Focused ultrasound in conjunction with circulating microbubbles is an investigational, noninvasive drug delivery method that crosses biologic barriers such as blood-brain or blood-tumor. To date, the success of this method has been measured by a contrast-enhanced magnetic resonance imaging scan with a gadolinium-based contrast agent, which provides invaluable information about the location and extent of blood-brain barrier opening. However, this method does not provide a quantifiable estimate of drug delivery enhancement. In a Lancet Oncology article, Dr Antonios Pouliopoulos from King’s College of London, UK, discussed recent clinical evidence of an increase in drug delivery by up to 6 times with an implantable ultrasound device and microbubbles in patients with glioblastoma. In this phase I trial, serial biopsy samples showed an increase in brain tissue concentration of chemotherapy in areas treated with ultrasound. The inclusion of biopsies in addition to gadolinium enhancement provides key evidence for further translation and adoption of ultrasound therapy for drug delivery.
Dr Pouliopoulos listed multiple advantages of this technology, the greatest being that ultrasound treatment can be done during resection surgery, facilitating in-line serial measurements of drug concentration and pharmacokinetics in peritumoral regions. He also stated that the fixed treatment volume of the implanted device helps simplify the clinical workflow and minimizes potential positioning errors that may arise with alternative approaches. The low cost and simplicity of this treatment regimen increase its potential to be implemented in a variety of health systems, including in underresourced environments with limited access to medical imaging systems.
Currently, an implantable ultrasound device for drug delivery has a fixed treatment volume. Disease progression may occur with tumor volume increase and changes in vascular density, and metastases may occur outside the treatment envelope. Additionally, the number of microbubbles exposed to the ultrasound beam is likely to change over time with the evolution of the vascular network. The author suggested that future developments should include personalization and adaptability of treatment, with the device design modified to allow for electronic focus on different brain regions. If the footprint of the current 9-element device, which covers a large part of the skull, could be reduced, the risk of morbidity or infection would also be lessened, and adoption of the technology may become more widespread.
Further research is needed to measure the impact of ultrasound-mediated drug delivery on progression-free and overall survival. However, given the ethical barriers of active control trials in this patient population, constant interaction between academia, industry, and regulatory authorities is essential to overcome the challenges and support further research of drug delivery enhancement. Dr Pouliopoulos suggested that implantable transducers may also have future application in the treatment of other brain diseases, such as Alzheimer or Parkinson disease. More research is needed to explore whether agents considered to have inadequate efficacy in clinical trials due to their inability to cross the blood-brain barrier, such as antibodies and liposomes, might be reused in conjunction with ultrasound treatments.
While studies have shown increased drug concentration following ultrasound treatment, current evidence is not yet sufficient for clinical adoption of drug delivery enhancement technology. Future studies are needed to determine whether ultrasound-mediated drug delivery increases survival, but given the ethical barriers of active control trials in this patient population, both patient and public involvement will be needed to support further research and advancement.