Posts tagged drug delivery
Articles and news from the latest research reports.
New Non-Invasive Technique Controls the Size of Molecules Penetrating the Blood-Brain Barrier
A new technique developed by Elisa Konofagou, professor of biomedical engineering and radiology at Columbia Engineering, has demonstrated for the first time that the size of molecules penetrating the blood-brain barrier (BBB) can be controlled using acoustic pressure—the pressure of an ultrasound beam—to let specific molecules through. The study was published in the July issue of the Journal of Cerebral Blood Flow & Metabolism.
“This is an important breakthrough in getting drugs delivered to specific parts of the brain precisely, non-invasively, and safely, and may help in the treatment of central nervous system diseases like Parkinson’s and Alzheimer’s,” says Konofagou, whose National Institutes of Health Research Project Grant (R01) funding was just renewed for another four years for an additional $2.22 million. The award is for research to determine the role of the microbubble in controlling both the efficacy and safety of drug safety through the BBB with a specific application for treating Parkinson’s disease.
Most small—and all large—molecule drugs do not currently penetrate the blood-brain barrier that sits between the vascular bed and the brain tissue. “As a result,” Konofagou explains, “all central nervous system diseases remain undertreated at best. For example, we know that Parkinson’s disease would benefit by delivery of therapeutic molecules to the neurons so as to impede their slow death. But because of the virtually impermeable barrier, these drugs can only reach the brain through direct injection and that requires anesthesia and drilling the skull while also increasing the risk of infection and limiting the number of sites of injection. And transcranial injections rarely work—only about one in ten is successful.”
Focused ultrasound in conjunction with microbubbles—gas-filled bubbles coated by protein or lipid shells—continues to be the only technique that can permeate the BBB safely and non-invasively. When microbubbles are hit by an ultrasound beam, they start oscillating and, depending on the magnitude of the pressure, continue oscillating or collapse. While researchers have found that focused ultrasound in combination with microbubble cavitation can be successfully used in the delivery of therapeutic drugs across the BBB, almost all earlier studies have been limited to one specific-sized agent that is commercially available and widely used clinically as ultrasound contrast agents. Konofagou and her team were convinced there was a way to induce a size-controllable BBB opening, enabling a more effective method to improve localized brain drug delivery.
Konofagou targeted the hippocampus, the memory center of the brain, and administered different-sized sugar molecules (Dextran). She found that higher acoustic pressures led to larger molecules accumulating into the hippocampus as confirmed by fluorescence imaging. This demonstrated that the pressure of the ultrasound beam can be adjusted depending on the size of the drug that needs to be delivered to the brain: all molecules of variant sizes were able to penetrate the opened barrier but at distinct pressures, i.e., small molecules at lower pressures and larger molecules at higher pressures.
“Through this study, we’ve been able to show, for the first time, that we can control the BBB opening size through the use of acoustic pressure,” says Konofagou. “We’ve also learned much more about the physical mechanisms associated with the trans-BBB delivery of different-sized agents, and understanding the BBB mechanisms will help us to develop agent size-specific focused ultrasound treatment protocols.”
Konofagou and her Ultrasound Elasticity Imaging Laboratory team plan to continue to work on the treatment of Alzheimer’s and Parkinson’s in a range of models, and hope to test their technique in clinical trials within the next five years.
“It is frightening to think that in the 21st century we still have no idea how to treat most brain diseases,” Konofagou adds. “But we’re really excited because we now have a tool that could potentially change the current dire predictions that come with a neurological disorder diagnosis.”
(Source: engineering.columbia.edu)
New knowledge about the brain’s effective bouncer
Research from the University of Copenhagen is shedding new light on the brain’s complicated barrier tissue. The blood-brain barrier is an effective barrier which protects the brain, but which at the same time makes it difficult to treat diseases such as Alzheimer’s. In an in vitro blood-brain barrier, researchers can recreate the brain’s transport processes for the benefit of the development of new pharmaceuticals for the brain. The new research findings are published in the AAPS Journal.
