A Northwestern University research team has developed a promising nanomaterial-based biomedical device that could be used to deliver chemotherapy drugs locally to sites where cancerous tumors have been surgically removed.

The flexible microfilm device, which resembles a piece of plastic wrap and can be customized easily into different shapes, has the potential to transform conventional treatment strategies and reduce patients’ unnecessary exposure to toxic drugs.  The device takes advantage of nanodiamonds, an emergent technology, for sustained drug release.

The researchers demonstrated that the device releases the chemotherapy agent Doxorubicin in a sustained and consistent manner -a requirement of any implanted device for localized chemotherapy.  The results of the study are published online today (Oct.  2) by the journal ACS Nano.

“The thin device -a sort of blanket or patch -could be used to treat a localized region where residual cancer cells might remain after a tumor is removed,” said Dean Ho, assistant professor of biomedical engineering and mechanical engineering at Northwestern’s McCormick School of Engineering and Applied Science, who led the research.

If a surgical oncologist, for example, was removing a tumor from the breast or brain, the device could be implanted in the affected area as part of the same surgery.  This approach, which confines drug release to a specific location, could mitigate side effects and complications from other chemotherapy treatments.

“Several surgeons at Northwestern’s Feinberg School of Medicine, as well as other medical schools and hospitals, are very interested in the device because it is biocompatible and provides such stable and consistent drug release,” said Ho, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

In their study, Ho and his colleagues embedded millions of tiny drug-carrying nanodiamonds in the FDA-approved polymer parylene.  Currently used as a coating for implants, the biostable parylene is a flexible and versatile material resembling plastic wrap.  A substantial amount of drug can be loaded onto clusters of nanodiamonds, which have a high surface area.  The nanodiamonds then are put between extremely thin films of parylene, resulting in a device that is minimally invasive.

To test the device’s drug release performance, the researchers used Doxorubicin, a chemotherapeutic used to treat many types of cancer.  They found the drug slowly and consistently released from the embedded nanodiamond clusters for one month, with more Doxorubicin in reserve, indicating a more prolonged release (several months and longer) was possible.  The device also avoided the “burst” or massive initial release of the drug, a common disadvantage with conventional therapy.

In control experiments, where the drug was present but without the nanodiamonds, virtually all of the drug was released within one day.  By adding the drug-laden nanodiamonds to the device, drug release was instantly lengthened to the months-long timescale.

In addition to their large surface area, nanodiamonds have many other advantages that can be utilized in drug delivery.  They can be functionalized with nearly any type of therapeutic.  They can be suspended easily in water, which is important for biomedical applications.  The nanodiamonds, each being four to six nanometers in diameter, are minimally invasive to cells, biocompatible and do not cause inflammation, a serious complication.  And they are very scalable and can be produced in large quantities.

The architecture of the device is amenable to housing small molecule, protein, antibody or RNAor DNA-based therapeutics.  This gives the technology the potential to impact a range of treatment strategies where implanted, long-term drug release is needed.

Ho and his research group previously pioneered the application of nanodiamonds for systemic drug-carrying applications.  This new work successfully transitions the nanodiamonds from basic materials to serving as a foundation for device manufacturing.

To build the biomedical device, the researchers developed a streamlined approach where a double layer of parylene was fabricated, with the nanodiamond-drug complexes sandwiched in between.  The bottom layer, approximately 20 to 30 microns thick, serves as the backbone of the device, allowing it to be easily handled.  For the top layer, the research team created a thinner semi-porous film that allows the drug to slowly release from the device.

“One of the most significant aspects of this work is that the fabrication procedures are highly scalable, meaning hundreds, or even thousands, of devices potentially could be manufactured in parallel and at low cost,” said Ho.

“The nanodiamonds are quite economical and have already been mass-produced as lubrication components for automobiles and for use in electronics,” added Robert Lam, a graduate student in Ho’s research group and the article’s lead author.

In the area of localized chemotherapy, the team hopes that this technology will bring new levels of treatment efficacy that can complement injected chemotherapy to reduce dosages and decrease devastating side effects.

Because of the proven biocompatibility and massively parallel deposition capabilities of parylene, the researchers are engaged with pre-clinical trials of the nanodiamond-embedded parylene.

A UC Riverside-led team of biomedical scientists has found that a readily available drug called minocycline, used widely to treat acne and skin infections, can be used to treat Fragile X syndrome, the most common inherited cause of mental impairment and the most common cause of autism.

The study’s findings have already impacted future therapies, with the approval of a new clinical trial in Toronto, Canada, that will test minocycline in patients with Fragile X.

Neurons in the brain communicate with each other at specialized contact sites called synapses, with many of these synapses occurring on small mushroom-shaped structures called dendritic spines.

