Key Points
- Researchers summarized the current use of focused ultrasound for delivering drugs across the blood-brain barrier for the treatment of gliomas.
- The team analyzed 60 published studies plus 13 clinical trials, for a total of 73 projects.
A collaborative team of French researchers have conducted a comprehensive review of preclinical and clinical studies to summarize the varying approaches of using focused ultrasound to deliver anticancer drugs across the blood-brain and blood-tumor barriers (BBB, BTB) for the treatment of glioma.
Glioblastoma (GBM) is the most common glioma and occurs in 3 per 100,000 people annually in developed countries, is not curable, and has a grim prognosis (a 5-year survival rate of less than 10%) that has remained unchanged for more than 30 years.
The researchers found several approaches in use to deliver drugs to glioma with focused ultrasound, including the delivery of free drugs, drug-loaded microbubbles, and drug-loaded nanocarriers. They discussed each approach in detail followed by the current state of clinical trials, devices being used, and the challenges that are preventing clinical translation.
60 Published Studies
The team analyzed 60 published studies (51 preclinical and 9 clinical trials). Among these, there were 29 that delivered free drugs (22/29 preclinical), 22 that employed drug-loaded nanoparticles (20/22 preclinical), and 9 that used drug-loaded microbubbles (all preclinical). Both large- and small-molecule anticancer agents have been delivered, including conventional chemotherapies, monoclonal antibodies, immunotherapies, and modified cell-based therapies. These various therapies were introduced via intravenous bolus, intravenous infusion, intraperitoneal injection, orally, intranasally, or intra-gastrically.
13 Ongoing Clinical Trials
Searching clinicaltrials.gov revealed 13 GBM additional clinical trials, six of which have published data. The authors found that the safety and feasibility of using focused ultrasound BBB disruption (FUS-BBBD) has been established for different devices, repeated sessions, and different chemotherapies in patients with newly diagnosed GBM, recurrent GBM, and high-grade gliomas.
The five focused ultrasound devices that are currently being used in clinical trials for BBBD are ExAblate Neuro® (InSightec), NaviFUS® (NaviFUS), a Columbia University device now called Delsona, the SonoCloud-1®, and the SonoCloud-9® (CarThera). Three of these systems use imaging guidance, including MRI for ExAblate Neuro and neuronavigation for NaviFUS and Delsona. The two Carthera systems do not use image guidance because they are surgically implanted into the skull, providing intracranial, unfocused sonications.
Intracerebral/Tumor Drug Accumulation
Sonicated healthy brain or tumor compared with non-sonicated contralateral hemisphere (healthy brain or brain without tumor)
Importantly, the authors found that using focused ultrasound for BBBD improved the intracerebral concentration of anticancer therapies in both healthy brains (a 1.4- to 16.6-fold increase) and in glioma models (a 1.6- to 8-fold increase) compared with the non-sonicated contralateral hemisphere. In glioma models, focused ultrasound increased the delivery of the therapeutic agents in the healthy contralateral hemisphere, averaging 4.2-fold for small molecules and small targeted therapies, and 3.6-fold for larger monoclonal antibodies.
Sonicated brain tumor compared with non-sonicated contralateral tumor
Furthermore, transient focused ultrasound BBB disruption also improved the concentration of anticancer therapies in brain tumors when compared with non-sonicated tumors (a 1.4- to 13.9-fold increase). As might be expected, this increase was higher for small molecules (5.2-fold) than for monoclonal antibodies (3.7-fold).
Comments from the Study
When summarizing their findings throughout the manuscript, the research team made the following statements:
- Improving the accumulation of drugs in tumors slows tumor progression and improves median survival time.
- Antibodies are large molecules, but they have a lower toxicity profile, spend more time in circulation, and are retained longer in tumors than chemotherapy.
- Targeting membrane proteins with microbubbles may be more beneficial than loading microbubbles with drugs.
- The best drug delivery carriers might be those that are small enough to cross the BBB after focused ultrasound BBBD but large enough to avoid rapid clearance by the kidneys (e.g., small nanoparticles are rapidly eliminated from the bloodstream, so they may not be the best candidates for drug delivery).
- FUS-BBBD with drug delivery is complex and depends on the rodent model used, tumor growth stage, anticancer drug, route of drug administration, therapeutic schedule, time interval between animal grafting and first treatment, timing between the focused ultrasound application and drug administration, type/concentration of microbubble, and focused ultrasound parameters.
- More thorough evaluation of various drug delivery protocols is needed to refine therapeutic strategies and design clinical trials.
- Further immunomodulation preclinical studies are needed before translating these focused ultrasound strategies to clinical trials.
- Investigations could also focus on the development of antibody-drug conjugates, a promising new emerging therapeutic class, which have not yet been studied with FUS-BBBD in gliomas.
“This article highlights the incredible past and ongoing interest in researching how focused ultrasound can potentially make a difference in the care of patients with gliomas by increasing the amount of therapeutics delivered to specific parts of the tumor and surrounding margins,” says Suzanne LeBlang, MD, the Foundation’s Director of Clinical Relationships. “The timing of this recent publication is a perfect summary of the state of the field in preparation for our upcoming workshop, March 6–7, 2024, in Arlington, Virginia, titled ‘Bench to Bedside: Opportunities to Open the BBB for Therapeutic Delivery and Liquid Biopsy for GBM,’ held jointly by the Focused Ultrasound Foundation and the Sontag Foundation.”