Genes Found Linked to Breast Cancer Drug Resistance Could Guide Future Treatment Choices

Researchers at Dana-Farber Cancer Institute have discovered a gene activity signature that predicts a high risk of cancer recurrence in certain breast tumors that have been treated with commonly used chemotherapy drugs.

Despite their resistance to drugs of the anthracycline class, the breast cancers bearing this gene signature will probably still be vulnerable to other types of chemotherapy agents, say scientists in a letter to be published in Nature Medicine on its Web site and later in a print edition. Thus, the findings could lead to a genetic test of breast cancers to help physicians choose the best initial treatment for an individual patient.

With this guidance, physicians could avoid the current trial-and-error approach that in some cases exposes patients to the toxic side effects of a cancer drug that is destined to be ineffective. The new report underscores the potential of personalized cancer care, in which knowing the specific molecular features of a patient's cancer helps direct the course of care.

The investigators from the Dana-Farber Women's Cancers Program undertook the studies to search for molecular traits in tumors that cause some patients to suffer recurrences in the wake of breast cancer surgery despite post-surgery, or "adjuvant," chemotherapy, while other patients do well for many years.

Led by Andrea Richardson, MD, PhD, and Zhigang Charles Wang, MD, PhD, the investigators identified two genes that, when abnormally active, enabled cancer cells to resist the effects of drugs called anthracyclines. This class of agents includes doxorubicin, daunorubicin, and epirubicin, which are often used as adjuvant therapy in breast cancer.

The scientists probed stored breast tumor specimens from 85 patients and found the gene signature associated with drug resistance in about 1 in 5 samples, according to the report. Clinical records on file showed that those patients had poorer outcomes than those without the culprit gene signature.

However, the overexpression of the two genes did not protect laboratory-grown breast cancer cells against other classes of drugs, including paclitaxel and cisplatin, reported Richardson, Wang, and the first author, Yang Li, PhD.

"These results suggest that tumors resistant to anthracyclines may still be sensitive to other agents," said Richardson, who is also on faculty at Brigham and Women's Hospital and Harvard Medical School. "So this would be very useful as a test to help pick the therapy that's going to be most effective for these patients."

Such a tool should not be difficult to develop, she said, and could be available for clinical testing within a year or two.

It's been known that some breast tumors acquire, during the course of treatment, altered genes or chromosomes that make them resistant to many cancer drugs. But with one or two exceptions, "No tests are done before treatment begins to predict who's going to be resistant or sensitive to different compounds," says Richardson. "Most breast cancer patients are initially given the same drugs."

Exceptions include patients whose tumors are spurred by estrogen and are often less sensitive to any chemotherapy; hormonal treatment is generally prescribed in that case. Also, breast cancers found to be HER2-positive are treated with the antibody trastuzumab – another example of "personalized" or tailored therapy.

In search of genetic alterations that might explain disease recurrence despite treatment with adjuvant chemotherapy in some breast cancer patients, the Dana-Farber scientists scanned the genome (all the DNA) of stored breast cancer samples from patients who had been treated according to modern guidelines, including the use of anthracyclines. The samples had been taken in the operating room during breast surgery – before any drug therapy had begun – and thus enabled the scientists to look for DNA alterations that could be linked to the patients' subsequent disease recurrence.

Richardson and Wang's laboratory team sifted the tumor DNA and spotted a region on chromosome 8 that contained many redundant, or amplified, copies in the drug-resistant tumors. They found that this small region, labeled 8q22, was associated with a poor outcome in the breast cancer patients. In parallel, they discovered that 12 genes in that region were consistently "overexpressed" – making abnormal amounts of protein – as a result of amplification. "This was the only region of the genome that was tightly associated with poor outcomes despite the adjuvant chemotherapy treatment," Wang noted.

Wang, Richardson, and colleagues singled out the genes in the region that might be involved in tumors' drug resistance, based on their structures and functions. They then experimentally narrowed the field to two likely candidates - LAPTM4B and YWHAZ.

When the researchers knocked out the two genes' function in cancer cells grown in the laboratory, the cells became vulnerable to anthracycline compounds. Conversely, when the genes were overexpressed, the cells resisted anthracycline compounds, but were killed by other agents, cisplatin and paclitaxel.

To clinch their case, the researchers needed to carry out a blind test in which they didn't know ahead of time which patients' tumors had responded well to drug therapy. Fortunately, they learned of a Belgian clinical trial in which breast cancer patients had been treated prior to surgery with epirubicin – one of the anthracyclines – and their tumors were studied to determine the drug's effectiveness. Among other things, the researchers had obtained gene expression data from the tumors. The Dana-Farber researchers used that data to predict the degree of patients' tumors' response to the drug by measuring the LAPTM4B and YWHAZ activity in the tumors.