During early development dendritic spines have immature finger-like shapes.  But learning stabilizes the synapses and dendritic spines take on a mature mushroom shape, which make them more efficient.

The brains of patients with Fragile X syndrome have an overabundance of immature dendritic spines.

In their report, the researchers, led by Iryna Ethell and Douglas Ethell, faculty members in UCR’s Division of Biomedical Sciences, describe how dendritic spine development in mice with Fragile X is delayed by enzymes called matrix metalloproteinases (MMPs), which are involved in normal brain development and physiological processes.  They report that high levels of certain MMPs keep the synapses immature and inefficient.

But minocycline, they found, reduces these MMP levels in the mice, allowing the synapses to mature and make more efficient contacts between neurons in the brain.  The outcome: corrected brain abnormalities in dendritic spines, reduced anxiety and improved cognitive function.

Study results appear online, ahead of print, in the Journal of Medical Genetics.

In their experiments, the Ethells found that young Fragile X mice treated with minocycline showed an increase of dendritic spine maturation in the hippocampus, a brain area that is critical for learning and memory.  Besides less anxiety, minocycline-treated mice showed better exploration skills as compared to untreated mice.

The Ethells are enthusiastic about how their discovery already is leading to a clinical trial.

“Clinical studies often quickly follow such basic science because once there is a solid understanding of how problems arise, it is much easier to come up with solutions,” said Iryna Ethell, an associate professor of biomedical sciences.

The study was funded by a grant from the FRAXA Research Foundation.  FRAXA was founded in 1994 by three parents of children with Fragile X to support scientific research aimed at finding a treatment and a cure for Fragile X.

Dr. Michael Tranfaglia, FRAXA’s chief scientific officer, said of the UCR researchers, “This group has done something unique and incredibly valuable: They have identified an off-the-shelf treatment for Fragile X through their basic research.  By bringing their unique perspective to Fragile X research, they have helped us to understand why neurons are malformed in this disorder, and more importantly, how we can treat it.

“We were so impressed with their work that we just awarded Dr. Iryna Ethell the FRAXA Breakthrough Award for 2008.  This is easily the most important scientific breakthrough in the Fragile X field in many years.”

According to Dr. Carl Paribello, president of Fragile X Research Foundation of Canada and the director of the clinical trial (scheduled for early 2009) at Surrey Place Centre Fragile X Clinic in Toronto, Canada, the UCR-led study “will go a long way towards dispelling the idea that mental impairment cannot be treated.”

“The work could lead to the first treatment that actually targets the underlying defect in Fragile X syndrome and not just the symptoms,” Dr. Paribello said.

UCR’s Douglas Ethell, an assistant professor of biomedical sciences, noted that effective therapies for Fragile X syndrome are few and far between.  “This is a good time for identifying highly effective therapeutic strategies that might work in Fragile X patients,” he said.  “We are excited that our research has the potential to affect many lives.”

Fragile X affects 1 in 4000 males and 1 in 6000 females of all races and ethnic groups.  About 1 in 259 women carry Fragile X and could pass it to their children.  About 1 in 800 men carry Fragile X; their daughters will also be carriers.

Minocycline belongs to a group of antibiotics that has been used in people for more than fifty years to treat Lyme disease, acne, and other skin infections.

Minocycline may have beneficial effects in other disorders where higher-than-normal brain levels of MMP-9 are found.  It is currently under study for treating rheumatoid arthritis, multiple sclerosis (MS), Parkinson’s disease, and several other neurodegenerative conditions.

“In the future, new compounds that more specifically target MMP-9 can be developed and tested,” Douglas Ethell said.

Next in their research, the Ethells and their colleagues plan to refine the therapeutic strategy in Fragile X mice to determine the optimal age, if any, to administer minocycline.  They will also explore other MMP inhibitors that may be more effective than minocycline.

“We will investigate whether a combination of MMP inhibitors with other drugs, such as fenobam, can help mature the synapses in Fragile X mice,” Iryna Ethell said.

Researchers are describing progress toward developing a new generation of chemotherapy agents that target and block uncontrolled DNA replication — a hallmark of cancer, viral infections, and other diseases — more effectively than current drugs in ways that may produce fewer side effects.  Their article is scheduled for the Aug. 27 issue of ACS’ Biochemistry, a weekly journal.

In the article, Anthony J. Berdis updates and reviews worldwide research efforts to develop drugs that target DNA polymerases, the enzymes responsible for assembling DNA from its component parts.  Several promising strategies are already in use that inhibit uncontrolled DNA replication, particularly in anticancer therapy, but most produce severe side effects and are hampered by drug resistance, the researcher notes.