Ninety-five per cent of all tested pharmacological agents for treating brain disorders fail, because they cannot cross the blood-brain barrier. It is therefore important to find a possible method for transporting drugs past the brain’s efficient outpost and fervent protector.
Researchers at the Department of Pharmacy at the University of Copenhagen have recreated the complex blood-brain barrier in a laboratory model, which is based on cells from animals. In a new study, the researchers have studied the obstreperous bouncer proteins in the barrier tissue. The proteins protect the brain, but also prevent the treatment of brain diseases:
"The blood-brain barrier is chemically tight because the cells contain transporter proteins which make sure that substances entering the cells are thrown straight back out into the bloodstream again. We have shown that the barrier which we have created in the laboratory contains the same bouncer proteins – and that they behave in the same way as in a ‘real’ brain. This is important, because the model can be used to test drive the difficult way into the brain. Complex phenomena – which we have so far only been able to study in live animals –can now be investigated in simple laboratory experiments using cultivated cells," says postdoc Hans Christian Cederberg Helms from the Department of Pharmacy.
The research team has shown that the transporter proteins P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated protein 1 are active in the artificially created barrier tissue. The proteins pump pharmacological agents from the ‘brain side’ to the ‘blood side’ in the same way as in the human blood-brain barrier.
Collaboration finds a way
The new findings have resulted from collaboration with industrial scientists from the pharmaceutical company H. Lundbeck A/S. “It is important to the treatment of brain diseases such as Alzheimer’s that we find a way of circumventing the brain’s effective defence. The university and industry must work together to overcome the fundamental challenges inherent in developing pharmaceuticals for the future,” says Lassina Badolo, Principal Scientist with H. Lundbeck A/S and an expert on the absorption of medicines in the body.
Associate Professor Birger Brodin adds: “We have shown that the models have the same bouncer proteins as the ones found in the intact barrier. We are now in the process of studying the proteins in the blood-brain barrier that accept pharmacological agents instead of throwing them out. If we can combine a beneficial substance which the brain needs with a so-called ‘absorber protein’, we will in the long term be able to smuggle pharmacological agents across the blood-brain barrier.”
Birger Brodin heads the Drug Transporters in ADME research group which is responsible for the in vitro blood-brain barrier.
(Source: healthsciences.ku.dk)
Fungal protein found to cross blood-brain barrier
In a remarkable series of experiments on a fungus that causes cryptococcal meningitis, a deadly infection of the membranes that cover the spinal cord and brain, investigators at UC Davis have isolated a protein that appears to be responsible for the fungus’ ability to cross from the bloodstream into the brain.
The discovery — published online June 3 in mBio, the open-access, peer-reviewed journal of the American Society for Microbiology — has important implications for developing a more effective treatment for Cryptococcus neoformans, the cause of the condition, and other brain infections, as well as for brain cancers that are difficult to treat with conventional medications.
“This study fills a significant gap in our understanding of how C. neoformans crosses the blood-brain barrier and causes meningitis,” said Angie Gelli, associate professor of pharmacology at UC Davis and principal investigator of the study. “It is our hope that our findings will lead to improved treatment for this fungal disease as well as other diseases of the central nervous system.”
Normally the brain is protected from bacterial, viral and fungal pathogens in the bloodstream by a tightly packed layer of endothelial cells lining capillaries within the central nervous system — the so-called blood-brain barrier. Relatively few organisms — and drugs that could fight brain infections or cancers — can breach this protective barrier.
The fungus studied in this research causes cryptococcal meningoencephalitis, a usually fatal brain infection that annually affects some 1 million people worldwide, most often those with an impaired immune system. People typically first develop an infection in the lungs after inhalation of the fungal spores of C. neoformans in soil or pigeon droppings. The pathogen then spreads to the brain and other organs.