When their predictions were matched with the Belgian outcome data, "it turned out that the expression level of these two genes was highly associated with anthracycline resistance in the tumors," said Richardson.

Eric Winer, MD, director of the Breast Oncology Center at Dana-Farber, commented, "While this work remains preliminary, it may ultimately help us use the anthracyclines in a much more thoughtful manner and allow us greater ability to personalize our breast cancer treatments to the tumor and the patient."

The research was supported by the Breast Cancer Research Foundation of New York and the US Department of Defense.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding.

Contact: Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute

Gaia BioPharma to Manufacture AlphaRx GAI-122 Employing Nano-Emulsion Formulation for Clinical Trials of Intracellular Neuroprotectant for Stroke Victims

AlphaRx Inc. on January 21^st, 2010 announced that its licensee, Gaia BioPharma Limited, has signed an agreement with a contract manufacturing organization (CMO), to manufacture GAI-122 for use in the planned Phase I and II clinical trials of that product candidate. GAI-122 is being developed as I.V. administered formulation of an intracellular neuroprotectant that employs AlphaRx's proprietary nano-emulsion formulation technology. More specifically, GAI-122 is being developed for the amelioration of stroke-induced injury and disability in China and as a preventive therapy for postoperative delirium in the U.S.A.

"We are very pleased with the progress of the GAI-122 development program; it is on track to enter human trials in 2010," said Michael Lee, President and CEO of AlphaRx. "The NINDS (National Institute of Neurological Disorders and Stroke) has recently initiated clinical trials using the oral form of GAI-122, for the treatment of Multiple Sclerosis. It further validated our clinical development strategy for GAI-122 as a neuroprotectant."

About GAI-122

GAI-122, an investigational, injectable nanoemulsion of a Mitochondria-targeted neuroprotective agent formulated with AlphaRx's proprietary drug delivery technology, has been shown to provide significant neuro-protection in multiple in vitro and in vivo animal studies, suggesting that this injectable nanoemulsion formulation has the potential to treat patients with acute ischemic stroke or to prevent postoperative delirium.

About AlphaRx Inc.

AlphaRx (OTCBB: ALRX) is a specialty pharmaceutical company dedicated to developing proven therapies by reformulating FDA approved and marketed drugs which through the application of its proprietary site-specific nano drug delivery technology, offers improved medical benefits and a potential for significant commercial product development.

About Gaia BioPharma

Gaia BioPharma Limited, a privately held, early stage biopharmaceutical company focused on hospital-based injectable therapeutics. Gaia BioPharma seeks to address key unmet therapeutic needs by taking established compounds and changing their administration routes to create patent-protected, value-added products.

Mexico-US Collaboration Launched to Study Major Human Diseases, Carlos Slim Institute of Health to Fund Genomic Research on Cancer, Type 2 Diabetes, and a Form of Kidney Disease

Mexican business leader Carlos Slim Helú on January 19^th announced the launch of a major research project in genomic medicine that will help accelerate progress in public health in Mexico and around the world. The project will be carried out by the Carlos Slim Institute of Health in partnership with the Broad Institute of MIT and Harvard and the National Institute for Genomic Medicine of the Mexican Secretariat of Health. The major goal is to understand the genomic basis of cancer in worldwide populations and of type 2 diabetes in Mexican and Latin American populations.

The project, called Slim Initiative for Genomic Medicine, will last three years and will receive US $65M in support from the Carlos Slim Institute of Health. It will leverage the Broad Institute's expertise and capabilities in the most advanced technologies in genomic sequencing.

The project also involves the training of Mexican experts under the leadership of the National Institute of Genomic Medicine of the Mexican Secretariat of Health, the leading institution in genomic research in Latin America.

The findings of this research will help accelerate both the prevention of disease as well as the development of improved therapies in Mexico and beyond.

Referring to the importance of the project, Carlos Slim said, "I am convinced that only through genomics will we be able to face the costly burden of illnesses that strain the budgets of even the richest countries."

"Carlos Slim is making a visionary commitment to public health in the Americas in two ways," said Dr. Eric S. Lander, director and president of the Broad Institute of MIT and Harvard. "First, in recognizing that progress in public health must be built on a foundation of scientific understanding of the genetic basis of disease. Second, in recognizing that deepening the scientific ties between the US and Mexico can have great benefits for both countries. We look forward to making common cause with our colleagues in Mexico."

The research project will make use of new technologies for decoding or "sequencing" DNA, which have made it possible for researchers to study DNA more rapidly and at a lower cost than ever before. In cancer, the scientists will create catalogs of the genetic abnormalities (called "mutations") that occur across different cancer types. Such knowledge aims to reveal key genetic weaknesses that can be exploited by new cancer therapies and to identify which patients are most likely to respond to specific cancer drugs.

