A researcher at Lawrence Berkeley National Laboratory thinks she might have found a solution to transporting therapeutics across the blood-brain barrier to treat a deadly form of brain cancer. Ting Xu, Ph.D., a polymer scientist, who specializes in self-assembling bio/nano hybrid materials, has developed a new family of nanocarriers formed from the self-assembly of amphiphilic peptides and polymers.
The research (“Self-assembled 20-nm 64Cu-micelles enhance accumulation in rat glioblastoma”) is published in the Journal of Controlled Release.
Called 3HM for coiled-coil 3-helix micelles, these new nanocarriers meet all the size and stability requirements for effectively delivering a therapeutic drug to GBM tumors, according to Dr. Xu. Amphiphiles are chemical compounds that feature both hydrophilic and lipophilic properties. Micelles are spherical aggregates of amphiphiles.
In a recent collaboration between Dr. Xu and scientists at the University of California Davis, and UC San Francisco, 3HM nanocarriers were tested on glioblastoma multiforme (GBM) tumors in rats. Using the radioactive form of copper (copper-64) in combination with positron emission tomography (PET) and magnetic resonance imaging (MRI), the collaboration demonstrated that 3HM can cross the blood brain barrier and accumulate inside GBM tumors at nearly double the concentration rate of current FDA-approved nanocarriers.
“Our 3HM nanocarriers show very good attributes for the treatment of brain cancers in terms of long circulation, deep tumor penetration and low accumulation in off-target organs such as the liver and spleen,” says Dr. Xu. “The fact that 3HM is able to cross the blood brain barrier of GBM-bearing rats and selectively accumulate within tumor tissue, opens the possibility of treating GBM via intravenous drug administration rather than invasive measures. While there is still a lot to learn about why 3HM is able to do what it does, so far all the results have been very positive.”
Although there are FDA-approved therapeutic drugs for the treatment of GBM, these treatments have had little impact on patient survival rate because the blood brain barrier has limited the accumulation of therapeutics within the brain. Typically, GBM therapeutics is ferried across the blood brain barrier in special liposomes that are approximately 110 nanometers in size. The 3HM nanocarriers developed by Dr. Xu and her group are only about 20 nanometers in size. Their smaller size and unique hierarchical structure afforded the 3HM nanocarriers much greater access to rat GBM tumors than 110-nanometer liposomes in the tests carried out by Dr. Xu and her colleagues.
“3HM is a product of basic research at the interface of materials science and biology,” continues Dr. Xu. “When I first started at Berkeley, I explored hybrid nanomaterials based on proteins, peptides, and polymers as a new family of biomaterials. During the process of understanding the hierarchical assembly of amphiphilic peptide-polymer conjugates, my group and I noticed some unusual behavior of these micelles, especially their unusual kinetic stability in the 20 nanometer size range. We looked into critical needs for nanocarriers with these attributes and identified the treatment of GBM cancer as a potential application.”
Copper-64 was used to label both 3HM and liposome nanocarriers for systematic PET and MRI studies to find out how a nanocarrier's size might affect the pharmacokinetics and biodistribution in rats with GBM tumors. The results not only confirmed the effectiveness of 3HM as GBM delivery vessels, they also suggest that PET and MRI imaging of nanoparticle distribution and tumor kinetics can be used to improve the future design of nanoparticles for GBM treatment.
“I thought our 3HM hybrid materials could bring new therapeutic opportunities for GBM but I did not expect it to happen so quickly,” says Dr. Xu, who has been awarded a patent for the 3HM technology.