Nanotechnology Tackles Brain Cancer
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:
Click to access monthly_feature_2005_dec.pdf
http://www.nanowerk.com/spotlight/spotid=6269.php#axzz2D4yx1btl
http://www.dana.org/news/brainwork/detail.aspx?id=35524
Enjoyed reading this post very much.
Thank you very much Dr.Lev-Ari, much appreciated!
Excellent, illustrative; there are start-ups in emerging markets which intend to apply nanotechnology to develop anticancer drugs.
Post deleted ?
O.K. , I get the hint….regardless of the nature of my well-intended / constructive of input was…never-fear , I won’t be back…bye bye now ;(
Dear DDHawk, I apologize if your comment was accidentally deleted……I am not sure what happened if any. Please comment/reply again and I will try to address it as much as possible……
We all appreciate constructive inputs….so no fear at all.
Hope to hear from you again
Sincerely,
Tilda
[…] Nanotechnology Tackles Brain Cancer […]
[…] Nanotechnology Tackles Brain Cancer […]
Congratulations… it is really an excellent work
Thank you Mohamed, much appreciated
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.