Scientists at the Rogel Cancer Center at the University of Michigan were hopeful when they discovered a small molecule blocking a major pathway in brain tumors. However, there was a problem: they were not sure how to transport the inhibitor through the bloodstream and into the brain to come in contact with the tumor.
Glioma cells. Image Credit: University of Michigan Rogel Cancer Center
In collaboration with many laboratories, the researchers created a nanoparticle to hold the inhibitor and the results were even better than expected.
Nanoparticles not only transported the inhibitor to the tumor in mouse models, where the drug effectively activated the immune system to destroy the cancer, but also activated the immune memory through the process of removing a reintroduced tumor, a indication that this potential. The new method could treat brain tumors and delay or prevent relapses.
No one could introduce this molecule into the brain. It’s really a big milestone. Outcomes for patients with glioma have not improved over the past 30 years.
Maria G. Castro, Ph.D., Senior Author of the RC Study and Associate Professor of Neurosurgery Schneider, Michigan Medicine
The study was published in the journal ACS Nano.
Despite the gains in survival in many types of cancer, glioma remains a stubborn challenge, with only 5% of patients living five years after diagnosis.
Pedro R. Lowenstein, MD, Ph.D., study author and associate professor of neurosurgery Richard C. Schneider, Michigan Medicine
Gliomas are usually resistant to conventional therapies and the tumor environment dominates the immune system, making new immune-based therapies unproductive. In addition, there is the challenge of crossing the blood-brain barrier and it becomes even more complicated to offer functional treatments to these tumors.
The Castro-Lowenstein laboratory saw an opening. The small molecule inhibitor AMD3100 was created to block the action of CXCR12, a cytokine discharged by glioma cells that forms a buffer around the immune system, preventing it from burning against the invasive tumor.
Scientists demonstrated in glioma mouse models that AMD3100 prevented CXCR12 from binding to immunosuppressive myeloid cells. By demobilizing these cells, the immune system remains intact and can destroy tumor cells.
However, AMD3100 was unable to reach the tumor. The drug did not flow well through the bloodstream and did not cross the blood-brain barrier, a crucial problem with drug transport to the brain.
The Castro-Lowenstein Laboratory worked with Joerg Lahann, Ph.D., Wolfgang Pauli, Professor of Chemical Engineering at UM College of Engineering, to develop protein-centered nanoparticles to close the inhibitor, in the hope of ‘help him travel through the bloodstream.
Castro is also associated with Anuska V. Andjelkovic, MD, Ph.D., a professor of pathology and a professor of neurosurgery research at Michigan Medicine, whose work focuses on the blood-brain barrier. They found that glioma tumors form abnormal blood vessels that obstruct regular blood flow.
The scientists administered the AMD3100-loaded nanoparticles as an injection to mice with gliomas. The nanoparticles contained a peptide on the surface that binds to a protein normally found in brain tumor cells.
As the nanoparticles moved through the bloodstream to reach the tumor, they discharged AMD3100, which restored the functionality of the blood vessels. At that time, the nanoparticles could come into contact with their target, where they discharged the drug, making it difficult for immunosuppressive myeloid cells to invade the tumor mass. This allowed the immune cells to destroy the tumor and slow down its development.
If you do not have blood flow, nothing will reach your goal. That’s why tumors are so smart. But AMD3100 restores the ducts, which is what allows the nanoparticles to reach the tumor.
Maria G. Castro, Ph.D., Senior Author of the RC Study and Associate Professor of Neurosurgery Schneider, Michigan Medicine
Additional studies in mice and patient cell lines showed that coupling the AMD3100 nanoparticle with radiotherapy enhanced the effect beyond just the nanoparticle or radiation.
Among the mice whose tumors were destroyed, the team reintroduced the tumor, mimicking a relapse. Without requiring any additional therapy, 60% of the mice remained cancer-free. This indicates that, similar to a vaccine, AMD3100 formed immune memory, allowing the immune system to detect and kill reintroduced cells. Although he stopped a relapse in mice, Castro explains that it is a good omen to at least delay the relapse in humans.
Each glioma is repeated. It is very important that glioma therapy has this immune memory.
Maria G. Castro, Ph.D., Senior Author of the RC Study and Associate Professor of Neurosurgery Schneider, Michigan Medicine
Preliminary tests revealed little or no impact on renal, hepatic, or cardiac function and regular blood counts in mice after treatment. The nanoparticle has a basis similar to those previously tested in humans and has been shown to be safe. Additional safety tests are needed before moving on to a clinical trial phase.
Funding for this work was provided by grants from the National Institutes of Health R37-NS094804, R01-NS105556, R01-NS122536, R01-NS124167, R21-NS123879-01, R37-NS094804, R051-NS6161, R051-NS6 , R051-NS6161, R051-NS6161, R21-NS123879-01, T32-CA009676, F31CA247104, F31CA247104; Rogel Cancer Center; Michigan Department of Neurosurgery Medicine; Foundation for Pediatric Brain Tumors; Leah’s Happy Hearts Foundation; Ian Friends Foundation; Chad Tough Foundation; Smiles for Sophie Forever Foundation; National Agency for Scientific and Technological Promotion, Argentina; Argentine National Cancer Institute, Financial Assistance IV.
Magazine reference:
Alghamri, MS, et al. (2022) Systemic delivery of a CXCR4-CXCL12 adjuvant signaling inhibitor encapsulated in nanoparticles of synthetic proteins for glioma immunotherapy. ACS Nano. doi.org/10.1021/acsnano.1c07492.
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