In type 2 diabetes, the researchers will also assemble systematic descriptions of the genetic factors underlying the disease, with a special focus on Latin American populations. Diabetes is among the most common inherited diseases in Latin America, yet a deep knowledge of the genetic risk factors in the region's populations is lacking. A profound understanding of these factors is needed in order to foster prevention, treatment, and control.

During the three years of the project, major findings will be publicly announced. In order to guarantee that the project benefits science and the population in general, the main recipient of its findings will be the National Institute for Genomic Medicine.

To supervise the scientific progress of the project a Scientific Advisory Board has been established. It is composed of renowned scientists from around the world with vast experience in the fields of cancer, diabetes, and genomic science.

The Scientific Advisory Board members include (in alphabetical order):

Carlos Bustamante

Professor, Department of Genetics, Stanford School of Medicine

Thomas Hudson

President and Scientific Director of Ontario's Institute for Cancer Research

Gerardo Jiménez Sánchez

Professor of genomic medicine at the National Autonomous University of Mexico, Advisor to the OECD's Working Group on Biotechnology and Scientific Director of BioFields

David Nathan

Director of the Center of Diabetes and Director of the Center for General Clinical Research, Massachusetts General Hospital

Guillermo Ruiz Palacios

Head of the Infection Diseases Department of the Salvador Zuribán National Institute of Medical Sciences and Nutrition, Mexican Secretariat of Health

Xavier Soberón

General Director of the National Institute of Genomic Medicine, Mexican Secretariat of Health

About the Broad Institute of MIT and Harvard

The Eli and Edythe L. Broad Institute of MIT and Harvard was founded in 2003 to empower this generation of creative scientists to transform medicine with new genome-based knowledge. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods, and data openly to the entire scientific community.

Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff, and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to www.broadinstitute.org.

About the Carlos Slim Health Institute

The Carlos Slim Health Institute was created in 2007 by the initiative of Mr. Carlos Slim Helú for the development and funding of programs aimed at contributing to the solution of the principal health problems in Latin America and the Caribbean under an innovative and human spirit and with a clear concern for the neediest populations.

The Institute contributes to cover the demand of services by spurring the creation of primary health care units; in a like manner, it facilitates the approximation of health resources to the population via communication technology that serves as information, accompaniment and contact means, and through leading-edge educational communication actions it also encourages people and populations to participate in their own welfare.

In addition to the above, the Institute also provides support to other not-for-profit organizations that promote people's welfare by favoring their physical health, a proper household as well as natural and community environments.

Ultimately, the Institute encourages health knowledge through grants for students and professionals; awards for leading applied-sciences researchers and institutions, and through the generation of innovative and reliable information for national decision makers. The Carlos Slim Institute works day after day with a single goal: help people live longer and better. www.salud.carso.org

About the National Institute of Genomic Medicine

The National Institute of Genomic Medicine (INMEGEN), is the eleventh National Institute of Health in Mexico, founded in 2004. INMEGEN´s mission is to contribute to the health care of the Mexican population by developing cutting-edge scientific research and well-trained human resources in order to apply the knowledge of genomic medicine through innovation, state-of-the-art technology, and strategic partnerships, all the while complying with universal ethical principles.

INMEGEN´s main research areas focus on principal complex diseases in Mexico, including population genomics of the Mexican population, genomics of metabolic diseases (diabetes mellitus and obesity), cancer, infectious diseases, cardiovascular diseases, nutrigenomics, and pharmacogenomics.

One of the features of INMEGEN's innovative culture is scientific research and development of technology, which leads to goods and services that can then be used to contribute to better health care for the Mexican people in the knowledge-based economy. www.inmegen.gob.mx

Nanomedicine: Compounds that Help Protect Nerve Cells Discovered By Duke University Team

Scientists at Duke University Medical Center (Durham, NC) have found some compounds that improve a cell's ability to properly "fold" proteins and could lead to promising drugs for degenerative nerve diseases, including Huntington's disease, Alzheimer's disease and Parkinson's disease.

Misfolded proteins in nerve cells (neurons) are a common factor in all of these diseases. The Duke team has identified many new chemicals that activate a master regulator to increase the supply of "protein chaperone" molecules that help fold proteins properly.

The scientists further explored one of the candidate molecules to activate the master regulator of chaperone gene expression, Heat Shock Factor 1 (HSF1), to learn whether it would work in model systems of Huntington's disease, a devastating neurodegenerative disease of protein misfolding.

They were able to show that the molecule stimulated protein chaperones in cells and in an animal system. The damage to early-state rat neurons was much lower in cells pre-treated with the HSF1 activator, and damage to the neurons of fruit flies that had a Huntington's-like disorder was also greatly reduced.