Unique protein identified
In an effort to discover how C. neoformans breaches the blood-brain barrier, the investigators isolated candidate proteins from the cryptococcal cell surface. One was a previously uncharacterized metalloprotease that they named Mpr1. (A protease is an enzyme — a specialized protein — that promotes a chemical reaction; a metalloprotease contains a metal ion — in this case zinc — that is essential for its activity.) The M36 class of metalloproteases to which Mpr1 belongs is unique to fungi and does not occur in mammalian cells.
The investigators next artificially generated a strain of C. neoformans that lacked Mpr1 on the cell surface. Unlike the normal wild-type C. neoformans, the strain without Mpr1 could not cross an artificial model of the human blood-brain barrier.
They next took a strain of common baking yeast — Saccharomyces cerevisiae — that does not cross the blood-brain barrier and does not normally express Mpr1, and modified it to express Mpr1 on its cell surface. This strain then gained the ability to cross the blood-brain barrier model.
Investigators then infected mice with either the C. neoformans that lacked Mpr1 or the wild-type strain by injecting the organisms into their bloodstream. Comparing the brain pathology of mice 48 hours later, they found numerous cryptococci-filled cysts throughout the brain tissue of mice infected with the wild-type strain; these lesions were undetectable in those infected with the strain lacking Mpr1. In another experiment, after 37 days of being infected by the inhalation route, 85 percent of the mice exposed to the wild-type C. neoformans had died, while all of those given the fungus without Mpr1 were alive.
“Our studies are the first clear demonstration of a specific role for a fungal protease in invading the central nervous system,” said Gelli. “The details of exactly how it crosses is an important new area under investigation.”
New targeted therapies possible
According to Gelli, their discovery has significant therapeutic potential via two important mechanisms. Either Mpr1 — or an aspect of the mechanism by which it crosses the blood-brain barrier — could be a target of new drugs for treating meningitis caused by C. neoformans. In a person who develops cryptococcal lung infection, such a treatment would ideally make the fungus less likely to enter the brain and lead to a rapidly fatal meningitis.
Secondly, Mpr1 could be developed as part of a drug-delivery vehicle for brain infections and cancers. An antibiotic or cancer-fighting drug that is unable to cross the blood-brain barrier on its own could be attached to a nanoparticle containing Mpr1, allowing it to hitch a ride and deliver its goods to where it is needed.
“The biggest obstacle to treating many brain cancers and infections is getting good drugs through the blood-brain barrier,” said Gelli. “If we could design an effective delivery system into the brain, the impact would be enormous for treating some of these terrible diseases.”
Gelli’s group is currently pursuing such a nanoparticle drug-delivery system using Mpr1. They are also further investigating the exact molecular mechanism by which Mpr1 breaches the blood-brain barrier.
(Source: ucdmc.ucdavis.edu)
Breakthrough: Nasal spray may soon replace the pill
When the doctor gives us medicine, it is often in the shape of a pill. But when it comes to brain diseases, pills are actually an extremely ineffecient way to deliver drugs to the brain, and according to researchers from University of Southern Denmark we need to find new and more efficient ways of transporting drugs to the brain. Spraying the patient’s nose could be one such way.
Every time we have an infection or a headache and take a pill, we get a lot more drugs than our body actually needs. The reason is that only a fraction of the drugs in a pill reaches the right places in the body; the rest never reaches its destination and may cause unwelcome side effects before they are flushed out of the body again. This kind of major overdosing is especially true when doctors treat brain diseases, because the brain does not easily accept entering drugs.
"People with brain diseases are often given huge amounts of unnecessary drugs. During a long life, or if you have a chronic disease, this may become problematic for your health", says Massimiliano Di Cagno, assistant professor at the Department of Physics, Chemistry and Pharmacy, University of Southern Denmark.