Berdis says that one of the more promising strategies to date involves the use of so-called nucleoside analogues, artificial pieces of DNA that inhibit replication by substituting for natural segments.  Most nucleoside analogues directly target the active site of the polymerase enzyme, a non-specific approach that can also harm healthy cells which contain the enzyme.  Berdis describes an alternative approach in which the drugs directly target damaged DNA while avoiding healthy DNA, side-stepping the polymerase enzymes of normal cells.  The development, which shows promise in preliminary lab studies, could lead to improved nucleoside analogues with fewer side effects, he says.

Drugs known as HDAC inhibitors, which have antitumor activity and can be used to treat some forms of skin cancer and some types of leukemia, are also known to have anti-inflammatory properties, but the mechanisms by which they modulate the immune system have not been determined.  New data, generated by Pavan Reddy and colleagues, at the University of Michigan Cancer Center, Ann Arbor, have now indicated one mechanism by which HDAC inhibitors modulate the mouse and human immune system and the information gained has been used to develop an approach to protect mice from graft-versus-host disease after bone marrow transplantation.

In the study, two different HDAC inhibitors were shown to prevent mouse and human immune cells known as dendritic cells (DCs) from initiating proinflammatory immune responses in vitro.  Further, if Dcs treated ex vivo with HDAC inhibitors were injected into mice after they had received a bone marrow transplant, the incidence and severity of graft-versus-host disease was dramatically reduced.  Detailed analysis revealed that the HDAC inhibitors mediated their effects by inducing Dcs to express more of a molecule known as IDO, which is a suppressor of DC function.  The authors therefore hope that their data provide support for studies to determine whether HDAC inhibitors might be of benefit to individuals receiving bone marrow transplants and to those with other immune-mediated diseases.

Drugs that target members of the EGFR family of proteins have proven effective for the treatment of certain types of cancer, including breast cancer.  However, in a large number of patients for whom the treatment initially works well, the tumor recurs and is resistant to the effects of the drug.  New insight into the mechanisms of tumor resistance to a drug known as gefitinib, which targets EGFR, has now been provided by a team of researchers at Vanderbilt University Medical Center, Nashville, and Massachusetts General Hospital Cancer Center, Charlestown.  As discussed by both the authors and, in an accompanying commentary, Mark Greene and Qiang Wang, at the University of Pennsylvania Medical Center, Philadelphia, these observations help us understand why tumors become resistant to the effects of EGFR-targeted drugs, information that is essential if more effective therapies are to be developed.

The team, led by Carlos Arteaga and Jeffrey Engelman, generated cancer cells resistant to the effects of gefitinib and found that these cells were constantly sending signals from a protein on their surface known as IGF1R.  This meant that two proteins known as IRS-1 and PI3K were always associated.  If this association was disrupted then the cells once again became susceptible to the effects of gefitinib.  Further analysis showed that if mice with a human tumor were treated with gefitinib and a drug inhibiting IGF1R their tumors did not recur, whereas neither drug alone could prevent tumor recurrence.  The authors therefore suggest that drug combinations that target both EGFR and IGF1R might be of benefit to individuals with cancers that are responsive to EGFR-targeted therapies.

The development of resistance to anticancer chemotherapeutic agents remains a large problem. In some cases, such resistance is associated with altered control of a cellular process known as translation, which is central to the generation of proteins. New data, generated by Jerry Pelletier and colleagues, at McGill University, Montreal, have identified a drug that can enhance the sensitivity of mouse cancer cells to standard anticancer chemotherapeutic agents.

In the study, small molecules were screened for their ability to inhibit the initiation of translation by modifying the function of a protein known as eIF4A, which has a central role in translation initiation. A class of natural drugs known as cyclopenta[b]benzofuran flavaglines were found to have the desired effects and one member of this class of compounds was shown to reverse the resistance of cancer cells to anticancer chemotherapeutic agents in a mouse model of lymphoma. The authors therefore suggest that developing approaches to inhibit translation initiation by targeting eIF4A might provide a way to altering drug resistance in cancers exhibiting altered control of translation initiation.

A novel type of drug can shrink primary breast cancer tumors significantly in just 6 weeks Research provides leads to a new target in cancer treatment -the cancer stem cell.

(Berlin, Germany) A drug that targets the cell surface receptors that play an important role in many types of cancer can bring about significant tumour regression in breast cancer after only six weeks of use, a scientist told the 6th European Breast Cancer Conference (EBCC-6) today (Thursday 17 April).  Dr. Angel Rodriguez, from the Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, USA, said that the work demonstrated for the first time that the tyrosine kinase inhibitor lapatinib could decrease tumour-causing breast cancer stem cells in the primary breast cancers of women receiving neoadjuvant treatment (treatment given before the primary surgery for the disease).

