearby tumor material.” The particles’ gold cores, enhanced as they are by specialized coatings, would then render the particles simultaneously visible to three distinct methods of imaging, each contributing uniquely to an improved surgical outcome.
One of those methods, magnetic resonance imaging, is already frequently used to give surgeons an idea of where in the brain the tumor resides before they operate. MRI is well-equipped to determine a tumor’s boundaries, but when used preoperatively it can’t perfectly describe an aggressively growing tumor’s position within a subtly dynamic brain at the time the operation itself takes place.
The Gambhir team’s nanoparticles are coated with gadolinium, an MRI contrast agent, in a way that keeps them stably attached to the relatively inert spheres in a blood-like environment. (In a 2011 study published in Science Translational Medicine, Gambhir and his colleagues showed in small animal models that nanoparticles similar to those used in this new study, but not containing gadolinium, were nontoxic.)
A second, newer method is photoacoustic imaging, in which pulses of light are absorbed by materials such as the nanoparticles’ gold cores. The particles heat up slightly, producing detectable ultrasound signals from which a three-dimensional image of the tumor can be computed. Because this mode of imaging has high depth penetration and is highly sensitive to the presence of the gold particles, it can be useful in guiding removal of the bulk of a tumor during surgery.
The third method, called Raman imaging, leverages the capacity of certain materials (included in a layer coating the gold spheres) to give off almost undetectable amounts of light in a signature pattern consisting of several distinct wavelengths. The gold cores’ surfaces amplify the feeble Raman signals so they can be captured by a special microscope.
To demonstrate the utility of their approach, the investigators first showed via various methods that the lab’s nanoparticles specifically targeted tumor tissue, and only tumor tissue.
Next, they implanted several different types of human glioblastoma cells deep into the brains of laboratory mice. After injecting the imaging-enhancing nanoparticles into the mice’s tail veins, they were able to visualize, with all three imaging modes, the tumors that the glioblastoma cells had spawned.
The MRI scans provided good preoperative images of tumors’ general shapes and locations. And during the operation itself, photoacoustic imaging permitted accurate, real-time visualization of tumors’ edges, enhancing surgical precision.
But neither MRI nor photoacoustic imaging by themselves can distinguish healthy from cancerous tissue at a sufficiently minute level to identify every last bit of a tumor. Here, the third method, Raman imaging, proved crucial. In the study, Raman signals emanated only from tumor-ensconced nanoparticles, never from nanoparticle-free healthy tissue. So, after the bulk of an animal’s tumor had been cleared, the highly sensitive Raman-imaging technique was extremely accurate in flagging residual micrometastases and tiny fingerlike tumor projections still holed up in adjacent normal tissue that had been missed on visual inspection. This, in turn, enabled these dangerous remnants’ removal.
“Now we can learn the tumor’s extent before we go into the operating room, be guided with molecular precision during the excision procedure itself and then immediately afterward be able to ‘see’ once-invisible residual tumor material and take that out, too,” said Gambhir, who suggested that the nanoparticles’ propensity to heat up on photoacoustic stimulation, combined with their tumor specificity, might also make it possible for them to be used to selectively destroy tumors. He also expressed optimism that this kind of precision could eventually be brought to bear on other tumor types.

Source: Stanford University Medical Center

Particles could manufacture cancer drugs at tumor sites

James Street — Sun, 15 Apr 2012 05:54:35 +0000

Drugs made of protein have shown promise in treating cancer, but they are difficult to deliver because the body usually breaks down proteins before they reach their destination.

To get around that obstacle, a team of MIT researchers has developed a new type of nanoparticle that can synthesize proteins on demand. Once these “protein-factory” particles reach their targets, the researchers can turn on protein synthesis by shining ultraviolet light on them.

The particles could be used to deliver small proteins that kill cancer cells, and eventually larger proteins such as antibodies that trigger the immune system to destroy tumors, says Avi Schroeder, a postdoc in MIT’s David H. Koch Institute for Integrative Cancer Research and lead author of a paper appearing in the journal NanoLetters.

“This is the first proof of concept that you can actually synthesize new compounds from inert starting materials inside the body,” says Schroeder, who works in the labs of Robert Langer, MIT’s David H. Koch Institute Professor, and Daniel Anderson, an associate professor of health sciences and technology and chemical engineering.

Langer and Anderson are also authors of the paper, along with former Koch Institute postdocs Michael Goldberg, Christian Kastrup and Christopher Levins

Mimicking nature

The researchers came up with the idea for protein-building particles when trying to think of new ways to attack metastatic tumors — those that spread from the original cancer site to other parts of the body. Such metastases cause 90 percent of cancer deaths.

They decided to mimic the protein-manufacturing strategy found in nature. Cells store their protein-building instructions in DNA, which is then copied into messenger RNA. That mRNA carries protein blueprints to cell structures called ribosomes, which read the mRNA and translate it into amino acid sequences. Amino acids are strung together to form proteins.

“We wanted to use machinery that has already proven to be very effective. Ribosomes are used in nature, and they were perfected by nature over billions of years to be the best machine that can produce protein,” Schroeder says.