Previous studies suggested that elevating the abundance of protein chaperones is effective in treating cell and animal models of Huntington's and Parkinson's diseases. This work provides a new approach to address the root cause of these diseases -- protein misfolding. Earlier attempts had used heat shock and other approaches that stress a nerve cell in order to produce more chaperone molecules, but at a cost of damaging the cell to save it.

"The advantage of our screen is that it identifies molecules that can elevate the levels of chaperones without inducing cellular stress and that don't inhibit a key protein chaperone called Hsp90 that is needed for cells to function normally," said senior author Dennis J. Thiele, Ph.D., Professor of Pharmacology and Cancer Biology. "We found a creative way to identify new molecules that can activate the body's natural protein folding machinery."

The research was published in the Jan. 19 online issue of PLoS Biology.

Lead author Daniel Neef, Ph.D., says they used genetically altered yeast to find compounds that might aid chaperone development. The scientists took yeast with a deleted HSF1 (master regulator) gene and inserted the related human HSF1 gene. These yeast, however, still weren't able to activate human HSF1 on their own, and in effect, died. They needed an additional molecule to make human HSF1 become active.

The team put these "humanized yeasts" into wells and started testing compounds that would provide the missing link. In several of the wells, if the compound worked, the yeast started multiplying. "Out of over 12,000 compounds tested from chemical libraries, about 50 compounds worked," Neef said. The team decided to explore one of these compounds (HSF1A) in further experiments.

"The humanized yeast-based screening results in our study provide a way to identify new classes of small molecules, small enough to penetrate the blood-brain barrier to work in neurons, in flies as well as in humans," Thiele said. "These small molecules may be effective therapies in neurodegenerative diseases caused by protein conformational disorders such as Huntington's, Alzheimer's and Parkinson's disease."

The scientists found that HSF1A could stimulate more protein chaperones and reduce the protein misfolding. They showed that adding a small amount of HSF1A to the developing rat neurons kept the proteins dissolved throughout the cell, rather than clumping visibly as speckled areas (as seen under microscopes).

"We enhanced the cells' viability by four or five times by pre-treating them with this molecule," Neef said. "Otherwise, the cells would have died."

They used fruit flies with Huntington's disease for experiments to prove that the principle would work in an animal. Adding HSF1A to the fly's food produced more chaperone molecules in their neurons. This suggests that the molecule could travel from the fly's stomach into its circulation and cross a barrier to the fly brain.

In the key experiment, the Huntington's disease flies received either their usual food or food plus HSF1A. Those with untreated food developed eyes with dying photoreceptor neurons and lacking the normal red color. Those that ate HSF1A went on to have normal-colored eyes, indicating a repair had taken place, just by eating food laced with the promising compound.

Michelle Turski, now with Stanford University, was a co-author of the study. The work was supported by grants from the National Institutes of Health.

New Nanoburrs Target Cardiovascular Disease, Could Potentially Eliminate Need for Arterial Stents in Some Patients Says MIT & Harvard Team

MIT and Harvard Nanoburr

Image Credit: MIT

Researchers at Massachusetts Institute of Technology (MIT) (Cambridge, MA) and Harvard Medical School have built targeted nanoparticles that can cling to artery walls and slowly release medicine, an advance that potentially provides an alternative to drug-releasing stents in some patients with cardiovascular disease.

The particles, dubbed "nanoburrs" because they are coated with tiny protein fragments that allow them to stick to target proteins, can be designed to release their drug payload over several days. They are one of the first such particles that can precisely home in on damaged vascular tissue, says Omid Farokhzad, associate professor at Harvard Medical School and an author of a paper describing the nanoparticles in the Jan. 18 issue of the Proceedings of the National Academy of Sciences.

Farokhzad and MIT Institute Professor Robert Langer, also an author of the paper, have previously developed nanoparticles that seek out and destroy tumors.

The nanoburrs are targeted to a specific structure, known as the basement membrane, which lines the arterial walls and is only exposed when those walls are damaged. Therefore, the nanoburrs could be used to deliver drugs to treat atherosclerosis and other inflammatory cardiovascular diseases. In the current study, the team used paclitaxel, a drug that inhibits cell division and helps prevent the growth of scar tissue that can clog arteries.

"This is a very exciting example of nanotechnology and cell targeting in action that I hope will have broad ramifications," says Langer.

The researchers hope the particles could become a complementary approach that can be used with vascular stents, which are the standard of care for most cases of clogged and damaged arteries, or in lieu of stents in areas not well suited to them, such as near a fork in the artery.

The particles, which are spheres 60 nanometers in diameter, consist of three layers: an inner core containing a complex of the drug and a polymer chain called PLA; a middle layer of soybean lecithin, a fatty material; and an outer coating of a polymer called PEG, which protects the particle as it travels through the bloodstream.