Dr. Rodriguez and colleagues studied 45 patients with locally advanced breast cancer in which the gene HER-2 was over-expressed.  The patients received lapatinib for six weeks, followed by a combination of weekly trastuzumab and three-weekly docetaxel, given over 12 weeks, before primary surgery.  Biopsies were performed at the time of diagnosis and also after six weeks of lapatinib and cells from the tumours were obtained and analyzed.

“We saw significant tumour regression after six weeks of single agent lapatinib,” said Dr. Rodriguez.  “Bi-dimensional tumour measurements showed a median decrease of minus 60.8%. We had previously showed that tumour-causing breast cancer stem cells were resistant to conventional preoperative chemotherapy; indeed, residual cancers that were exposed to such chemotherapy showed an increase in tumour-causing cells and enhanced tumour initiation by the formation of mammospheres, small tumours that form when tumour-causing cells are cultured in a test tube, which reflect the capacity of the cells to self-renew.  So we were excited to see that the results with lapatinib were different.”

Dr. Rodriguez’s results suggest that specific signalling inhibitors of the pathways responsible for stem cell self-renewal could provide a possible therapy for eliminating tumour-causing cells in order to achieve the long-term eradication of cancer.

Cancer stem cells help maintain the malignant tissue in the tumour by regenerating the tumour after attack from chemotherapy drugs.  “This indicates that the stem cells themselves should be the specific target of chemotherapy drugs,” said Dr: Rodriguez.  “Rather than the broad brush approach, in which cells are killed indiscriminately, targeting the stem cells may be more effective and also prevent some of the unpleasant side effects associated with conventional chemotherapy treatment.”

Scientists believe that cancer stem cells come into being through damage to their own DNA, which affects the regulation of their self-renewal.  Other cells divide into two ‘daughter’ cells, but a stem cell can divide into a new stem cell and a ‘progenitor’ cell.  The progenitor cell loses the power of self-renewal, but can still change into the cell type of the tissue served by the stem cell.  The stem cell population then continues to renew itself as it generates new cells for the tissue.  “This means that, unlike other cells, the stem cell has lost control over its own population size,” said Dr. Rodriguez.

Lapatinib has few side effects, and those that exist are minimal, including diarrhoea and acne.  But it is expensive.  “In the US it costs between $2000 and $3000 a month,” he said.

“This is an exciting finding, and we will be starting further studies on stem cells in order to confirm it.  We will also look into its applicability in testing novel agents targeting tumour-initiating cells.  This finding should also apply to other types of cancers and research of tumour-initiating stem cells in other cancers is ongoing,” said Dr. Rodriguez.

“International studies are currently underway looking at the effect of lapatinib in lung, colon, head and neck, gastric, oesophageal, and bladder cancer and lymphoma, among others,” he said.

Note:  Lapatinib has not yet been licensed for use in the EU, although it has been approved in Switzerland and received a positive opinion regarding a conditional marketing authorisation from the European Medicines Agency in December.  This conditional authorisation refers to its use in patients with advanced or metastatic breast cancer with HER-2 over-expression in the tumours.

Catalogue no: 204, Thursday 18 April, 17.15 hrs CEST (Hall 1)

A new drug compound leads to the death of ovarian cancer cells resistant to chemotherapy.

Dr. Gil Mor, Associate Professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.

Credit: Yale University

In a discovery that may be useful for maintaining remission in chemo-resistant ovarian cancer, Yale scientists report that pre-clinical studies have shown the drug compound NV-128 can induce the death of ovarian cancer cells by halting the activation of a protein pathway called mTOR.

Gil Mor, M.D., associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine, and associate research scientist Ayesha Alvero, M.D. presented the data April 15 during an oral presentation at the annual meeting of the American Association for Cancer Research.

In cancer cells, mTOR signals enhance tumor growth and may be associated with resistance to conventional therapies.  Inhibition of mTOR could shut down many of these survival pathways, including proteins that protect the mitochondria of cancer cells.

NV-128, developed by Novogen Limited, holds promise as a more targeted therapy for ovarian cancer because it works differently from traditional therapies that are dependent on enzymes known as caspases to trigger cell death.  Therapies using caspases to kill cancer cells can be ineffective in chemo-resistant cancer cells due to mutations that short-circuit signals that trigger cancer cell death.

“We consider that the capacity of NV-128 to trigger caspase-independent cell death, in otherwise chemoresistant ovarian cancer cells, opens new possibilities for the use of NV-128 as a potential addition to conventional chemotherapy targeting ovarian cancer cells,” said Mor.

In the context of developing therapies for late stage ovarian cancer, Mor said, the finding may be “a key step to the development of alternative targeted therapy for patients with cancer recurrence.”