The researchers designed the new nanoparticles to self-assemble from a mixture that includes lipids — which form the particles’ outer shells — plus a mixture of ribosomes, amino acids and the enzymes needed for protein synthesis. Also included in the mixture are DNA sequences for the desired proteins.

The DNA is trapped by a chemical compound called DMNPE, which reversibly binds to it. This compound releases the DNA when exposed to ultraviolet light.

“You want to be able to trigger it so the system turns on only when you want it to work,” Schroeder says. “When the particles are hit by light, the DNA is released from a caging compound and then can enter the cycle of producing the protein.”

Programmable factories

In this study, particles were programmed to produce either green fluorescent protein (GFP) or luciferase, both of which are easily detected. Tests in mice showed that the particles were successfully prompted to produce protein when UV light shone on them.

Waiting until the particles reach their destination before activating them could help prevent side effects from a particularly toxic drug, says James Heath, a professor of chemistry at the California Institute of Technology. However, more testing must be done to demonstrate that the particles would reach their intended destination in humans, and that they can be used to produce therapeutic proteins, he says.

“There are lots of details left to be worked out for this to be a
viable therapeutic approach, but it is a really terrific and innovative concept, and it certainly gets one’s imagination going,” says Heath, who was not part of the research team.

The researchers are now working on particles that can synthesize potential cancer drugs. Some of these proteins are toxic to both cancerous and healthy cells — but using this delivery method, protein production could be turned on only in the tumor, avoiding side effects in healthy cells.

The team is also working on new ways to activate the nanoparticles. Possible approaches include production triggered by acidity level or other biological conditions specific to certain body regions or cells.

Normalizing tumor blood vessels improves delivery of only the smallest nanomedicines

James Street — Tue, 10 Apr 2012 05:15:10 +0000

Posted: Apr 9th, 2012

(Nanowerk News) Combining two strategies designed to improve the results of cancer treatment – antiangiogenesis drugs and nanomedicines – may only be successful if the smallest nanomedicines are used. A new study from Massachusetts General Hospital (MGH) researchers, appearing in Nature Nanotechnology (“Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner”), finds that normalizing blood vessels within tumors, which improves the delivery of standard chemotherapy drugs, can block the delivery of larger nanotherapy molecules.
“We found that vascular normalization only increases the delivery of the smallest nanomedicines to cancer cells,” says Vikash P. Chauhan, of the Steele Laboratory of Tumor Biology in the MGH Radiation Oncology Department, lead author of the report. “We also showed that the smallest nanomedicines are inherently better than larger nanomedicines at penetrating tumors, suggesting that smaller nanomedicines may be ideal for cancer therapy.”
Tumors need to generate their own blood supply to continue growing, but vessels supplying tumors tend to be disorganized, oversized and leaky. Not only does this prevent the delivery of chemotherapy drugs to cells not close to tumor vessels, but the leakage of plasma out of blood vessels increases pressure within the tumor, further reducing the ability of drugs to penetrate tumors. Treatment with drugs that inhibit angiogenesis – the process by which new vessels are generated – reduces some of these abnormalities, a process called vascular normalization that has been shown to improve treatment of some cancers with standard chemotherapy drugs.
Nanomedicines are actually designed to exploit tumor vessel abnormality. While the molecules of standard chemotherapy drugs are about one nanometer – a billionth of a meter – nanomedicine molecules are from 10 to 100 times larger, too large to penetrate the pores of blood vessels in normal tissues but small enough to pass through the oversized pores of tumor vessels. Since the size of nanomedicines should keep them out of normal tissues, they are prescribed to reduce the negative side effects of chemotherapy.
The current study was designed to investigate whether the use of antiangiogenesis drugs to normalize tumor vasculature would improve or impede delivery of nanomedicines to tumor cells. In studies using a mouse model of breast cancer, the investigators first confirmed that treatment with DC101, an antibody to a molecule essential to blood vessel growth, temporarily decreased the diameter of enlarged tumor blood vessels. They then showed that this vascular normalization improved the penetration into tumors of 12-nanometer particles but not of 60- or 125-nanometer molecules.
A mathematical model prepared by the MGH team predicted that, while the abnormally large pores in the walls of tumor blood vessels lead to increased pressure within the tumor that impedes the entry of drugs, reducing pore size by antiangiogenesis treatment would relieve intratumor pressure, allowing the entry of those molecules that fit through the smaller pores. To test this prediction, they treated mice with implanted breast tumors either with DC101 and Doxil, a 100-nanometer version of the chemotherapy drug doxorubicin, or with DC101 and Abraxane, a 10-nanometer version of paclitaxel. Although treatment with both chemotherapeutics delayed tumor growth, vascular normalization with DC101 improved the effectiveness only of Abraxane and had no effect on Doxil treatment.
“A variety of anticancer nanomedicines are currently in use or in clinical trials,” says Chauhan, who is a graduate student at the Harvard School of Engineering and Applied Sciences (SEAS). “Our findings suggest that combining smaller nanomedicines with antiangiogenic therapies may have a synergistic effect and that smaller nanomedicines should inherently penetrate tumors faster than larger nanomedicines, due to the physical principles that govern drug penetration. While it looks like future development of nanomedicines should focus on making them small – around 12 nanometers in size – we also need to investigate ways to improve delivery of the larger nanomedicines that are currently in use.”
“Antiangiogenic agents are prescribed to a large number of cancer patients in combination with conventional therapeutics,” explains Rakesh K. Jain, PhD, director of the Steele Lab and senior and corresponding author of the Nature Nanotechnology report. “Our study provides guidelines on how to combine the antiangiogenic drugs with nanotherapeutics.” Jain is Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School.