The drug can only be released when it detaches from the PLA polymer chain, which occurs gradually by a reaction called ester hydrolysis. The longer the polymer chain, the longer this process takes, so the researchers can control the timing of the drug's release by altering the chain length. So far, they have achieved drug release over 12 days, in tests in cultured cells.

In tests in rats, the researchers showed that the nanoburrs can be injected intravenously into the tail and still reach their intended target — damaged walls of the left carotid artery. The burrs bound to the damaged walls at twice the rate of nontargeted nanoparticles.

Because the particles can deliver drugs over a longer period of time, and can be injected intravenously, patients would not have to endure repeated and surgically invasive injections directly into the area that requires treatment, says Juliana Chan, a graduate student in Langer's lab and lead author of the paper.

How they did it: The researchers screened a library of short peptide sequences to find one that binds most effectively to molecules on the surface of the basement membrane. They used the most effective one, a seven-amino-acid sequence dubbed C11, to coat the outer layer of their nanoparticles.

Next steps: The team is testing the nanoburrs in rats over a two-week period to determine the most effective dose for treating damaged vascular tissue. The particles may also prove useful in delivering drugs to tumors.

"This technology could have broad applications across other important diseases, including cancer and inflammatory diseases where vascular permeability or vascular damage is commonly observed," says Farokhzad.

Source: "Spatiotemporal controlled delivery of nanoparticles to injured vasculature," Juliana Chan, Liangfang Zhang, Rong Tong, Debuyati Ghosh, Weiwei Gao, Grace Liao, Kai Yuet, David Gray, June-Wha Rhee, Jianjun Cheng, Gershon Golomb, Peter Libby, Robert Langer, Omid Farokhzad. Proceedings of the National Academy of Sciences, week of Jan. 18, 2010.

Contact: Jen Hirsch

jfhirsch@mit.edu

617-253-1682

Human Trials to Begin Soon for Envision Scientific Nano Particle Based Polymer Free Drug Eluting Stent for Coronary Artery Disease Treatment, Nano Drug Eluting Balloon Under Development

Envision Scientific Pvt. Ltd has been involved in working on the behavior of drug molecules when converted to nano size for the treatment of coronary artery diseases.

Dr. Manish Doshi – President & CEO of Envision Scientific Pvt. Ltd. (Surat, Gujarat, India) says that nanotechnology will change the treatment options for Coronary Heart Disease. The company has developed nano particle based Polymer free Drug Eluting stent (npDES) while Nano Drug Eluting Balloon (npDEB) is being developed in their other company - Concept Medical Research (CMRPL) for delivering the most widely accepted drug – Sirolimus in vessels.

This method will help in dealing with current complications associated with coronary artery treatment. The newly designed Products and Equipments to do these sophisticated coatings have been applied for patent by the company.

It is proven fact that Polymers in Drug Eluting Stents (DES) create problems in the treatment. The company has designed product which eliminates use of polymer with sustained drug release in tissue. Animal trials conducted at Dr. Renu Virmani’s Center in Washington D.C, have given very positive results.

Currently npDES is undergoing Animal trial at Thoraxcenter, Rotterdam, Netherlands under Prof. Patrick Serryus, world renowned Interventional cardiologist. The company has plans to initiate FIM (First-in-Man) trials to assess the efficacy of the product.

In addition to Sirolimus drug, company has also worked on developing Paclitaxel eluting stent / balloon which it plans to license to prospective buyers. The technology can be applied to deliver other drugs and company has capabilities to deliver the same. The key areas which the company has focused are to try and reduce complications associated with Angioplasty and reduce its anticipated treatment cost.

Drug Eluting Balloons are fast catching up as the treatment of choice but has inherent problems of coating drug on balloon surface without polymers. With conversion of drug into nano size and enclosing it inside Excipient significantly enhances the drug delivery to the coronary artery tissue. This will reduce complexity of procedure and simplify the treatment option which may include long term medications.

Dr. Doshi says that Envision Scientific (ESPL) & Concept Medical (CMRPL) are a new entrant against the current big boys like Cordis, Abbott, Medtronic and Boston Scientific, but with its IP Portfolio and practical design will create a standing for itself. Currently, ESPL & CMRPL are involved in finalizing the product portfolio.

While nanotechnology’s promise remains immense – the potential advances in energy, medicine, electronics field have attracted millions of dollars worth investments – it remains to be seen which patents will prove the most valuable. ESPL and CMRPL will not enter the funding market with just the patent portfolio but aim to have a consistent revenue stream. Both these companies are a part of the growing segment of nanotechnology startups with positive results for its developments.

Exploding Silicon Nanobombs Kill Cancer with No Toxicity to Normal Cells Nor Side Effects say Korean Researchers

Korean researchers at the Inha-Industry Partnership Institute have developed a new weapon for the war on cancer: silicon nanobombs. The smart nanobombs kill cancer cells but leave normal cells unharmed.  

