Localized delivery and uncaging of glutamate from MRI-visible albumin nanoclusters in the rat hippocampus using focused ultrasound

Academic Article

Abstract

  • Abstract Neuropharmacological manipulations have been crucial for advancing fundamental neuroscience and elucidating the relationship between neurotransmitter function, channel kinetics, cellular signaling and behavior. However, systemic delivery of neuropharmacological agents can produce off-target effects that outweigh clinical benefit and confound preclinical results, preventing such interventions from reaching their full potential as therapeutic drugs and tools for research. Localization to specific brain regions requires injections, cannulae, pumps, or other invasive methods that can damage tissue and complicate or prevent translation to humans. Focused ultrasound (FUS) mediated blood-brain barrier (BBB) opening (BBBO) can deliver agents to specific brain regions non-invasively without damaging tissue. FUS can be targeted anywhere in the brain to open the BBB with high spatial resolution, but the use of BBB impermeable agents for localized delivery lacks temporal control, and circulating drugs can still cause systemic effects. Encapsulation of drugs prevents them from acting in non-target areas, and release from the capsules can provide temporal control. Here we demonstrate that MRI visible, albumin-based nanoclusters (NCs) can be used to encapsulate neuromodulators for non-invasive delivery to target rat brain regions via FUS facilitated BBBO. Glutamate and NBQX showed a very low baseline release rate from IV injected NCs. The NCs diffused locally into the brain with FUS facilitated BBBO and provided enhanced MRI contrast at the delivery site. Drug release into brain tissue was triggered by a second FUS treatment (FUS-release) using different parameters from the FUS used for BBBO. Furthermore, FUS-release caused a change in MRI contrast and provided in vivo confirmation of drug release. Using FUS, dye was locally released from NCs 30 minutes after delivery and release of dye into target brain regions was observed 24 hrs after delivery. The drug loading capacity of the NCs was sufficient for inducing localized changes in neural activity in response to glutamate release from NCs in vivo.
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    Author List

  • Rich M; Sherwood J; Bartley A; Willoughby WR; Dobrunz L; Lubin F; Bao Y; Bolding M