Summary: To breach the blood-brain barrier without invasive surgery, the team utilized MRI-guided focused ultrasound (FUS) combined with systemic microbubbles. The focused sound waves temporarily and non-invasively open tight endothelial junctions in target brain regions, allowing the miRNA-bearing nanoparticles to permeate the tumor microenvironment.
In preclinical glioblastoma models, this targeted delivery system significantly slowed tumor progression and extended overall survival, establishing a versatile delivery blueprint for brain cancers and central nervous system disorders.
Key Facts
- Multi-Gene RNA Interference: Unlike small-molecule drugs that target a single mutated protein, therapeutic miRNAs can suppress dozens of malfunctioning, driver genes simultaneously, preventing glioblastoma cells from developing single-pathway resistance.
- Non-Invasive BBB Opening: MRI-guided focused ultrasound uses targeted acoustic waves to oscillate circulating microbubbles within brain microvessels, temporarily opening endothelial tight junctions for localized drug delivery.
- Brain-Penetrating Nanoparticle Optics: The miRNA payloads are encapsulated within custom brain-penetrating nanoparticles engineered to traverse dense extracellular matrix spaces within brain tissue without triggering immediate clearance.
- Preclinical Efficacy: In animal models of glioblastoma, the combined FUS-nanoparticle-miRNA regimen achieved high intratumoral accumulation, suppressed multi-gene oncogenic signaling, delayed tumor progression, and prolonged survival.
- Broad Translational Scope: Beyond glioblastoma, this non-invasive delivery platform holds therapeutic implications for other primary and metastatic brain tumors, as well as neurodegenerative conditions restricted by the blood-brain barrier.
Source: UVA
University of Virginia Comprehensive Cancer Center scientists have developed a promising new experimental approach to targeting glioblastoma, the most common and deadliest brain cancer. The approach could overcome many of the limitations of treatments using existing drugs.
UVA’s Roger Abounader, MD, PhD, and colleagues have identified “microRNAs” that can simultaneously suppress multiple malfunctioning genes responsible for glioblastoma’s formation and growth. The scientists use a combination of brain penetrating nanoparticles, focused ultrasound waves and microbubbles to deliver the miRNAs through the brain’s natural protective barrier – a barrier that typically blocks treatments for tumors and neurodegenerative diseases.
“This new approach could help target numerous molecules that promote cancer growth, including those for which no drugs exist, at the same time to achieve better therapies,” said Abounader, a professor at UVA’s School of Medicine, Department of Microbiology Immunology and Cancer Biology, Comprehensive Cancer Center and Center for RNA Science and Medicine. “We are hoping to translate our findings into future clinical trials for patients with glioblastoma and other brain tumors.”
Treating Glioblastoma
Glioblastoma is the most common and aggressive malignant brain tumor in adults, killing more than 13,000 people in America alone every year. It is difficult to treat because the tumors thread their way through healthy brain tissue, making them extremely hard to remove. Meanwhile, the natural “blood-brain barrier” that protects the brain from infections and toxins also keeps out anti-tumor drugs.
Doctors now typically remove as much of the cancer as they can with surgery, then use radiation and chemotherapy to help patients survive as long as possible.
By using miRNA – tiny molecules of genetic material – Abounader’s approach would let doctors suppress the effects of multiple faulty genes at one time. This would slow or stop tumor growth by blocking the genes driving the cancer. Attempting to target multiple genes with existing treatments is complicated by the toxicity caused by combining multiple cancer drugs and by the fact that many molecules do not have drugs that target them.
Abounader would direct the miRNA to the brain using focused ultrasound guided by magnetic resonance imaging (MRI). The highly focused sound waves guide tiny “microbubbles” to open the blood-brain barrier just long enough for the miRNA nanoparticle carriers to make their way through.
Testing their approach in the lab, Abounader and his team found that the miRNA was effective at slowing tumor growth and extending survival in glioblastoma animal models. More research will be needed before the approach could be tested in people, but Abounader says the results are a positive indicator for the approach’s potential not just for glioblastoma but for other cancers as well.
“This approach could have broad applications for several brain and other human diseases,” Abounader said. “We and many others are intensively working to lighten the burden of cancer, and hopefully also completely cure it, but this requires a continued investment in cancer and medical research.”
Focused Ultrasound at UVA
UVA Health was one of the earliest pioneers in the field of focused ultrasound. UVA’s expertise with the technology has led to a robust research program examining the use of focused ultrasound to treat many different conditions.
The technology’s tremendous promise prompted UVA and the Charlottesville-based Focused Ultrasound Foundation to launch the Focused Ultrasound Immuno-Oncology (FUSION) Center, the world’s first center dedicated specifically to exploring the benefits of combining focused ultrasound with cancer immunotherapy. Experts hope the treatment approach could revolutionize cancer care for the 21st century.
Finding new ways to improve patient care is a core mission of both UVA Comprehensive Cancer Center and UVA’s Paul and Diane Manning Institute of Biotechnology. UVA Comprehensive Cancer Center is one of only 57 cancer centers in the country to earn the elite “comprehensive” designation from the National Cancer Institute in recognition of their exceptional patient care and cutting-edge cancer research.
