The race is on to create the best nanomedicine approach for brain cancer. Julia Ljubimova, who directs the research of nanomedicine at Cedars-Sinai Medical Center in Los Angeles, tells me she can’t comment on other people’s work in the field: “It is very competitive.” One nanomedicine company based in Germany refuses to talk to reporters “until next year.”
Perhaps this secrecy is because there is a lot to be gained by developing a new nanomedicine to combat brain cancer (as well as other cancers). Brain cancers are among the most difficult cancers to treat; almost all involve surgery to remove the bulk of the tumor followed by chemotherapy or radiotherapy to remove the last traces of cancer cells.
Gliobastoma and medulloblastoma are the most common brain cancers for adults and children, respectively. Doctors call these brain tumors “aggressive” because they are so deadly: After treatment, people with gliobastoma survive at a median of five more months. Of children with medulloblastoma, 70 percent to 80 percent survive to five years or more after treatment.
The follow-up chemotherapy or radiotherapy also comes with nasty side effects, such as nausea and hair loss. Toxic chemotherapy drugs can accumulate in their liver, kidneys, and bone marrow.
Nanomedicines—treatments using materials modified at the atomic or molecular level—have the potential to be game-changers for these patients. For example, some nano-sized molecules can travel through the physiological obstacles to drug treatment: the blood-brain barrier (BBB), a semi-permeable membrane of tightly knit capillary endothelial cells that protects the brain from harmful substances in the blood, and the tumor cell membrane itself. Also, nano-sized particles (between 1 and 100 nanometers) can behave in extraordinary ways—such as reacting to magnetic fields and light—opening up new possibilities for treatment.
Overheating tumor cells
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. In a study of 59 people with recurring glioblastomapublished in Neuro-Oncology in 2010, those treated with Nano-Therm therapy survived a median time of more than 13 months—more than double the control group. 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 person 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.
“Our vision is to establish this new technology alongside surgery, chemotherapy, and radiation as an additional pillar of cancer therapy,” Magforce’s founder and chief scientific officer Andreas Jordan said in a statement.
Magforce’s already approved nano-treatment is an exception. Most research into nanomedicines for brain cancer is occurring at the level of basic research in the lab or in animal studies.
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.
One example of the Trojan horse approach includes a tool called “molecular envelope technology” (MET). Andreas Schatzlein, on the research team at the London School of Pharmacy, says: “What we are trying to do is create an envelope around hydrophobic drugs. This is similar to what a detergent does, but a detergent would destroy cells, so we created a molecule that has the properties of a detergent: a fat-loving part and a water-loving part. This can shield a lipid-based drug from the water, which is what we are made of.”
Research in a 2006 paper in Biomacromolecules [DOI: 10.1021/bm0604000] showed that 10 times more drug is taken up across the blood-brain barrier using these nanoparticles than using conventional suspensions. This experiment was done in mice, and used an anesthetic as the drug, but it shows that drugs encapsulated by MET can get through the BBB.
Research is ongoing into a lipid-based drug that would control cancer growth in the brain; the London researchers have already reported that MET works to control pancreatic cancer growth using an oral peptide drug. “We know we can get a peptide into the brain that is very similar to the one we used in the pancreatic cancer study. We are quite optimistic,” says Schatzlein. He estimates that Phase I (safety) clinical trials could start within two years, depending on funding.
Another nanotech method to carry therapies into brain cancer cells is called “nanobioconjugates.” These are built around the foundation of a natural polymer, with different chemical “modules” attached (conjugated) by strong covalent bonds. Because the bonds are strong, the molecules are stable; only when they hook onto specific targets will they react. This means that nanobioconjugates do not degrade in blood plasma.
Julia Ljubimova has worked on the creation of a nanobioconjugate that has been shown in mice to inhibit brain tumor growth; that research was published in the Proceedings of the National Academy of Sciences in 2010. Their nanobioconjugate works by including molecules that prevent tumor cell growth by blocking the growth of the blood vessels feeding the tumor.
The Cedars-Sinai nanobioconjugate is still some years away from approval for use in doctor’s offices. Ljubimova says that their data will soon be submitted for FDA approval. She envisions the treatment would be used in combination with surgery to prevent the recurrence of the disease.
Nanoparticles vs nanobioconjugate
Nanobioconjugates targeted at brain cancers do not affect healthy cells; the treatment seems to be nontoxic and does not provoke an immune system response. Ljubimova tells me that nanobioconjugates are “next generation” nanomedicines, better than nanoparticles.
“Nanoparticles, it’s like an eggshell,” she says; the shell is porous and the drug inside can just leak out. “With nanobioconjugate, everything is together. This is like a spaceship: If it goes through the stratosphere, part of the ship is ejected. It is controlled.” The nanobioconjugate targets only specific tumor vessel cells, it is designed to go through the BBB, and also to have an “escape device” to help the conjugate penetrate the tumor cell fluid (explained further here). Some other forms of nanoparticles can be unstable in blood plasma because they have weak chemical bonds.
The BBB is at the nub of the controversy. Ljubimova says of nanoparticles: “Some small molecules can go through BBB, but they go in and they go out with the same speed, and they do not have time to treat cancer. [And] it is difficult for a big molecule to pass through the BBB.”
But that may be an argument for using nanoparticles to cross the BBB rather than nanoconjugates, says Andreas Schatzlein. “One approach is trying to use receptors at the BBB, and then using conjugates with those ligands for receptors at the BBB so that they will be taken up in increased amounts and carried into the brain.” He points out that 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.
Furthermore, there is huge potential to develop hybrid nanomedicines to perform various tasks once inside the body; not only to treat tumors but to help with imaging and diagnosis as well. This is called the “theranostic” approach. For example, nano shells can carry quantum dots or magnetic particles, or nanobioconjugates can carry a tracer dye. This can help show the outline of the tumor more clearly under an MRI scan, which is particularly useful to help diagnosis of tumors compared to infections in the brain, especially when a biopsy cannot be performed.
Sometimes, Ljubimova tells me, an enhanced MRI image can even help discern whether the tissue is part of a primary tumor or a secondary brain tumor, metastasized from lung cancer, for example. This understanding can lead to a different diagnosis and a different treatment. “This is our future,” she says.