Posts Tagged ‘MRI contrast agents’

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.



Click to access monthly_feature_2005_dec.pdf


Click to access amiji.pdf




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