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Researchers from the University of Michigan report they have developed a new synthetic protein nanoparticle capable of passing through the nearly impermeable blood-brain barrier (BBB) in mice that could deliver cancer-killing drugs directly to malignant brain tumors.
Their findings, “ Systemic brain tumor delivery of synthetic protein nanoparticles for glioblastoma therapy, ” is published in the journal Nature Communications and led by Joerg Lahann, PhD, the Wolfgang Pauli collegiate professor of chemical engineering, and Maria Castro, PhD, the R.C. Schneider collegiate professor of neurosurgery.
“Inspired by the capacity of natural proteins and viral particulates to cross the BBB, we engineered a synthetic protein nanoparticle (SPNP) based on polymerized human serum albumin (HSA) equipped with the cell-penetrating peptide iRGD,” the researchers wrote.
The BBB comprises a layer of endothelial cells that line the blood vessels in the brain, which allows only select types of molecules to pass from the bloodstream into the fluid surrounding the neurons and other cells of the brain. The BBB prevents the transfer of most small-molecule drugs and macromolecules, such as peptides, proteins, and gene-based drugs, which has limited the treatment of CNS diseases, such as neurodegenerative disorders, brain tumors, brain infections, and stroke. Although the blood-brain barrier is considered “leaky” in the core part of glioblastomas (GBMs), the efficient passage of cancer therapeutics, including small molecules and antibodies are still prevented.
Glioblastoma is one of the most common, deadly, and difficult-to-treat adult brain tumors. Surgical removal of the tumor, followed by radiotherapy, and temozolomide (TMZ) administration, is the current treatment modality, but this regimen only improves overall patient survival. The current median survival (MS) for patients with glioblastoma is around 18 months; the average five-year survival rate is below 5%.
In combination with radiation, the researchers injected therapy intravenously and observed long-term survival in seven out of eight mice. When those seven mice experienced a recurrence of glioblastoma, their immune responses kicked in to prevent the cancer’s regrowth—without any additional therapeutic drugs or other clinical treatments.
“It’s still a bit of a miracle to us,” declared Lahann, a co-senior author of the study. “Where we would expect to see some levels of tumor growth, they just didn’t form when we rechallenged the mice. I’ve worked in this field for more than 10 years and have not seen anything like this.”
The combination of therapeutic drugs and nanoparticle delivery methods also resulted in immunological memory.
“This is a huge step toward clinical implementation,” added Castro. “This is the first study to demonstrate the ability to deliver therapeutic drugs systemically, or intravenously, that can also cross the blood-brain barrier to reach tumors.”
Five years ago, Castro knew how she wanted to target glioblastoma. She wanted to stop a signal that cancer cells send out, known as STAT3, to trick immune cells into granting them safe passage within the brain. But she didn’t have a way to get past the blood-brain barrier.
Castro attended a workshop at the Biointerfaces Institute, which Lahann leads, and the two discussed the problem. Lahann’s team began working on a nanoparticle that could ferry a STAT3 inhibitor past the blood-brain barrier.
Lahann’s team used a protein called human serum albumin, which is one of the few molecules that can cross the blood-brain barrier, as the structural building block for their nanoparticles. They used synthetic molecules to link these proteins up and then attached the STAT3 inhibitor and a peptide called iRGD, which serves as a tumor homing device.
“To further test the efficacy of SPNPs in vivo, GBM-bearing mice were treated intravenously with multiple doses of STAT3i SPNPs over the course of a three-week treatment regimen,” noted the researchers. “After tumor implantation, the MS of untreated mice was about 28 days. In mice that received multiple doses of empty SPNPs, the MS remained unaltered (28 days). In contrast, when SPNPs loaded with STAT3i were administered, the MS increased to 41 days, a statistically significant increase of 45%. Delivery of the same doses of free STAT3i resulted in a modest extension of MS by 5 days, which is likely too low to elicit a significant therapeutic effect. The low efficacy of free STAT3i can be explained by the rapid degradation of genetic material following systemic administration—in addition to siRNA’s inability to cross the BBB.”
Seven of the eight mice reached long-term survival and appeared completely tumor-free, with no signs of malignant, invasive tumor cells.
Their study is the first to demonstrate an intravenous medication that can cross the blood-brain barrier. The discovery may one day lead to new clinical therapies for treating glioblastoma, and could lead to further therapies adopting their method for other “undruggable” tumors.
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