Millimeter Precision Non-Invasive Targeted Drug Delivery to Brain

Targeted non-invasive drug delivery to the brain could lead to great advancements in the treatment of psychiatric disorders by enabling circuit- and receptor-specific modulation of regions that drive disease pathology. To this end, we developed ultrasound-controlled drug carriers and designed a unique two component ultrasound sequence that achieves high drug concentration in local brain regions without Blood-Brain Barrier (BBB) opening. We systemically inject the drug loaded carriers, following which our ultrasound sequence repeatedly aggregates and then uncages the drugs in the brain region of interest. As a proof of concept, we test this method in the rat brain where we inhibit information flow from vibrissae sensory cortex (vS1) to vibrissae motor cortex (vM1). We load the ultrasound-controlled drug carriers with muscimol (an ionotropic GABAA receptor agonist) which readily crosses the BBB, we sonicate in vS1 and record evoked neural activity with a penetrating multi-electrode array from vM1. We show that the method requires orders of magnitude less drug than systemic drug delivery to achieve equivalent inhibition in the same brain region and we show that drug delivery is confined to a small area by recording from a cortical circuit which is not involved the information flow between vS1 and vM1. Using MRI contrast agents and Evans Blue dye, which do not cross the intact BBB, we show that we deliver drug without BBB opening. Moreover, we show that Focused Ultrasound and microbubbles assisted BBB (FUS+MBs) opening causes repeated transient seizures at gamma frequency range which are followed by silent periods, revealing more insight into consequences of FUS+MBs assisted BBB opening and further underscoring the concerns regarding its safety. Finally, we introduce an affordable, automated 3D scanning system for measuring skull induced distortions on FUS beam. The system helps in determining pressures used for the FUS sequence that we designed for our drug delivery method and could be used to validate numerical skull models in a fast and reliable manner. Collectively, these works significantly expand on neurotechnologies and basic neuroscience

Non-invasive molecularly-specific millimeter-resolution manipulation of brain circuits by ultrasound-mediated aggregation and uncaging of drug carriers

Non-invasive, molecularly-specific, focal modulation of brain circuits with low off-target effects can lead to breakthroughs in treatments of brain disorders. We systemically inject engineered ultrasound-controllable drug carriers and subsequently apply a novel two-component Aggregation and Uncaging Focused Ultrasound Sequence (AU-FUS) at the desired targets inside the brain. The first sequence aggregates drug carriers with millimeter-precision by orders of magnitude. The second sequence uncages the carrier’s cargo locally to achieve high target specificity without compromising the blood-brain barrier (BBB). Upon release from the carriers, drugs locally cross the intact BBB. We show circuit-specific manipulation of sensory signaling in motor cortex in rats by locally concentrating and releasing a GABAA receptor agonist from ultrasound-controlled carriers. Our approach uses orders of magnitude (1300x) less drug than is otherwise required by systemic injection and requires very low ultrasound pressures (20-fold below FDA safety limits for diagnostic imaging). We show that the BBB remains intact using passive cavitation detection (PCD), MRI-contrast agents and, importantly, also by sensitive fluorescent dye extravasation and immunohistochemistry

Non-invasive molecularly-specific millimeter-resolution manipulation of brain circuits by ultrasound-mediated aggregation and uncaging of drug carriers

Non-invasive, molecularly-specific, focal modulation of brain circuits with low off-target effects can lead to breakthroughs in treatments of brain disorders. We systemically inject engineered ultrasound-controllable drug carriers and subsequently apply a novel two-component Aggregation and Uncaging Focused Ultrasound Sequence (AU-FUS) at the desired targets inside the brain. The first sequence aggregates drug carriers with millimeter-precision by orders of magnitude. The second sequence uncages the carrier’s cargo locally to achieve high target specificity without compromising the blood-brain barrier (BBB). Upon release from the carriers, drugs locally cross the intact BBB. We show circuit-specific manipulation of sensory signaling in motor cortex in rats by locally concentrating and releasing a GABAA receptor agonist from ultrasound-controlled carriers. Our approach uses orders of magnitude (1300x) less drug than is otherwise required by systemic injection and requires very low ultrasound pressures (20-fold below FDA safety limits for diagnostic imaging). We show that the BBB remains intact using passive cavitation detection (PCD), MRI-contrast agents and, importantly, also by sensitive fluorescent dye extravasation and immunohistochemistry.ISSN:2041-172