Tiny Hitchhikers Attack Cancer Cells: Gold Nanostars First to Deliver Drug Directly to Cancer Cell Nucleus

James Street — Mon, 09 Apr 2012 06:24:43 +0000

ScienceDaily (Apr. 5, 2012) — Nanotechnology offers powerful new possibilities for targeted cancer therapies, but the design challenges are many. Northwestern University scientists now are the first to develop a simple but specialized nanoparticle that can deliver a drug directly to a cancer cell’s nucleus — an important feature for effective treatment.

They also are the first to directly image at nanoscale dimensions how nanoparticles interact with a cancer cell’s nucleus.

“Our drug-loaded gold nanostars are tiny hitchhikers,” said Teri W. Odom, who led the study of human cervical and ovarian cancer cells. “They are attracted to a protein on the cancer cell’s surface that conveniently shuttles the nanostars to the cell’s nucleus. Then, on the nucleus’ doorstep, the nanostars release the drug, which continues into the nucleus to do its work.”

Odom is the Board of Lady Managers of the Columbian Exposition Professor of Chemistry in the Weinberg College of Arts and Sciences and a professor of materials science and engineering in the McCormick School of Engineering and Applied Science.

Using electron microscopy, Odom and her team found their drug-loaded nanoparticles dramatically change the shape of the cancer cell nucleus. What begins as a nice, smooth ellipsoid becomes an uneven shape with deep folds. They also discovered that this change in shape after drug release was connected to cells dying and the cell population becoming less viable — both positive outcomes when dealing with cancer cells.

The results are published in the journal ACS Nano.

Since this initial research, the researchers have gone on to study effects of the drug-loaded gold nanostars on 12 other human cancer cell lines. The effect was much the same. “All cancer cells seem to respond similarly,” Odom said. “This suggests that the shuttling capabilities of the nucleolin protein for functionalized nanoparticles could be a general strategy for nuclear-targeted drug delivery.”

The nanoparticle is simple and cleverly designed. It is made of gold and shaped much like a star, with five to 10 points. (A nanostar is approximately 25 nanometers wide.) The large surface area allows the researchers to load a high concentration of drug molecules onto the nanostar. Less drug would be needed than current therapeutic approaches using free molecules because the drug is stabilized on the surface of the nanoparticle.

The drug used in the study is a single-stranded DNA aptamer called AS1411. Approximately 1,000 of these strands are attached to each nanostar’s surface.

The DNA aptamer serves two functions: it is attracted to and binds to nucleolin, a protein overexpressed in cancer cells and found on the cell surface (as well as within the cell). And when released from the nanostar, the DNA aptamer also acts as the drug itself.

Bound to the nucleolin, the drug-loaded gold nanostars take advantage of the protein’s role as a shuttle within the cell and hitchhike their way to the cell nucleus. The researchers then direct ultrafast pulses of light — similar to that used in LASIK surgery — at the cells. The pulsed light cleaves the bond attachments between the gold surface and the thiolated DNA aptamers, which then can enter the nucleus.

In addition to allowing a large amount of drug to be loaded, the nanostar’s shape also helps concentrate the light at the points, facilitating drug release in those areas. Drug release from nanoparticles is a difficult problem, Odom said, but with the gold nanostars the release occurs easily.

That the gold nanostar can deliver the drug without needing to pass through the nuclear membrane means the nanoparticle is not required to be a certain size, offering design flexibility. Also, the nanostars are made using a biocompatible synthesis, which is unusual for nanoparticles.

Odom envisions the drug-delivery method, once optimized, could be particularly useful in cases where tumors are fairly close to the skin’s surface, such as skin and some breast cancers. (The light source would be external to the body.) Surgeons removing cancerous tumors also might find the gold nanostars useful for eradicating any stray cancer cells in surrounding tissue.

The National Institutes of Health supported the research.

First targeted nanomedicine to enter cancer clinical studies

James Street — Mon, 09 Apr 2012 06:15:40 +0000

Researchers call it a paradigm shift in anti-tumor efficacy and safety in cancer patients

A team of scientists, engineers and physicians from Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts Institute of Technology, BIND Biosciences, Translational Genomics Research Institute (TGen), Wayne State University Karmanos Cancer Institute, and Weill Cornell Medical College have found promising effects of a first-in-class targeted cancer drug called BIND-014 in treating solid tumors.

Artist rendering of BIND-014 (credit Digizyme)

BIND-014 is the first targeted and programmed nanomedicine to enter human clinical studies. The study will be published online by Science Translational Medicine on April 4.

In the study, the researchers demonstrate BIND-014′s ability to effectively target a receptor expressed in tumors to achieve high tumor drug concentrations, as well as show remarkable efficacy, safety and pharmacological properties compared to the parent chemotherapeutic drug, docetaxel (Taxotere).