He is concerned with finding more efficient ways of delivering drugs to the brain. He and his colleagues at University of Southern Denmark and Aalborg University have turned their attention to the nose - specifically the nasal wall and the slimy mucosa that covers it.
As we know from e.g. cocaine addicts, substances can be assimilated extremely quickly and directly through the nose. But many medical substances, however, need help to be transported through the nasal wall and further on to the relevant places in the brain.
Researchers have long struggled with this challenge and have come up with different kinds of transport vehicles that are very good at transporting the active ingredients through the nasal wall into the brain. The problem with these vehicles, though, is that they cannot release their cargo of drugs once they have reached the inside of the brain. The drugs stay locked inside the strong vehicles.
“If the drugs cannot get out of their vehicles, they are no help to the patient. So we needed to develop a vehicle that does not lock the drug in”, explains Massimiliano Di Cagno.
The vehicles for drug delivery through the nose are typically made of so called polymers. A polymer is a large molecule composed of a large number of repeats of one or more types of atoms or groups of atoms bound to each other. Polymers can be natural or synthetic, simple or complex.
Direct track to the brain
Massimiliano Di Cagno and his colleagues tested a natural sugar polymer and they now report that this particular polymer is not only capable of carrying the drugs through the nasal wall but also – and most importantly – releasing the drug where it is needed.
"This is an important breakthrough, which will bring us closer to delivering brain drugs by nasal spray", says Massimiliano Di Cagno.
With this discovery two out of three major challenges in nasal delivery of brain drugs have been met:
“We have solved the problem of getting the drug through the nose, and we have solved the problem of getting the drug released once it has entered the brain. Now there is a third major challenge left: To secure a steady supply of drugs over a long period. This is especially important if you are a chronic patient and need drug delivery every hour or so”, says Massimiliano Di Cagno.
When a patient sprays a solution with active drugs into his nose cavity, the solution will hit the nasal wall and wander from here through the nasal wall to the relevant places in the brain.
“But gravity also rules inside the nose cavity and therefore the spray solution will start to run down as soon as it has been sprayed up the nose. We need it to cling to the nasal wall for a long time, so we need to invent some kind of glue that will help the solution stick to the nasal wall and not run down and out of the nose within minutes”, says Massimiliano Di Cagno.
Biomaterial-delivered chemotherapy could provide final blow to brain tumours
A polymer originally designed to help mend broken bones could be successful in delivering chemotherapy drugs directly to the brains of patients suffering from brain tumours, researchers at The University of Nottingham have discovered.
Their study, published in the journal PLOS ONE, shows that the biomaterial can be easily applied to the cavity created following brain cancer surgery and used to release chemotherapy drugs over several weeks.
The targeted nature of the therapy could also reduce the toxic effects of chemotherapy drugs on healthy parts of the body, potentially reducing the debilitating side-effects that many patients experience after cancer treatment.
Patient survival
Dr Ruman Rahman, of the University’s Children’s Brain Tumour Research Centre (CBTRC), who led the study, said: “Our system is an innovative method of drug delivery for the treatment of brain tumours and is intended to be administered immediately after surgery by the operating neurosurgeon.
“Ultimately, this method of drug delivery, in combination with existing therapies, may result in more effective treatment of brain tumours, prolonged patient survival and reduced morbidity.”
Brain tumours are the major cause of cancer-related death in children and adults up to the age of 40. Most relapses occur when surgeons are unable to remove all of the cancerous cells during surgery – something which can be particularly challenging in very young children and babies and by the very nature of a type of adult brain cancer called glioblastoma.
Although alternative systems for delivery of drugs directly to the brain have been developed, they are used infrequently because their success has been limited. This new drug delivery system is the first that can be moulded to the shape of the brain tumour cavity and the first to deliver several different drugs over a clinically meaningful period of time.
The Nottingham polymer formulation is made from two types of micro-particles called PLGA and PEG and has been developed and patented by leading tissue engineer Professor Kevin Shakesheff, based in the University’s School of Pharmacy. A powder at room temperature, it can be mixed to a toothpaste-like consistency with the addition of water.