FIG. 10 from Inha-Industry Partnership Institute’s U.S Patent Application 20090326520  is a capture image of a cancer killing silicon nanobomb explosion occurring upon the irradiation of NIR light onto porous silicon nanobombs with sulfur entrapped within its pores. Silicon nanobombs have been successfully used to kill breast cancer cells.

Inha-Industry Partnership Institute (Incheon, KR) researchers Chongmu Lee, Hohyeong Kim and Chanseok Hong developed a method for treating cancer using a porous silicon nanobomb. The porous silicon nanobomb can be exploded by NIR light irradiation at a low intensity to selectively destroy cancer cells. Also, porous silicon itself shows good biocompatibility and biodegradability. According to U.S. Patent Application 20090326520,  the silicon nanobomb can be used as an efficient method for treating cancer without the accumulation of toxic side effects.

The porous silicon nanobomb of the present invention can be heated by NIR light with an irradiation intensity of from 100 to 400 mW/cm², which is only about one hundredth of that required for heating nanoshells, that is, 35 W/ cm². For carbon nanotubes, the irradiation intensity of NIR light amounts to 1 to 4 W/cm² Therefore, the nanobombs are useful in the treatment of cancer without damaging normal cells, in contrast to nanoshells and carbon nanotubes.

Thermotherapy is a minimally invasive cancer treatment technique that can replace invasive surgical treatment. Entailing a relatively simple operation in addition to minimal invasiveness, thermotherapy makes possible a short recovery time. Also, thermotherapy is a type of physical therapy with fewer limitations than chemotherapy and is typically used in combination with both of the invasive therapies. In addition, it allows repeated treatments without the accumulation of toxic side effects. Thermotherapy (or thermal ablation therapy) includes laser-induced thermotherapy, microwave and radiofrequency (RF) ablation, magnetic thermal ablation, and focused ultrasound.

Most of them, however, have shortcomings in that the treatment takes a long period of time and that its lesion boundaries are not well defined. Alternatively proposed was magnetic thermotherapy based on using alternating current to heat oxide nanoparticles in tumor cells. Although disadvantageous in that it requires a large quantity of iron for sufficient thermal effects, this magnetic thermotherapy has an advantage over the other thermotherapies in that it can selectively heat only the cells filled with oxides of iron.

Inha-Industry Partnership Institute’s method for treating cancer uses biocompatible and biodegradable porous silicon nanobombs which can generate heat sufficient to selectively kill cancer cells upon exposure to NIR light at a low intensity, with accompaniment of neither toxicity to normal cells nor side effects.

FIG. 1 is a schematic diagram of an electrochemical anodization cell for use in the preparation of nano-porous silicon

FIG. 2 is an scanning electron microscope (SEM) image showing nano-porous silicon in a plan view.

FIG. 3 is an SEM showing nano-porous silicon in a cross-sectional view

FIG. 9 is a captured  image of an explosion occurring upon the irradiation of NIR light onto the porous silicon bombs with NaClO₄.1H₂O entrapped within the pores thereof.  As seen in FIGS. 9 and 10, the bombs of sulfur (FIG. 10) were exploded on a larger scale than were the bombs of NaClO₄.1H₂O (FIG. 9).

FIG. 11 is optical microphotographs of breast cancer cells before NIR irradiation. FIG. 11 is microphotographs of PSi/S/NaCl-treated breast cancer cells before exposure to NIR light, and

FIG. 12 is that of after exposure to NIR light for 20 min. A drama is seen between the cells of FIGS. 12 and 11.

Upon NIR exposure in the presence of the PSi suspension, the cells seemed to be blown up and burnt black. Explosion was observed to occur inside the cell clusters as inferred from the morphology of dead cells. Also, the bubbles showed that the cells were blown up in the explosion. Bubbles found around dead cells were evidence of the vigorous boiling of the NaCl solution within porous silicon particles, implying that the explosion of porous silicon particles resulted from the temperature elevation of the NaCl solution localized within the silicon particles to exceed the boiling point.

University of Michigan Bioengineers Detect Nanoscale Changes in Bone Collagen to Diagnose Diseases with New Technique

A three-dimensional rendering from the surface of a mouse bone. In this 3.5 x 3.5 micrometer image (100 nanometer height), the rich sample topography characteristic of bone is evident. Type I collagen fibrils are seen running in a bundle from left to right near the top. A second layer of fibrils appears to be running below, almost perpendicular to this bundle, near the bottom corner.

 Image Credit: University of Michigan

Using a technique that provides detailed images of nanoscale structures, researchers at the University of Michigan and Detroit's Henry Ford Hospital have discovered changes in the collagen component of bone that directly relate to bone health.

Their findings, published online Dec. 16 in the journal Bone, could lead to new methods of diagnosing osteoporosis and other diseases affecting collagen-containing tissues. 