“BIND-014 demonstrates for the first time that it is possible to generate medicines with both targeted and programmable properties that can concentrate the therapeutic effect directly at the site of disease, potentially revolutionizing how complex diseases such as cancer are treated,” said Omid Farokhzad, MD, a physician-scientist in the Brigham and Women’s Department of Anesthesiology, associate professor at HMS, and study co-senior author.

“Previous attempts to develop targeted nanoparticles have not successfully translated into human clinical studies because of the inherent difficulty of designing and scaling up a particle capable of targeting, long-circulation via immune-response evasion, and controlled drug release,” said Robert Langer, ScD, David H. Koch Institute Professor, MIT, and study co-senior author.

According to the researchers, the drug is the first of its kind to reach clinical evaluation and demonstrates a differentially high drug concentration in tumors by targeting drug encapsulated nanoparticles directly to the site of tumors. This leads to substantially better efficacy and safety.

Phillip W. Kantoff, MD

In the study, the researchers produced data that include pharmacokinetic characteristics consistent with prolonged circulation and controlled drug release with plasma concentrations remaining up to at least 100-fold higher than conventional docetaxel for more than 24 hours, as well as up to a 10-fold increase in intratumoral drug concentrations with prolonged and enhanced tumor growth suppression in multiple tumor models compared with conventional docetaxel.

Moreover, initial clinical data in a heavily pretreated patient population with 17 patients with advanced or metastatic solid tumor cancers indicated that BIND-014 displays pharmacological characteristics consistent with preclinical findings of differentiated pharmacokinetics and accumulation at tumor sites with clinical effects seen at doses as low as 20 percent of the normally prescribed docetaxel dose and in cancers in which docetaxel has minimal activity (e.g., cervical cancer).

“The development of BIND-014 demonstrates that drug properties such as solubility, metabolism, plasma binding, biodistribution and target tissue accumulation will no longer be constrained to the same extent by the drug chemical composition. It will also become the function of the physicochemical properties of nanoparticles. This will allow for an unprecedented ability to make better medicines for our patients as demonstrated by our emerging clinical data,” said Farokhzad.

The researchers note that while the science and technology of BIND-014 builds upon docetaxel’s mechanism of action, the emerging evidence is that BIND-014 significantly changes the biological effects of docetaxel by virtue of fundamental changes in pharmacology including major increases in tumor concentration.

To date, the researchers note that BIND-014 has been administered at doses of up to 75 mg/m2 and dose escalation is ongoing. It has been well-tolerated with no new toxicities observed.

Edward J. Benz Jr., MD

“It has been a privilege to be a part of the team that developed this technology at its conception through its clinical translation. The emerging BIND-014 clinical data showing signals of efficacy even at relatively low doses validates the potential for the revolutionary impact of nanomedicines and is a paradigm shift for the treatment of cancer,” said Philip W. Kantoff, MD, Chief Clinical Research Officer at Dana-Farber, professor of Medicine at HMS, and study co-author.

“It is wonderful to witness a world-class team of scientists, engineers, physicians, for-profit and non-project organizations converge to develop this potentially revolutionary technology for treatment of cancers. The effectiveness of this team has been remarkable and serves as model for translational research,” said Edward J. Benz, Jr., MD, president of Dana-Farber, Richard and Susan Smith Professor of Medicine at HMS.

The research and development of the first targeted programmable nanomedicine to show anti-tumor effects in humans represents the culmination of more than a decade of investigation initially carried out in academic labs at BWH and MIT, and supported by funding from the National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering; The David H. Koch Institute for Integrative Cancer Research at MIT; the Prostate Cancer Foundation,; philanthropic gift from David H. Koch, and the Dana-Farber Harvard Cancer Center Prostate Cancer SPORE; and subsequently carried out in the laboratories of BIND Biosciences leading to the development of BIND-014, and supported by funding from the National Cancer Institute, National Institute of Standards and Technology and BIND Biosciences.

BIND Biosciences was launched in 2007 based on technologies that were licensed from BWH and MIT and developed, respectively, in the laboratories of Farokhzad and Langer, co-founders of BIND Biosciences, the biopharmaceutical company responsible for developing BIND-014.

This press release was written in collaboration with BIND Biosciences and The Yates Network.

Novel Prostate Nanomedicine Delivers High Drug Concentration Directly and Safely to Tumors in Phase I Trials

James Street — Mon, 09 Apr 2012 06:13:15 +0000

Highly-Targeted Nanoparticles Act as “Trojan Horse” to Deliver Powerful Chemotherapy Agent Without Affecting Healthy Cells

SANTA MONICA, Calif., Apr 04, 2012 (BUSINESS WIRE) — Nanomedicine research at the David H. Koch Institute for Integrative Cancer Research at MIT funded by a $5 million grant from the Prostate Cancer Foundation (PCF) has delivered the first nanomedicine shown to successfully target prostate cancer cells and deliver docetaxel chemotherapy in high concentrations in Phase I clinical trials. Docetaxel is used in prostate cancer patients who have failed hormone therapy and is currently delivered via infusion which floods the body and affects both cancerous and healthy cells. By using targeted nanoparticles to deliver the therapeutic, healthy cells are widely spared from undesired side effects of treatment.

