Moving toward Noninvasive, Focused Ultrasound Therapeutic Delivery of Drugs in the Brain: Prolonged Opening of Blood-Brain Barrier May Not Be Needed.

D of therapeutic agents across the blood-brain barrier (BBB), especially with spatial selection of the target, has not yet reached mainstream medical care. It requires complex and invasive pharmacologic interventions, such as intra-arterial administration of hypertonic mannitol. The importance of trans-BBB delivery cannot be underestimated. The ability to allow drug delivery into the brain (including nucleic acid and gene delivery vehicles), preferably to particular areas, will have a profound effect on the practices of modern medicine. It will aid in treatment of brain tumors, Alzheimer disease, Parkinson disease, and many other conditions and diseases. Image-guided, focused ultrasound is on the verge of providing transient BBB opening, and the study by Morse et al presented in this issue of Radiology (1) proposes an unexpected yet very simple approach modification that may aid in achieving the desired therapeutic goals. Focused ultrasound ablative treatments in the brain have already reached the clinic. High-power, localized ultrasound hyperthermia under MRI guidance and temperature control is approved for treatment of essential tremor (2) and tremor-dominant Parkinson disease (and is being investigated for several other applications). Image-guided therapy systems capable of focusing ultrasound through the intact skull are now in practical use in many imageguided therapy centers worldwide. In addition to thermal ablation, these focused ultrasound systems may provide localized drug delivery using ultrasound power levels that are orders of magnitude lower than those used in ablative hyperthermia. As a tool for transient BBB opening, focused ultrasound typically results in increased vascular permeability that persists for up to several hours following insonations. Pioneered by Hynynen et al, this procedure includes intravascular administration of gas-filled biocompatible microbubbles, routinely used as blood pool contrast ultrasound imaging agents in the clinic (3). These microbubbles compress and expand upon the action of ultrasound pressure waves. Injected intravenously, the microbubbles, which are smaller than blood cells, pass through all the vasculature, including the vessels and capillaries in the area of the brain where ultrasound is focused on the target tissue. Vascular endothelium is mechanically massaged by the expanding and compressing microbubbles that pass through the vessel lumen. In response to this localized mechanical action, tight junctions between endothelial cells are altered so the BBB stops being an obstacle to drug transport across the vessel wall and therapeutic agents can be delivered to the brain. This mechanical stimulation also results in active transport across the BBB and a reduction in drug efflux. In animal models, success in drug delivery has been exciting. In a rodent model of glioma, 40% of animals receiving BBB opening in combination with intravascular microbubbles and long-circulating doxorubicin liposomes were essentially cured (ie, disease-free for 140 days) (4). The drug (including nanoparticle drug) was likely delivered to the areas where glioma cells were present and active, yet the vasculature there was not sufficiently leaky to allow drug delivery without ultrasound. Delivery of therapeutics to treat Alzheimer disease in a murine model demonstrated reduction of amyloid plaque (5), and clinical testing of the BBB opening has also been initiated (6). In these trials, focused ultrasound was mostly performed under MRI guidance and clearly demonstrated transfer of MRI contrast agent to the brain. Delivery of antitumor agents has also reached clinical trial stage. Early results look promising (7). There is concern that while the BBB is open, other materials besides the therapeutic agent from the bloodstream may enter the brain. These materials (eg, highly abundant serum albumin) may exert some levels of neurotoxicity. Therefore, it may be beneficial to assure effective trans-BBB delivery yet minimize the exposure of the brain to undesirable blood components. In the traditional process of scientific invention, researchers try to find a compromise in which positive results are not overshadowed by undesirable side effects (eg, lower acoustic power and longer pulse length). An alternative, disruptive, and nonlogical methodology from decades ago (8) applies nontraditional designs (known in the USA as Technical Inventive Problem Solving), including a suggestion to “design the system in an opposite direction. ” In the study by Morse et al (1), they have done just that, proposing an alternative version of focused ultrasound application to microbubbles that allows trans-BBB delivery while reducing delivery of undesirable materials (eg, serum albumin). Moving toward Noninvasive, Focused Ultrasound Therapeutic Delivery of Drugs in the Brain: Prolonged Opening of Blood-Brain Barrier May Not Be Needed