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Posts Tagged ‘BBB’


Author: Tilda Barliya PhD

Primary malignant central nervous system (CNS) tumors only represent about 2% of all cancers.  But treatment is elusive. Tumors may be embedded in regions of the brain that are critical to orchestrating the body’s vital functions, while they shed cells to invade other parts of the brain, forming more tumors too small to detect using conventional imaging techniques. Brain cancer’s location and ability to spread quickly makes treatment with surgery or radiation like fighting an enemy hiding out among minefields and caves, and explains why the term “brain cancer” is all too often associated with the word “inoperable.” Nanotechnology may alter this situation. It offers a new promise for cancer diagnosis and treatment. This emerging technology, by developing and manufacturing materials using atomic and molecular elements, can provide a platform for the combination of diagnostics, therapeutics and delivery to the tumor, with subsequent monitoring of the response. This review focuses on recent developments in cancer nanotechnology with particular attention to nanoparticle systems, important tools for the improvement of drug delivery in brain tumor.

Making treatment even more challenging, there is a system of blood vessels and protective cells in the brain — the blood brain barrier — that admits only essential nutrients and oxygen, and keeps out everything else, including about 95 percent of all drugs. This natural barrier puts serious limits on how much a patient can benefit from traditional chemotherapy and new cancer drugs.

The blood-brain barrier permits the exchange of essential nutrients and gases between the bloodstream and the brain, while blocking larger entities such as microbes, immune cells and most drugs from entering. This barrier system is a perfectly logical arrangement, since the brain is the most sensitive and complex organ in the human body and it would not make sense for it to become the battleground of infection and immune response.

This biological “demilitarization zone” is enforced by an elaborate and dense network of capillary vessels that feeds the brain and removes waste products. Each capillary vessel is bound by a single layer of endothelial cells, connected by “tight junctions,” thereby making it very difficult for most molecules to exit the capillaries and permeate into the brain.  Instead of “leaking” material, brain capillary walls closely regulate the flow of material using molecular pumps and receptors that recognize and transport nutrients such as glucose, nucleosides, and specific proteins into the brain. In other words, substances need to be pre-recognized to enter.

Since most drugs. including old-school chemotherapy, can not cross the BBB it very hard to treat brain-tumor patients.  In certain conditions such as grade IV glioblastoma, the BBB is loosened up (becomes more permeable  due to changes in the gene expression and tight-junction protein expression, making the cross over of materials much easier. Having  said that,  the loosened up BBB represent a double-edge sword as it not only allows the transfer of drugs but allow the escape of metastatic tumor cells.

Therefore, in order to enable drugs to enter the brain regardless of the presence of the BBB, nanotechnology has designed drugs that used the already-existing transporters located at the barrier. Among them are: glucose transporter,  transferrin transporter and LDL receptor.

Trojan Horse approach:

 Nanoparticles have excellent potential as carriers of drugs, because if they are small enough, they can penetrate the BBB. That way, a treatment could be injected into the bloodstream rather than performing surgery to insert it. Many researchers are exploring using nanoparticles in the manner of a Trojan horse, to carry treatments including chemotherapy, gene therapy, or immune boosters into the brain. As impressive as it may sound, receptor uptake of nanocarriers (Trojan horses) have also limitations;  this can limit the amount of therapy one person can have—if all of the receptors are taken up (filled) no more of the drug could get in.

 

Some of these extensive beautiful work conducted by several research labs including Dr. Raoul Kopleman, Dr. Miqin Zhang and Dr. Panos Fatouros  are summaried in this article “Nanotechnology Tackles Brain Tumors” (http://www.fightplga.org/files/monthly_feature_2005_dec.pdf).

I’d like to shift the discussion to FDA/EU-approved nanomedicine to treat brain tumors.

Using nanomedicines to treat brain tumors was first proposed more than three decades ago . Currently there is one nanoparticle treatment available to people with hard brain tumors: Nano-Therm therapy. Available at a clinic in Berlin, the treatment has been through trials in humans to demonstrate its safety and effectiveness. (http://www.dana.org/news/brainwork/detail.aspx?id=35524)

In the study, 59 patients with recurring glioblastoma treated with Nano-Therm therapy survived a median time of more than 13 months—more than double the control group, published in Neuro-Oncology in 2010.  The EU approved the treatment developed by Magforce, in July 2010.

Nano-Therm uses “thermotherapy,” which involves surgery to insert a liquid containing 15 nanometer-wide magnetic particles into the brain tumor. Next, the patient being treated lies in a machine that emits an alternating magnetic field. This causes the nanoparticles, which have an iron oxide core, to oscillate, penetrating the tumor cells. The longer the magnetic field is on, the warmer the nanoparticles grow. Doctors can take the heat up to about 45 degrees Celsius, where the tumor cells are primed for chemotherapy or radiotherapy, or even higher, which can destroy the tumor cells. It important thought to ensure that normal brain cells are not affected.