Bone is a composite material made up of a flexible collagen matrix impregnated with and surrounded by a stiffer, stronger mineral component. Though much is known about the importance of bone health to overall health, there's a critical lack of knowledge about the sub-microscopic structure of bone and how collagen and mineral -- and the interactions between them -- contribute to properties of healthy and diseased bone.

"Our initial question was, could we discover more about the nanoscale structure of the collagen in bone, using the technique of atomic force microscopy," said Mark Banaszak Holl, a U-M professor with joint appointments in chemistry and macromolecular science and engineering. 

The atomic force microscope, one of the most valuable tools for imaging, measuring and manipulating matter at the nanoscale level, works something like a phonograph with a motion detector attached to its needle. As the tip systematically moves across a bumpy surface, the motion detector records its every movement. The result is a three-dimensional image of the surface's contours.

Using such an instrument, the researchers were able to see and measure key features of collagen fibrils in mouse bone. Each collagen fibril is made up of many individual collagen molecules packed together in a staggered array that resembles a railroad track.

"For each fibril, we measured the mean spacing of the 'railroad track' cross hatches," said post doctoral associate Joseph Wallace, the paper's lead author. Wallace, Banaszak Holl and coworkers found that not all fibrils had the same mean spacing, a finding that ran counter to conventional wisdom in the field.

"As opposed to a single value, our data indicate that normal bone contains a distribution of collagen fibril spacings," Wallace said.

Next, the team wanted to know if the distribution of fibril spacings differed in bone from healthy and diseased individuals. To address that question, they collaborated with Clifford Les of Henry Ford Hospital, who has been studying how bone changes when estrogen wanes, as it does in menopause. To model the age-related estrogen depletion that occurs in humans, Les uses sheep that have had their ovaries removed. The sheep exhibit some of the same symptoms as menopausal women, and they undergo some bone remodeling, but they don't develop osteoporosis.

When the researchers compared bone from normal and ovariectomized sheep, they found striking differences in fibril spacing distributions, suggesting that estrogen depletion has a significant effect on the spacing.

"This ability to measure fibril spacing and to distinguish between normal and diseased bone not only gives us a powerful method to study the mechanism of disease at the nanoscale, but it also has important implications to the future diagnosis of disease in bone and perhaps other collagenous tissues," said Banaszak Holl. "Collagen is the most common protein in the mammalian body. It's in bones, teeth, tendons, skin, arteries. We basically don't work well when it's not working well, so there are many diseases related to problems with collagen. We're very excited about developing this method as a diagnostic for all kinds of diseases of structural collagen."

The technique could be a powerful complement to the current gold standard for diagnosing osteoporosis: measuring bone mineral density (BMD) with dual energy X-ray absorptiometry (DEXA). Although widely used, DEXA isn't ideal, because people with normal BMD can still get fractures, and abnormalities often don't show up until after a fracture has occurred. Changes in collagen, on the other hand, may be apparent earlier in the disease's progression.

To further explore the method's potential, the researchers plan to use it to study collagen fibril spacing in human patients with and without osteoporosis. U-M has filed for patent protection and is seeking a commercialization partner to help bring the technology to market.

"This project is an example of what happens if you put the right group of people together on a problem," said Banaszak Holl. Wallace, a biomedical engineer, had experience working with bone in previous research; Banaszak Holl's lab group brought expertise in surface analysis; Les contributed knowledge about bone biology and understanding of the sheep model; and coauthors Bradford Orr, director of the Applied Physics Program, and Blake Erickson, a biophysics graduate student, are skilled in data analysis.

"All these different pieces were necessary to solve the problem," Banaszak Holl said. 

The research was funded by the National Institutes of Health (National Institute of Dental and Craniofacial Research and National Institute of Arthritis and Musculoskeletal and Skin Diseases).

$39 Billion Global Market for Smart Biomaterials to Reach $65 Billion by 2015 Says EU Report-Nanotechnology Impact Expected Following Lengthy Clinical Trials

The $39.6 billion (€27.6 billion) 2006 global smart biomaterials market reached $47 billion in 2009 and is forecast to surpass $65 billion (€45.5 billion) by 2015, reflecting an annual growth rate of about 6.7%. Nanomaterials are expected to have a growing presence in this market, but only after lengthy clinical trials, according to the recently released report, “Roadmaps in Nanomedicine Towards 2020.”  The global market for smart biomaterials is expected to grow to $113 billion (€78.8 billion) by 2025.

The Roadmaps table estimates the expected market size for smart biomaterials for each disease ranked by research complexity.  Since most of these diseases are age-related they are projected to grow with the increase of senior citizen population.  The smart biomaterials market is expected to have a global value in 2020 of $90 billion (€62.6 billion).