The Manning Institute, meanwhile, has been launched to accelerate the development of new drugs and cures for the most complex and challenging diseases. This is being complemented by a statewide clinical trials network that expands access to potential new treatments as they are developed and tested.
Findings Published
Abounader and his colleagues have described their approach and the results of their initial lab testing in JCI, the Journal of Clinical Investigation. The article is open access, meaning it is free to read.
The research team consisted of Shekhar Saha, Ying Zhang, Myron K. Gibert Jr., Collin Dube, Farina Hanif, Elizabeth Qian Xu Mulcahy, Sylwia Bednarek, Yunan Sun, Pawel Marcinkiewicz, Xiantao Wang, Gijung Kwak, Ahsan H. Polash, Haolin Li, Kadie Hudson, Manikarna Dinda, Tapas Saha, Matthew McCord, Fadila Guessous, Nichola Cruickshanks, Rossymar Rivera Colon, Lily Dell’Olio, Rajitha Anbu, Wenjie Liu, Songy Choi, Benjamin Kefas, Pankaj Kumar, Alexander L. Klibanov, David Schiff, Jung Soo Suk, Justin Hanes, Jamie Mata, Markus Hafner and Abounader.
The scientists have no financial interest in the work.
Funding: The research was supported by the National Institutes of Health’s National Cancer Institute, grants U01 CA220841 and P30 CA044579; the NIH’s National Institute of Neurological Disorders and Stroke, grants R01 NS122222 and R21 NS122136; a UVA Comprehensive Cancer Center pilot grant; a Schiff Foundation grant; the Ben and Catherine Ivy Foundation; and the Focused Ultrasound Foundation.
Key Questions Answered:
A: Glioblastoma cells invade surrounding healthy brain tissue along blood vessels and nerve tracts, preventing complete surgical removal. Furthermore, the blood-brain barrier acts as a physical shield, blocking more than 98 percent of small-molecule drugs and nearly 100 percent of large macromolecular therapies from entering the brain.
A: Focused ultrasound concentrates low-frequency sound waves onto a precise target area inside the brain under real-time MRI guidance. When these sound waves interact with microscopic, gas-filled microbubbles injected into the bloodstream, the bubbles expand and contract rhythmically, gently pushing apart the endothelial cells lining the blood vessels for a brief window without causing permanent tissue damage.
A: Traditional drugs usually target only one specific mutated protein, allowing aggressive cancers like glioblastoma to quickly mutate and bypass the drug. A single microRNA molecule can bind to and suppress multiple mRNA targets at once, effectively shutting down several redundant cancer growth pathways simultaneously.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this brain cancer and neurotech research news
Author: Josh Barney
Source: UVA
Contact: Josh Barney – UVA
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Discovery and therapeutic delivery of microRNAs targeting deregulated glioblastoma pathways inhibits tumor growth in mice” by Shekhar Saha, Ying Zhang, Myron K. Gibert Jr., Collin Dube, Farina Hanif, Elizabeth Qian Xu Mulcahy, Sylwia Bednarek, Yunan Sun, Pawel Marcinkiewicz, Xiantao Wang, Gijung Kwak, Ahsan H. Polash, Haolin Li, Kadie Hudson, Manikarna Dinda, Tapas Saha, Matthew McCord, Fadila Guessous, Nichola Cruickshanks, Rossymar Rivera Colon, Lily Dell’Olio, Rajitha Anbu, Wenjie Liu, Songy Choi, Benjamin Kefas, Pankaj Kumar, Alexander L. Klibanov, David Schiff, Jung Soo Suk, Justin Hanes, Jamie Mata, Markus Hafner, Roger Abounader. JCI
DOI:10.1172/JCI195639
Abstract
Discovery and therapeutic delivery of microRNAs targeting deregulated glioblastoma pathways inhibits tumor growth in mice
Glioblastoma is a fatal primary malignant brain tumor, with an average survival of 15 months despite surgical resection, chemotherapy, and radiation therapy. Due to the concurrent deregulation of numerous genes in glioblastoma, molecular monotherapies have not improved clinical outcomes.
Evidence suggests that targeting multiple deregulated molecules is essential for better therapies; however, this is limited by the lack of suitable drugs and increased toxicity of combination therapies.
To address this, we hypothesized that miRNAs, small gene-regulatory RNAs that suppress mRNA, could simultaneously inhibit multiple deregulated genes in glioblastoma, and be used for more effective therapies.
We identified regulatory miRNAs — those that target several deregulated genes in glioblastoma — using a combination of PAR-CLIP screening, TCGA data analyses and an algorithm to rank target importance and miRNA therapeutic potential.
We selected two tumor suppressor miRNAs, miR-340 and miR-382, and one oncogenic miRNA, miR-17 and showed that they target critical glioblastoma pathways and alter cell growth, survival, invasion, and in vivo tumor growth.
We developed and successfully applied a miRNA therapeutic delivery approach using Brain Penetrating Nanoparticles combined with MRI-guided focused ultrasound and microbubbles, to inhibit established tumor growth and to extend animal survival.
This strategy offers a promising approach for translating miRNA-based therapies into clinical trials for glioblastoma and other cancers.
