Researchers at the University of Toronto are getting closer to realizing a life-saving brain cancer treatment by using gold nanoparticles to make radiotherapy more effective and less toxic for patients.
In their battle against glioblastoma multiforme (GBM), a rare and fast-growing cancer that begins in the brain, the multidisciplinary team discovered that the nanoparticles can keep radiation focused on the tumor, shrinking its size and preventing damage to other parts of the brain. Body. .
Only a handful of researchers worldwide are focused on brain tumor research with radiolabelled nanoparticles.
Radioisotope anchoring in the brain
In animal studies, the use of gold nanoparticles in radiation resulted in tumors that were no longer detectable by MRI four weeks after treatment. The researchers also found evidence of prolonged survival, and a potential cure, after the 150-day trial.
“There is a small group of scientists working on radiation nanomedicines globally, and an even smaller group studying the therapeutic use of radiolabeled gold nanoparticles,” he says. Raymond Reily, a renowned radiopharmaceutical specialist and professor at the Leslie Dan School of Pharmacy who is overseeing the team.
“To my knowledge, we are one of the few groups in the world that has studied the local infusion of radiolabeled gold nanoparticles for the treatment of brain tumors.”
“We use gold nanoparticles to retain the radiation, or radioisotope, where we inject it into the brain,” he says. Constantine Georgiou, a graduate student in the pharmaceutical studies department who works with Reilly.
“Without the gold nanoparticle, the radiation leaves the brain tumor, so it’s not effective.”
The radiation also effectively killed tumor cells without causing any apparent damage to the brain or other body tissues, traveling no more than two millimeters from the injection site. In other words, there appears to be no toxicity associated with the treatment.
To assess the effectiveness of the therapy, Georgiou used innovative imaging techniques such as single-photon emission computed tomography (SPECT), a type of nuclear medicine imaging that allows researchers to visualize where gold nanoparticles are located in the brain, and bioluminescence and MRI to track tumor growth.
The project was initially developed under Noor Al-Saden, one of 10 U of T trainees to participate in the inaugural 2019 PRIME Fellowship Awards, a program to advance high-risk, high-reward multidisciplinary research in precision medicine. PRIME is a U of T Institutional Strategic Initiative (ISI) that connects scientists, engineers, and other innovators from different disciplines to accelerate drug discovery, diagnosis, and understanding of the biology of disease.
Preliminary results from Al-saden’s PRIME research and an initial grant from the Brain Tumor Foundation of Canada helped Reilly’s group win a $200,000 Canadian Cancer Society Innovation Grant.
The development of radiation nanomedicine requires a multidisciplinary approach.
At U of T, the research would not have been possible without the expertise of world-renowned polymer chemist Mitch Winnick, professor in the chemistry department of the College of Arts and Sciences. This is because the radioisotope, in this case lutetium-177, is bound to the gold nanoparticles by a polymer synthesized by Winnik’s group, a substance made up of large molecules with multiple metal-binding sites.
The team’s next phase of research will take place in a new space at U of T: the Good Manufacturing Practices (GMP) facility at the Leslie Dan College of Pharmacy. Made possible by a $1.3 million grant to Reilly from the Canadian Foundation for Innovation and the Ontario Research Fund, the facility opened earlier this year to create radiopharmaceuticals for clinical trials.
Georgiou and Reilly are currently studying radiation nanomedicine combined with immunotherapy to provide a more durable tumor response to treat GBM. The group also plans to study the efficacy of other radioisotopes attached to gold nanoparticles, which can achieve even greater precision in killing cancer cells.