Table in Millions of Euros. 1 Euro = $1.43

Source: Nanomedicine ETP, “Roadmaps in Nanomedicine Towards 2020"

The table below fills in the gaps in the Roadmaps table to make totaling easier. The table is in millions of Euros except for the total rows which are presented in euros (€) and dollars ($).

Yeshiva University Novel Nanotechnology Heals Abscesses Caused by Resistant Staph Bacteria

 Abscesses in mice that received placebo, nanoparticle alone or nanoparticle with nitric oxide for 4 days after MRSA abscess formation.

Image Credit:  Yeshiva University

Researchers at Albert Einstein College of Medicine of Yeshiva University have developed a new approach for treating and healing skin abscesses caused by bacteria resistant to most antibiotics. The study appears in the journal PLoS One.

Ph.D.; Adam Friedman, M.D.Abscesses are deep skin infections that often resist antibiotics and may require surgical drainage. For their new treatment strategy, the Einstein scientists developed tiny nanoparticles — smaller than a grain of pollen — that carry nitric oxide (NO), a gas that helps in the body's natural immune response to infection.

When topically applied to abscesses in mice, the particles released NO that traveled deep into the skin, clearing up the infections and helping to heal tissue.

"Our work shows that nitric oxide-releasing nanoparticles developed here at Einstein can effectively treat experimental skin abscesses caused by antibiotic-resistant Staphylococcus aureus, even without surgical drainage," says Joshua D. Nosanchuk, M.D., senior author of the study and associate professor of medicine and of microbiology & immunology.

"This is important," he notes, "because several million people are treated for staph infections every year in the U.S. Increasingly, these infections are caused by methicillin-resistant Staph aureus — or MRSA — the serious and potentially fatal "superbug" that we tackled in this study."

According to the Centers for Disease Control and Prevention, approximately 94,000 cases of invasive MRSA infections occur each year, resulting in 19,000 deaths. In a 2006 study involving multiple emergency rooms across the U.S., MRSA was isolated from 61 percent of abscesses. "To have a topical medication for staph infections instead of one that you have to take orally and systemically would revolutionize the way we take care of our patients," Dr. Nosanchuk adds.

 
The inset in the untreated group shows what the contents of the MRSA abscess look like at this time.In research published earlier this year in the Journal of Investigative Dermatology, the interdisciplinary Einstein team showed that NO-containing nanoparticles could clear up superficial skin infections caused by MRSA. The current study of abscesses was designed to learn whether the nanoparticles could combat infections deep in the skin.

The researchers experimentally induced MRSA abscesses in 60 mice. The abscesses were either left untreated, topically treated with "empty" nanoparticles, or topically treated with nanoparticles containing NO and were evaluated four days later.

The microbial concentration in the abscesses of mice treated with NO-containing nanoparticles was significantly reduced compared with abscesses in the other two groups.  In addition, the abscesses of mice treated with NO-containing nanoparticles had undergone much more healing, as shown by their improved appearance and by the far greater amounts of collagen (a protein important in maintaining the structure of skin) deposited within them.

The Einstein nanoparticle technology was developed by Joel M. Friedman, M.D., Ph.D., the Young Men's Division Chair of Physiology and professor of physiology & biophysics and of medicine, and Adam Friedman, M.D., currently the chief resident in the division of dermatology of the department of medicine at Montefiore Medical Center, The University Hospital and Academic Medical Center for Einstein.

When introduced on the skin or into the body, the tiny nanoparticles absorb water, swell up, and start releasing their cargo in a sustained manner. The nanoparticles can carry and release a variety of drugs as well as chemicals, including NO.

Produced naturally by cells throughout the body, NO has important biological properties including killing bacteria, healing wounds, and increasing blood flow by dilating blood vessels. "But NO is a very short-lived gas," notes Dr. Joel Friedman, "and, until now, methods to deliver it to targeted tissues in the proper doses have proven elusive."

Einstein researchers are also pursuing other potential therapeutic uses for their nanoparticles. For example, along with Kelvin Davies, Ph.D., associate professor of urology, the Friedmans recently showed that nanoparticles loaded with either NO or tadalafil (Cialis) show promise as a topical cream-like treatment for erectile dysfunction.

Earlier this month, Makefield Therapeutics, Inc., a biotechnology company based in Newtown, PA, licensed patent rights to Einstein's NO-containing nanoparticle technology. The company plans to use topical formulations of the NO-containing nanoparticles to treat antibiotic-resistant infections and erectile dysfunction.

The paper, "Nitric Oxide Releasing Nanoparticles Are Therapeutic for Staphylococcus aureus Abscesses in a Murine Model of Infection," was published in the November 12, 2009 issue of PLoS ONE.

Other Einstein authors of the study are George Han, an M.D.-Ph.D. candidate, Luis R. Martinez, Ph.D., and Mircea Radu Mihu, M.D.