Theranostic Strategy of Focused Ultrasound Induced Blood-Brain Barrier Opening for CNS Disease Treatment

Adequate supply of blood and structural and functional integrity of blood vessels is key to normal brain functioning. On the other hand, cerebral blood flow (CBF) shortfalls and blood-brain barrier (BBB) dysfunction are early findings in neurodegenerative disorders in humans and animal models. Here, we first examine molecular definition of cerebral blood vessels, and pathways regulating CBF and BBB integrity. Then, we examine the role of CBF and BBB in the pathogenesis of Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis. We focus on AD as a platform of our analysis because more is known about neurovascular dysfunction in this disease than in other neurodegenerative disorders. Finally, we propose a hypothetical model of AD biomarkers to include brain vasculature as a factor contributing to the disease onset and progression, and suggest a common pathway linking brain vascular contributions to neurodegeneration in multiple neurodegenerative disorders.

The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain.

Ultrasound contrast agents, in the form of gas-filled microbubbles, are becoming popular in perfusion monitoring; they are employed as molecular imaging agents. Microbubbles are manufactured from biocompatible materials, they can be injected intravenously, and some are approved for clinical use. Microbubbles can be destroyed by ultrasound irradiation. This destruction phenomenon can be applied to targeted drug delivery and enhancement of drug action. The ultrasonic field can be focused at the target tissues and organs; thus, selectivity of the treatment can be improved, reducing undesirable side effects. Microbubbles enhance ultrasound energy deposition in the tissues and serve as cavitation nuclei, increasing intracellular drug delivery. DNA delivery and successful tissue transfection are observed in the areas of the body where ultrasound is applied after intravascular administration of microbubbles and plasmid DNA. Accelerated blood clot dissolution in the areas of insonation by cooperative action of thrombolytic agents and microbubbles is demonstrated in several clinical trials.