Results from Phase I clinical trials of BIND-014 were published today in Science Translational Medicine. BIND Biosciences, the biopharmaceutical company that developed BIND-014, also presented the trials data today at the 2012 American Association of Cancer Research meeting in Chicago.

BIND-014 is a programmable nanomedicine that combines a targeting ligand and a therapeutic nanoparticle. BIND-014 contains docetaxel, a proven cancer drug which is approved in major cancer indications including breast, prostate and lung, encapsulated in FDA-approved biocompatible and biodegradable polymers. BIND-014 is targeted to prostate specific membrane antigen (PSMA), a cell surface antigen abundantly expressed on the surface of cancer cells and on new blood vessels that feed a wide array of solid tumors. In preclinical cancer models, BIND-014 was shown to deliver ten-fold more docetaxel to tumors than an equivalent dose of conventional docetaxel. The increased accumulation of docetaxel at the site of disease translated to marked improvements in antitumor activity and tolerability.

PCF has funded research on PSMA, the attractor antigen or “sticky tape” that is targeted by BIND-014 nanoparticles since 1996. This research further discovered that PSMA is also found on the surfaces of neovasculature (new blood vessels) in the tumors of other cancers.

“The development of BIND-014 represents a unique public, private, and philanthropic funding effort to fast-forward and realize the potential of nanomedicines for the benefit of cancer patients,” said Jonathan W. Simons, MD, president and CEO of the Prostate Cancer Foundation which provided $5 million to the collaborative research project in 2007. “This is a tour de force of transdisciplinary collaboration–bioengineers, chemical engineers, nanotechnologists, oncologists, and prostate cancer biologists all came together to advance multiple components and concepts to the clinic. PCF’s funding leveraged an early and significant NCI nanotechnology investment in this prostate cancer therapeutics research. With this exemplary new work across institutional boundaries, BIND-014 represents an entirely new, programmable platform for targeted, cancer drug delivery–and it moved to the clinic in a strikingly short period of time.”

The idea to develop aptamer-targeted nanoparticles was first conceived in 2002 and forwarded by the David H. Koch Institute for Integrative Cancer Research at MIT, Brigham and Women’s Hospital, the Dana-Farber Cancer Institute, Harvard Medical School and Weill Cornell Medical College. Funding for the research and development program was provided by both public and private sources including the MIT Institute for Integrative Center for Cancer Research, the National Institute for Biomedical Imaging and Bioengineering, a prostate cancer SPORE Grant awarded to Dana-Farber Cancer Institute, the National Cancer Institute, the NCI Alliance in Nanotechnology and the Prostate Cancer Foundation.

“These seminal data on BIND’s first clinical stage Accurin, BIND-014, demonstrates for the first time that it is possible to generate medicines with both targeted and programmable properties that can concentrate the therapeutic effect directly at the site of disease, potentially revolutionizing how complex diseases such as cancer are treated,” commented Omid Farokhzad, M.D., BIND Founder and Associate Professor, Harvard Medical School. “BIND’s data are a giant leap forward in achieving the true promise of nanomedicine by enabling the design of therapeutics with highly-differentiated efficacy and safety that go above and beyond the capabilities of traditional drug design through medicinal chemistry.”

“Previous attempts to develop targeted nanoparticles have not translated into clinical success because of the inherent difficulty of designing and scaling up a particle capable of targeting, long-circulation via immune-response evasion, and controlled drug release,” commented Robert Langer, Sc.D., BIND Founder and David H. Koch Institute Professor at MIT. “BIND-014 is the first therapeutic of its kind to reach clinical evaluation and has demonstrated an increases of up to ten fold in drug concentration in tumors, which lead to substantially better efficacy and safety.”

With these findings, multiple Phase I/II trials targeting other cancers expressing PSMA can be accelerated safely.

About the Prostate Cancer Foundation

The Prostate Cancer Foundation (PCF) is the world’s leading philanthropic organization funding and accelerating research. Founded in 1993 by Michael Milken, PCF has raised more than $479 million and provided funding to over 1,600 research projects at nearly 200 institutions in 15 countries around the world. Since 2008, it has supported 98 Young Investigators in seven countries and launched 17 PCF team science Challenge Awards. PCF advocates for greater awareness of prostate cancer and more efficient investment of governmental research funds supporting transformational cancer research. Prostate Cancer Foundation efforts over 19 years have helped produce a 20-fold increase in government funding for prostate cancer and fast-forward research on four new Food and Drug Administration (FDA) drugs for advanced prostate cancer in the past two years. More information about PCF can be found at pcf.org.

Photos/Multimedia Gallery Available: http://www.businesswire.com/cgi-bin/mmg.cgi?eid=50229137&lang=en

SOURCE: Prostate Cancer Foundation

        Prostate Cancer Foundation
        Dan Zenka, APR
        Vice President, Communications
        310-570-4714
        dzenka@pcf.org
        or
        Cara Lasala
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        310-570-4727
        clasala@pcf.org

MIT – Nanoparticles designed to home in on cancer cells achieve tumor shrinkage at lower doses than traditional chemotherapy.

