University of Michigan Rogel Cancer Center scientists were optimistic when they discovered a small molecule that blocked key pathways in brain tumors. However, one problem was how to get inhibitors through the bloodstream and into the brain to reach the tumor.
Collaborating with multiple laboratories, the team of researchers was able to fabricate a nanoparticle containing the inhibitor, with results in mouse models exceeding expectations.
Inhibitor Prevents the Shielding of Tumor Cells
Not only did the novel nanoparticles deliver the inhibitor to brain tumors in mouse models, where the drug was able to turn the immune system to eliminate cancer successfully, but the process also was able to rigger immune memory so that a reintroduced tumor was eliminated efficiently - a sign that the novel approach could both treat and prevent or delay brain tumors, reports PhysOrg.
Maria G Castro, Ph.D., lead author of the study and an R.C Schneider Collegiate Professor of Neurosurgery at the Michigan Medicine, says that no one before could get the molecule into the brain. Saying that the study is a milestone, especially considering that outcomes for glioma patients have not improved over the last 30 years.
Pedro Lowenstein, M.D., Ph.D., author of the study, adds that despite survival gains in various cancer types, glioma remains challenging, with only 5% of patients living five years past their diagnosis.
Traditional therapies are often insufficient for gliomas; the environment inside the tumor can suppress the immune system, rendering new immune-based therapies invalid. Adding to the challenges of passing the blood-brain barrier, delivering effective treatments to brain tumors becomes more difficult.
This is where the Castro-Lowenstein lab saw an opportunity. The small inhibitor known as AMD3100 was developed to block the action of a cytokine released by glioma cells that shields the immune system - CXCR12, which prevents the immune system from firing up against the invasion of tumor cells.
Researchers demonstrated via mouse glioma models that the inhibitor prevented the cytokine from binding with immune-suppressive myeloid cells. By disarming these cytokine cells, the immune system remains intact and can effectively attack the tumor cells.
A key issue now was getting the drug into the brain. The inhibitor alone has trouble getting to the tumor, and the drug did not travel through the bloodstream nor pass the blood-brain barrier.
Nanoparticles a Key Mode of Delivering Inhibitors to Gliomas
In collaboration with Joerg Lahann and Wolfgang Pauli, the Castro-Lowenstein lab developed a protein-based nanoparticle that can encapsulate the inhibitor in hopes of helping the drog pass through the bloodstream and reach the tumor.
In the study published in the journal ACS Nano, titled "Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy," researchers injected AMD3100-loaded nanoparticles into mice models with gliomas. The nanoparticles contained peptide on their surface that binds proteins found mostly on the brain tumor cells. As it traveled through the bloodstream to the tumor, it released the inhibitor, restoring the integrity of the blood vessels. The nanoparticles could reach their target, where the drug would be released, blocking the entry of immune-suppressive myeloid cells into the tumor mass. This method allowed the immune cells to kill the glioma and delay its progression.
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