A deeper understanding of energy metabolism in brain disorders by creating ‘mini brains’
Reilly and Georgiou’s research isn’t the only innovative brain-focused project supported by PRIME.
research by Angela DuongA U of T alumnus and 2019 PRIME Fellow, she developed 2D and 3D brain models of patients to gain insights into the role that mitochondrial function plays in neural activity, specifically in patients with bipolar disorder.
working together ana cristina andreazza – professor in the departments of pharmacology and toxicology and psychiatry at the Temerty School of Medicine, with a cross-appointment at the Center for Addiction and Mental Health – Duong built 3D in vitro brain cell cultures, also known as brain organoids, to identify biological targets that can be used to guide the development of treatments. In doing so, Duong overcame longstanding obstacles to understanding the biology of patients with psychiatric disorders, as researchers previously relied on two limited avenues for research: postmortem brain samples, which are in short supply, and brain imaging technologies that they are expensive and may require radioactive exposure. .
Duong describes his brain organoids as “mini-brains” that retain patients’ genetic backgrounds, allowing researchers to study specific human processes that might be related to patients’ clinical diagnoses. She says this tool is useful for modeling diseases compared to brain samples from animals that don’t carry the complex human genes that cause psychiatric disorders.
“In the brain, 20 percent of our body’s total energy budget is used to support neurotransmission. This is an energy-intensive process that allows brain cells to communicate with each other, Duong says. “So if there is metabolic dysfunction in the brain, the neurotransmission process is also affected, which we think is related to the symptoms and mood swings that we commonly see in patients with psychiatric disorders.”
“By developing ‘mini-brains’ to function as disease models, we can learn what metabolic changes are occurring in the brains of real brain disease patients without invasive brain biopsies or by studying the brains of mice or rats.”
To do this, Duong collected blood samples from patients with and without bipolar disorder and isolated their white blood cells. The cells were then reprogrammed into induced pluripotent stem cells (iPSCs), a stem cell that can be generated directly from a somatic cell, any cell in a living organism that is not reproductive. Using these iPSCs, Duong later created 2D and 3D brain cells or organoids.
Duong’s project was one of the first to fully characterize brain mitochondrial health, from white blood cells to iPSCs to brain organoids. That, in turn, offered validation as to whether mitochondria remain healthy during the process of reprogramming and differentiation. This study provides an important foundation for creating more sophisticated 2D and 3D patient brain cells for disease modeling and the study of mitochondrial dysfunction in a wide range of brain diseases.
The achievement required the multidisciplinary collaboration of three different U of T labs.
In addition to Andreazza’s lab, the PRIME project incorporated the expertise of two professors from the Temerty School of Medicine to work on 3D engineered organoids: Liliana Attisanoprofessor of biochemistry at the Temerty School of Medicine and the Donnelly Center for Cellular and Biomolecular Research, and Martin Beaulieuassociate professor in the department of pharmacology and toxicology at the Temerty School of Medicine.
Building self-developed brain cells
Organoid production relies on the self-organizing properties of the cell to develop the required cell types.
The goal of Attisano’s lab was to develop protocols for producing brain organoids that were all the same size and shape to decrease variability, making it easier for researchers to find the answers to their questions. To achieve this, the researchers added growth factors or inhibitors that moved the cells to a neuronal lineage. After that, the cells divided and developed for about a month, just as they would in a human brain. The lineage can also be modified to make organoids for other parts of the body, such as the liver.
Meanwhile, Beaulieu’s lab provided equipment and resources to characterize the electroactivity of neurons within the organoids.
Andreazza is now using Duong’s technological model to further develop brain organoids to further investigate a variety of psychiatric conditions.
Meanwhile, Attisano is making brain organoids available to Toronto researchers with an organoid production platform called the Applied Organoid Core (ApOC), funded by the Brain Canada Foundation’s 2019 Platform Support Grant and the Medicine by Strategic Initiative. U of T Design ApOC is a $1,425,000 grant. Through this project, Attisano is collaborating with other researchers who want to use brain organoids to map human brain development and disorders such as epilepsy.
“When it comes down to it, brain disorders are simply a type of alteration in molecular components that result in altered behavior. It is no different than a mutation that makes you susceptible to cancer. But we never had the ability to study this,” says Attisano.
“Brain organoids give us that potential.”
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