James Street — Mon, 09 Apr 2012 06:10:29 +0000

The nanoparticles feature a homing molecule that allows them to specifically attack cancer cells, and are the first such targeted particles to enter human clinical studies. Originally developed by researchers at MIT and Brigham and Women’s Hospital in Boston, the particles are designed to carry the chemotherapy drug docetaxel, used to treat lung, prostate and breast cancers, among others. The researchers demonstrate the particles’ ability to target a receptor found on cancer cells and accumulate at tumor sites. The particles were also shown to be safe and effective: Many of the patients’ tumors shrank as a result of the treatment, even when they received lower doses than those usually administered.

An artist’s rendering of BIND-014.Image: Digizyme, Inc.

Science Translational Medicine – Preclinical Development and Clinical Translation of a PSMA-Targeted Docetaxel Nanoparticle with a Differentiated Pharmacological Profile

Abstract – We describe the development and clinical translation of a targeted polymeric nanoparticle (TNP) containing the chemotherapeutic docetaxel (DTXL) for the treatment of patients with solid tumors. DTXL-TNP is targeted to prostate-specific membrane antigen, a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most nonprostate solid tumors. DTXL-TNP was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading, and drug release properties. Pharmacokinetic and tissue distribution studies in rats showed that the NPs had a blood circulation half-life of about 20 hours and minimal liver accumulation. In tumor-bearing mice, DTXL-TNP exhibited markedly enhanced tumor accumulation at 12 hours and prolonged tumor growth suppression compared to a solvent-based DTXL formulation (sb-DTXL). In tumor-bearing mice, rats, and nonhuman primates, DTXL-TNP displayed pharmacokinetic characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL, with total DTXL plasma concentrations remaining at least 100-fold higher than sb-DTXL for more than 24 hours. Finally, initial clinical data in patients with advanced solid tumors indicated that DTXL-TNP displays a pharmacological profile differentiated from sb-DTXL, including pharmacokinetics characteristics consistent with preclinical data and cases of tumor shrinkage at doses below the sb-DTXL dose typically used in the clinic.

By 2006, they had demonstrated that targeted nanoparticles can shrink tumors in mice, paving the road for the eventual development and evaluation of a targeted nanoparticle called BIND-014, which entered clinical trials in January 2011.

For this study, the researchers coated the nanoparticles with targeting molecules that recognize a protein called PSMA (prostate-specific membrane antigen), found abundantly on the surface of most prostate tumor cells as well as many other types of tumors.

One of the challenges in developing effective drug-delivery nanoparticles, Langer says, is designing them so they can perform two critical functions: evading the body’s normal immune response and reaching their intended targets.

“You need exactly the right combination of these properties, because if they don’t have the right concentration of targeting molecules, they won’t get to the cells you want, and if they don’t have the right stealth properties, they’ll get taken up by macrophages,” says Langer, also a member of the David H. Koch Institute for Integrative Cancer Research at MIT.

The BIND-014 nanoparticles have three components: one that carries the drug, one that targets PSMA, and one that helps evade macrophages and other immune-system cells. A few years ago, Langer and Farokhzad developed a way to manipulate these properties very precisely, creating large collections of diverse particles that could then be tested for the ideal composition.

“They systematically made a set of materials that varied in the properties they thought would matter, and developed a way to screen them. That’s not been done in this kind of setting before,” says Mark Saltzman, a professor of biomedical engineering at Yale University who was not involved in this study. “They’ve taken the concept from the lab into clinical trials, which is quite impressive.”

All of the particles are made of polymers already approved for medical use by the U.S. Food and Drug Administration.

Clinical results

The Phase I clinical trial involved 17 patients with advanced or metastatic tumors who had already gone through traditional chemotherapy. In Phase I trials, researchers evaluate a potential drug’s safety and study its effects in the body. To determine safe dosages, patients were given escalating doses of the nanoparticles. So far, doses of BIND-014 have reached the amount of docetaxel usually given without nanoparticles, with no new side effects. The known side effects of docetaxel have also been milder.

In the 48 hours after treatment, the researchers found that docetaxel concentration in the patients’ blood was 100 times higher with the nanoparticles as compared to docetaxel administered in its conventional form. Higher blood concentration of BIND-014 facilitated tumor targeting resulting in tumor shrinkage in patients, in some cases with doses of BIND-014 that correspond to as low as 20 percent of the amount of docetaxel normally given. The nanoparticles were also effective in cancers in which docetaxel usually has little activity, including cervical cancer and cancer of the bile ducts.

The researchers also found that in animals treated with the nanoparticles, the concentration of docetaxel in the tumors was up to tenfold higher than in animals treated with conventional docetaxel injection for the first 24 hours, and that nanoparticle treatment resulted in enhanced tumor reduction.

The Phase I clinical trial is still ongoing and continued dose escalation is underway; BIND Biosciences is now planning Phase II trials, which will further investigate the treatment’s effectiveness in a larger number of patients.