Unique properties
The unique properties of the polymer lie in its ability to set into a rigid structure only when it reaches body temperature (37 degrees), a feature perfectly tailored for use in medical therapies. It was originally developed as a scaffold on to which new bone cells could be grown to speed up the knitting back together of broken bones.
Dr Ruman Rahman at the CBTRC and Dr Cheryl Rahman from the School of Pharmacy spotted the potential for the polymer to deliver chemotherapy drugs directly to patients’ brain tumours. The work was performed at the CBTRC with neurosurgeon Mr Stuart Smith and neuro-oncologist Professor Richard Grundy. The cavity left by the removal of a tumour would be lined with the polymer while in paste form, which would start to solidify and gradually release the chemotherapy drugs after the incision has been closed. This would directly target any residual cells not initially removed during surgery.
In the lab, the Nottingham scientists were able to successfully demonstrate the slow-release properties of the material by placing paste loaded with three commonly used chemotherapy drugs into a solution of saline and measuring the quantities of the drugs given out by the material over time.
To establish whether the material itself is safe to use on patients in this form of therapy, they used it to create a 3D model onto which they were able to grow brain tumour cells and healthy brain blood vessel cells without any toxicity. They then simulated surgery on a sheep’s brain from an abattoir by moulding the paste around a brain cavity and warming the brain to human body temperature to harden the polymer.
The brain was then scanned using CT and MRI technology to demonstrate that it is still possible to distinguish the polymer from normal brain tissue on a routine brain scan, an aspect crucial for doctors when dealing with follow-up care for brain tumour patients who have undergone surgery.
Robust material
The team also dealt with concerns that the material could disintegrate and release its chemotherapy contents too quickly during the subsequent radiotherapy which many cancer patients undergo following surgery. By placing the biomaterial loaded with chemotherapy drugs into a head cavity of a medical training dummy and subjecting it to the same duration and intensity of radiotherapy used for brain tumour patients they were able to successfully demonstrate the robust integrity of the structure.
Finally they showed that a chemotherapy drug called etoposide could be effective at killing brain cancer cells in a mouse when released from the polymer formulation. The next stage of the research will be to extend the study in mice with brain tumours to test whether animals with the drug-loaded polymers survive longer. The team are also investigating the release of other chemotherapeutic drugs that hold promise, supported by a recent grant award from Sparks.
As the research used a biomaterial and chemotherapy drugs already approved for medical use, many of the usual ethical approval hurdles to allow further investigation have already been cleared.
The first clinical test, anticipated in 3 years’ time, will be to devise a multi-centre phase 0 clinical trial which would involve testing the therapy on a small number of patients for whom other clinical treatments have not been successful and would otherwise only be offered palliative care.
“This is a very exciting development and holds considerable promise for the treatment of malignant brain tumours in the near future” commented Professor Grundy, Co-Director of the CBTRC.
(Source: nottingham.ac.uk)
Using ultrasound waves, MIT engineers have found a way to enhance the permeability of skin to drugs, making transdermal drug delivery more efficient. This technology could pave the way for noninvasive drug delivery or needle-free vaccinations, according to the researchers.
“This could be used for topical drugs such as steroids — cortisol, for example — systemic drugs and proteins such as insulin, as well as antigens for vaccination, among many other things,” says Carl Schoellhammer, an MIT graduate student in chemical engineering and one of the lead authors of a recent paper on the new system.
Ultrasound — sound waves with frequencies greater than the upper limit of human hearing — can increase skin permeability by lightly wearing away the top layer of the skin, an effect that is transient and pain-free.
In a paper appearing in the Journal of Controlled Release, the research team found that applying two separate beams of ultrasound waves — one of low frequency and one of high frequency — can uniformly boost permeability across a region of skin more rapidly than using a single beam of ultrasound waves.