The main aim is to build a multifunctional nano-carrier; one that contains 3  aspects :

  • A target moiety- that will guide the nanoparticle (NP) to the brain tumors. Preferably will use a specific receptor to penetrate through the BBB.
  • An imaging agent- that will enable visualization of the target ” i.e brain rumor” .  MRI contrast agent are good such as gadolinium, fluorescent probes and quantum dots  are good candidates.
  • A destructive drug/toxin- that will eliminate the tumor cells.

In summary:

Nanotechnology has huge potential and a long way to go, thought there is a growing consensus that brain cancer is a problem in need of a radically different solution, and that nanotechnology fits the bill. Functionalized nanoparticles could provide precision detection, targeted treatment, and real-time tracking that conventional technology lacks. For a disease in which only 5 percent to 32 percent of patients are likely to survive after five years, large hope is riding on the potential success of “small” technology.

 

Ref:

http://www.fightplga.org/files/monthly_feature_2005_dec.pdf

http://www.nanowerk.com/spotlight/spotid=6269.php#axzz2D4yx1btl

http://www.touchbriefings.com/pdf/2514/amiji.pdf

http://www.dana.org/news/brainwork/detail.aspx?id=35524

 

 

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English: Schematic sketch showing the transpor...

English: Schematic sketch showing the transport types at the blood-brain barrier. Deutsch: Schematische Darstellung der Transportmechanismen an der Blut-Hirn-Schranke. Français : Schéma des types de transport à travers la barrière hémato-encéphalique (Photo credit: Wikipedia)

Larry H Bernstein, MD
Reporter

Provided without comment.  Quite interesting.

novel protease resistant peptide shuttles able to cross the blood-brain barrier (BBB) by binding to a specific brain receptor

Description

A Catalan Research Institute based in Barcelona (Spain) has identified novel protease resistant peptide shuttles able to cross the blood-brain barrier (BBB) by binding to a specific brain receptor. These shuttles are a powerful alternative to carry a wide variety of small and large molecules as cargos. This represents a novel opportunity to develop new delivery carriers able to cross actively a range of biological barriers.

New and innovative aspects

These compounds are novel drug delivery carriers that provide a non-invasive, non-antigenic, stable and receptor-specific way to transport drugs across the Blood-Brain Barrier and into the Central Nervous System.

These compounds show high permeability, biocompatibility, good solubility in water and resistance to proteases.

Specifications

The treatment of most neurological disorders has not been fully addressed mainly because of the neuroprotective role of the blood-brain barrier (BBB) that hinders the delivery of many diagnostic and therapeutic agents into the brain. Consequently, therapeutic molecules and genes that might otherwise be effective in diagnosis and therapy do not cross the BBB in adequate amounts: 98% of compounds smaller than 400Da and 100% of larger ones do not reach further drug development stages.

Most central nervous system (CNS) diseases, however, are complex disorders with difficult molecular targets that require larger, safer and more selective drugs. As a result, brain tumors, neurodegenerative diseases such as Parkinson’s and Alzheimer’s, and central nervous system (CNS) diseases such as schizophrenia are not successfully treated. Therefore, finding an efficient CNS delivery system is one of the major challenges in neurological treatment and one our technology can potentially overcome.

One of the best approaches for drug delivery to the brain is the use of endogenous transport mechanisms, such as receptor-mediated transcystosis. Peptides are biocompatible molecules able to transport cargos (i.e. therapeutic compounds) to specific tissues such as the brain. However, one of the main limitations of peptides as therapeutic agents is their low stability in plasma.

The use of non-natural amino acids in peptidic sequences can circumvent this problem because they are resistant to human serum proteases. Using this approach, we obtained several modified peptides. Two of them were selected based on their protease resistance and transport capacity across the blood-brain barrier, using a specific endogenous receptor. Both peptides showed enhanced membrane permeability in vitro in comparison to standard peptides and even greater stability in plasma (over 24h).

Main advantages of its use

Novel delivery technology that provides a non-invasive, non-antigenic, permeable, stable, soluble and receptor-specific way to transport drugs across the BBB and into the CNS.

This technology may ultimately allow the delivery of therapeutic agents, even large ones, across the BBB and other biological barriers, thus increasing the effectiveness of existing or new drugs.

Potential of application in a wide number of fields and in transport through various biological barriers.

Applications

Biotechnological and Pharmaceutical companies specialized in drug discovery, drug delivery, neurological disorders, tools to cross the Blood-brain barrier. The final aim is to increase the efficiency of existing molecules for the treatment of neurological disorders.

Molecule and treatment design, drug manufacture, treatment of neurological disorders, drug delivery across the blood-brain barrier (BBB).

Intellectual property status

This invention is protected by a priority application in Spain and we plan to apply for a PCT in due time.

 

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