Using radio waves to bake tumors

James Street — Mon, 09 Apr 2012 06:05:59 +0000

(Nanowerk News) Nanothermal therapy – the use of nanoparticles to cook a tumor to death – is one of the many promising uses of nanotechnology to both improve the effectiveness of cancer therapy and reduce its side effects. Now, a team of investigators from the Texas Center for Cancer Nanomedicine has shown that liver cancer cells will take up targeted gold nanoparticles, absorb radio waves, and generate heat that damages the cells. In addition, the researchers have discovered how to increase the thermal toxicity of these nanoparticles.
This research was led by Steven A. Curley, of the University of Texas M.D. Anderson Cancer Center, and Lon Wilson, of Rice University. The investigators published their results in the journal Nanomedicine (“Stability of antibody-conjugated gold nanoparticles in the endolysosomal nanoenvironment: implications for noninvasive radiofrequency-based cancer therapy”).
Biocompatible gold nanoparticles are ideal vehicles for delivering heat to tumors because they are non-toxic, stable, and can be coated with a variety of molecules to target them to tumors. Unlike conventional anticancer agents, gold nanoparticles are harmless unless first activated by an energy source, such as a near-infrared light delivered by a laser. In fact, laser-activated gold nanoparticles are being tested in human clinical trials for the treatment of head and neck cancer. Radio waves, however, have a potential advantage over laser energy because radio waves do not interact with biological tissues and thus can penetrate more deeply within the body than can laser light.
One of the major obstacles to using radiofrequency-activated gold nanoparticles to treat cancer is their tendency to clump together, which reduces their ability to absorb energy and convert it to heat. In the current study, the Texas researchers aimed to develop a precise understanding of why clumping occurs and develop the means to keep it from happening. Their experiments showed that the low pH within endosomes – the tiny vesicles that bring antibody-targeted nanoparticles into cells – is the primary cause of aggregation.
In an attempt to neutralize the acidic pH within endosomes, the investigators treated the cells with one of two different drugs – concanamycin A, an antibiotic not designed for use in humans, and chloroquine, an approved antimalarial agent – that are known to prevent endosome acidification. When the treated cells were exposed to antibody-targeted gold nanoparticles and then radiofrequency activation, heat-triggered cell death increased markedly compared to that seen with cells that were not pre-treated with the acid blockers, by preserving the protein coating on the gold nanoparticle surface. Based on these results, the investigators are now developing antibody-targeted nanoparticles with coatings that will prevent aggregation in the acidic environment of the endosome.

Source: National Cancer Institute

Programmable Nanomedicine Cancer Treatment Shrinks Human Tumors

James Street — Fri, 06 Apr 2012 07:27:11 +0000

By Katherine Harmon | April 4, 2012

Cancer cell illustration courtesy of iStockphoto/Eraxion

Chemotherapy treatment for cancer is a nasty process. Doctors must try to give patients just enough of the toxic drugs to kill off cancer cells without doing too much harm to the rest of the body’s healthy tissues, a balancing act that, even if successful, can nevertheless cause horrible side effects.

But what if you could program the harsh medicine to go only to the cancerous cells, sparing the rest of the body? Researchers have been aiming for this goal for more than 100 years and have achieved some success in targeted treatment by using monoclonal antibodies in immunotherapy. Getting chemotherapy to cancer cells, however, has proved difficult. A new nanotechnology might just finally bring it into reach.

Scientists have spent the past few decades tinkering with nanopaticles, and recently they have been able to cover them with cancer-seeking proteins and load them with a tumor-busting drug. But these tiny particles, hundreds of which could fit across the width of a human hair, have so far failed to perform in humans.

A new tumor-targeting, nanoparticle-based compound called BIND-014 is now in clinical trials in people, after showing promise in both mice and monkeys. Although this first trial is small, with only 17 patients, and still ongoing, researchers are reporting some positive results, and no obvious major safety setbacks, according to a paper published online April 4 in Science Translational Medicine.

The researchers could move quickly from animals to human studies because they relied on components that have already been used in humans. Specifically, they loaded the nanoparticles with the chemo drug docetaxel, which used to treat solid tumors in many parts of the body, including breast, head, lung, neck, prostate and stomach. They then outfitted the particles with a well-known tumor-specific antigen that targets newly forming blood vessels that develop to feed tumors and that’s also present in prostate cancer cells.

But the researchers did not just slap a few proteins on a nanoparticle and send it into tests. They screened more than 100 different nanoparticles with various sizes, surfaces and drug-release capabilities. “Previous attempts to develop targeted nanoparticles have not successfully translated into human clinical studies because of the inherent difficulties of designing and scaling up a particle capable of targeting, long-circulating via immune-response evasion and controlled drug release,” study co-author Robert Langer of the Massachusetts Institute of Technology said in a prepared statement.

In the current, phase 1 safety trial, patients with advanced or metastatic cancer received an injection of the nano-drug once every three weeks. The drug seemed to remain in the body for at least two days, giving it time to do its damage on the tumor cells. And damage it has seemed to do. Although final results from the trial will be forthcoming, tumor growth has slowed in many patients, and in some, tumors have been shrinking—or even going away. In one 51-year-old man with bile-duct cancer, the researchers found that several metastases had shrunk to near vanishing after just two doses of relatively low concentrations of the nano-drug. And the tonsil tumor of a 63-year-old patient shrank by about 25 percent after two doses as well. The researchers were all the more surprised at these early findings because in traditional forms, docetaxel has not proved to be terribly effective against many types of tumors in the study.

