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A New Glioblastoma Nanomedicine crossed in-vivo Blood-Brain Barrier

University of Michigan researchers have announced that they have produced a new synthetic protein nanoparticle capable of passing directly to malignant brain tumours via the nearly impermeable blood-brain barrier (BBB) in mice that could deliver cancer-killing drugs.

Their results, "Systemic brain tumor delivery of synthetic protein nanoparticles for glioblastoma therapy", are published in the journal Nature Communications headed by Joerg Lahann, PhD, Wolfgang Pauli College Professor of Chemical Engineering, and Maria Castro, PhD, R.C. Schneider College of Neurosurgery professor.

"Inspired by the ability of natural proteins and viral particles to cross the BBB, we developed a polymerized human serum albumin (HSA)-based synthetic protein nanoparticle (SPNP) equipped with the cell-penetrating peptide iRGD," the researchers wrote.

The BBB consists of a layer of endothelial cells that line the blood vessels in the brain, allowing only selected kinds of molecules to flow through the fluid surrounding the neurons and other brain cells from the bloodstream. Many small molecule drugs and macromolecules, such as peptides, proteins, and gene-based drugs, are prohibited from being transferred by the BBB, which has restricted the treatment of CNS diseases such as neurodegenerative disorders, brain tumours, brain infections and stroke. While the blood-brain barrier in the core portion of glioblastomas (GBMs) is known to be leaky, the successful passage of cancer therapeutics, including small molecules and antibodies, is still prevented.

One of the most prevalent, lethal, and difficult-to-treat adult brain tumours is glioblastoma. The current modality of treatment is surgical removal of the tumour, followed by radiotherapy and administration of temozolomide (TMZ), but this regimen only increases overall patient survival. For glioblastoma patients, the current median survival (MS) is around 18 months; the overall five-year survival rate is below 5 percent.

The researchers injected therapy intravenously in conjunction with radiation, and reported long-term survival in seven out of eight mice. When those seven mice experienced a glioblastoma recurrence, their immune responses kicked in without any additional chemotherapy medications or other clinical procedures to prevent the cancer's regrowth.

Lahann, a co-senior author of the report, said, "It is still a bit of a miracle to us." Where we would have expected to see some tumour growth levels, when we challenged the mice, they just did not shape. I've worked for more than 10 years in this area and haven't seen anything like this.

Immunological memory has also benefited from the combination of therapeutic drugs and nanoparticle delivery methods.

"This is an enormous step towards clinical adoption," Castro said. "This is the first research to show the ability to systemically or intravenously administer therapeutic drugs that can also cross the blood-brain barrier to meet tumours."

Castro knew, five years ago, how she decided to target glioblastoma. She tried to avoid a signal sent out by cancer cells, known as STAT3, to trick immune cells into allowing them to pass through the brain safely. Yet she had no means of getting over the blood-brain barrier.

At the Biointerfaces Institute, which Lahann leads, Castro attended a workshop and the two discussed the issue. Lahann's team started working on a nanoparticle that could ferry the blood-brain barrier past a STAT3 inhibitor.

As the structural building block for their nanoparticles, Lahann's team used a protein named human serum albumin, which is one of the few molecules that can cross the blood-brain barrier. In order to bind these proteins, they used synthetic molecules and then attached the STAT3 inhibitor and a peptide called iRGD, which serves as a tumour homing system.

GBM-bearing mice were treated intravenously with several doses of STAT3i SPNPs over a three-week treatment regimen to further assess the efficacy of SPNPs in vivo, the researchers noted. The MS of untreated mice after tumour implantation was 28 days or so. MS remained unaltered (28 days) in mice that received repeated doses of empty SPNPs. In comparison, the MS increased to 41 days, a statistically significant increase of 45 percent, when SPNPs loaded with STAT3i were given. The delivery of the same doses of free STAT3i resulted in a modest 5-day extension of MS, which is possibly too poor to have a meaningful therapeutic effect. Besides the failure of siRNA to cross the BBB, the poor efficacy of free STAT3i can be explained by the rapid degradation of genetic material following systemic administration.

Seven out of eight mice achieved long-term survival and appeared to be fully tumor-free, with no evidence of invasive malignant tumour cells.

Their study is the first to reveal an intravenous drug that can cross the blood-brain barrier. The discovery may one day lead to new therapeutic therapies for the treatment of glioblastoma and may lead to more therapies for other "undruggable" tumours implementing their process.

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