Microbubble Dose Optimization for Image-Guided Drug Delivery

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The development of new pharmaceuticals for the treatment of brain cancer and neurological disease has outpaced our ability to deliver them safely, largely due to the blood-brain barrier (BBB). Bypassing the BBB to access the brain parenchyma is often highly invasive, involving surgery to remove part of the skull and needle insertion directly into the brain tissue, resulting in lasting damage and significant costs. An alternative, microbubble-assisted focused ultrasound (MB+FUS), is a promising noninvasive, image-guided method of BBB disruption (BBBD) currently undergoing three human clinical trials. MB+FUS induces transient openings in the BBB via acoustically mediated pulsation of 1-10 µm diameter intravenously delivered gas-filled microbubbles, allowing for targeted drug delivery to brain regions as small as 2-3 mm diameter. The safe dosage of these microbubbles has become central to the polarizing debate that is ongoing in the MB+FUS community, and is critical to clinical translation. With recent findings indicating acute sterile immune response (SIR) after MB+FUS BBBD, elucidating the relationship between microbubble dose, pharmacokinetics (PK), ultrasound mechanical index, and MB+FUS-associated tissue effects has become essential. Efforts to do so, however, have been confounded by the product-to-product and batch-to-batch variations in the size, concentration and composition of commercially available microbubble ultrasound contrast agent formulations. Using size-isolated microbubbles (SIMBs) of different monodisperse sizes and uniform composition, our team of researchers at the University of Colorado and NIDA recently discovered that microbubble dosing can be simplified by unifying size and concentration into a single parameter: microbubble volume dose (MVD), which trends linearly with key figures-of-merit for microbubble PK and BBBD magnitude. In this project, we will investigate this effect further in order to create a clear framework for comparing results prospectively and retrospectively between studies performed by different laboratories and different microbubble agents. In Aim 1, we will test the hypothesis that figures-of-merit for PK scale linearly with MVD for FDA-approved ultrasound contrast agents currently used in human clinical trials and most preclinical research, as well as our own SIMBs. We will extend this research to establish a therapeutic window between the minimum MVDs to produce BBBD and acute SIR. In Aim 2, we will test the hypothesis that the minimum MVD required for successful BBBD decreases with increasing mechanical index (MI), which is a unifying ultrasound parameter incorporating frequency and amplitude. The robustness of this relationship will be explored by examining effects of microbubble size (using SIMB), ultrasound frequency and molecular weight of the model drug. Finally, in Aim 3, we will establish a therapeutic window between BBBD (efficacy) and acute SIR (safety) on a diagram of MVD vs. MI, which will help researchers and clinicians in the field to choose appropriate ultrasound and microbubble dose settings for safe BBBD by MB+FUS, and to guide their procedures.