“The emerging BIND-014 clinical data showing signals of efficacy even at relatively low doses validates the potential for the revolutionary impact of nanomedicines and is a paradigm shift for the treatment of cancer,” Philip Kantoff, of the Dana-Farber Cancer Institute and co-author of the new study, said in a prepared statement.

Because the particle homes in on cancer cells specifically, the drug is delivered to the tumor site in much higher—and thus more effective—concentrations than it is via standard plasma-based injections. The particles themselves also seem to have a good size and shape to evade the immune system, and they also shows low accumulation in the liver, suggesting they are relatively safe.

Still, considering the larger debate about the safety of nanoparticles, this nanomedicine will require further testing in this and future, larger trials. But, as the researchers noted in their paper, this compound has shown progress toward the century-old goal of creating a cancer treatment that “can increase efficacy and decrease toxicity.” In other words, they hope we are finally nearing a time when we will be able to kill off the cancer—and the treatment’s side effects.

About the Author: Katherine Harmon is an associate editor for Scientific American covering health, medicine and life sciences. Follow on Twitter @katherineharmon.More »
The views expressed are those of the author and are not necessarily those of Scientific American.

MIT research: Delivering RNA with tiny sponge-like spheres

James Street — Tue, 06 Mar 2012 02:19:16 +0000

Published: Monday, February 27, 2012 – 11:35 in Biology & Nature

For the past decade, scientists have been pursuing cancer treatments based on RNA interference — a phenomenon that offers a way to shut off malfunctioning genes with short snippets of RNA. However, one huge challenge remains: finding a way to efficiently deliver the RNA. Most of the time, short interfering RNA (siRNA) — the type used for RNA interference — is quickly broken down inside the body by enzymes that defend against infection by RNA viruses.

“It’s been a real struggle to try to design a delivery system that allows us to administer siRNA, especially if you want to target it to a specific part of the body,” says Paula Hammond, the David H. Koch Professor in Engineering at MIT.

Hammond and her colleagues have now come up with a novel delivery vehicle in which RNA is packed into microspheres so dense that they withstand degradation until they reach their destinations. The new system, described Feb. 26 in the journal Nature Materials, knocks down expression of specific genes as effectively as existing delivery methods, but with a much smaller dose of particles.

Such particles could offer a new way to treat not only cancer, but also any other chronic disease caused by a “misbehaving gene,” says Hammond, who is also a member of MIT’s David H. Koch Institute for Integrative Cancer Research. “RNA interference holds a huge amount of promise for a number of disorders, one of which is cancer, but also neurological disorders and immune disorders,” she says.

Lead author of the paper is Jong Bum Lee, a former postdoc in Hammond’s lab. Postdoc Jinkee Hong, Daniel Bonner PhD ’12 and Zhiyong Poon PhD ’11 are also authors of the paper.

Genetic disruption

RNA interference is a naturally occurring process, discovered in 1998, that allows cells to fine-tune their genetic expression. Genetic information is normally carried from DNA in the nucleus to ribosomes, cellular structures where proteins are made. siRNA binds to the messenger RNA that carries this genetic information, destroying instructions before they reach the ribosome.

Scientists are working on many ways to artificially replicate this process to target specific genes, including packaging siRNA into nanoparticles made of lipids or inorganic materials such as gold. Though many of those have shown some success, one drawback is that it’s difficult to load large amounts of siRNA onto those carriers, because the short strands do not pack tightly.

To overcome this, Hammond’s team decided to package the RNA as one long strand that would fold into a tiny, compact sphere. The researchers used an RNA synthesis method known as rolling circle transcription to produce extremely long strands of RNA made up of a repeating sequence of 21 nucleotides. Those segments are separated by a shorter stretch that is recognized by the enzyme Dicer, which chops RNA wherever it encounters that sequence.

As the RNA strand is synthesized, it folds into sheets that then self-assemble into a very dense, sponge-like sphere. Up to half a million copies of the same RNA sequence can be packed into a sphere with a diameter of just two microns. Once the spheres form, the researchers wrap them in a layer of positively charged polymer, which induces the spheres to pack even more tightly (down to a 200-nanometer diameter) and also helps them to enter cells.

After the spheres enter a cell, the Dicer enzyme chops the RNA at specific locations, releasing the 21-nucleotide siRNA sequences.

Peixuan Guo, director of the NIH Nanomedicine Development Center at the University of Kentucky, says the most exciting aspect of the work is the development of a new self-assembly method for RNA particles. Guo, who was not part of the research team, adds that the particles might be more effective at entering cells if they were shrunk to an even smaller size, closer to 50 nanometers.

Targeting tumors

In the Nature Materials paper, the researchers tested their spheres by programming them to deliver RNA sequences that shut off a gene that causes tumor cells to glow in mice. They found that they could achieve the same level of gene knockdown as conventional nanoparticle delivery, but with about one-thousandth as many particles.

The microsponges accumulate at tumor sites through a phenomenon often used to deliver nanoparticles: The blood vessels surrounding tumors are “leaky,” meaning that they have tiny pores through which very small particles can squeeze.

In future studies, the researchers plan to design microspheres coated with polymers that specifically target tumor cells or other diseased cells. They are also working on spheres that carry DNA, for potential use in gene therapy.