Localized anesthesia of a specific brain region using ultrasound-responsive barbiturate nanodroplets.

Background: Targeted neuromodulation is a valuable technique for the study and treatment of the brain. Using focused ultrasound to target the local delivery of anesthetics in the brain offers a safe and reproducible option for suppressing neuronal activity. Objective: To develop a potential new tool for localized neuromodulation through the triggered release of pentobarbital from ultrasound-responsive nanodroplets. Method: The commercial microbubble contrast agent, Definity, was filled with decafluorobutane gas and loaded with a lipophilic anesthetic drug, before being condensed into liquid-filled nanodroplets of 210 ± 80 nm. Focused ultrasound at 0.58 MHz was found to convert nanodroplets into microbubbles, simultaneously releasing the drug and inducing local anesthesia in the motor cortex of rats (n=8). Results: Behavioral analysis indicated a 19.1 ± 13% motor deficit on the contralateral side of treated animals, assessed through the cylinder test and gait analysis, illustrating successful local anesthesia, without compromising the blood-brain barrier. Conclusion: Pentobarbital-loaded decafluorobutane-core Definity-based nanodroplets are a potential agent for ultrasound-triggered and targeted neuromodulation.

Introduction

Purpose Drug delivery WITHOUT BBB opening

Study Objective To develop a tool for localized neuromodulation by triggering pentobarbital release from ultrasound-responsive nanodroplets.

Animal model / Human subject Rat (Rattus norvegicus), Sprague Dawley, None, Male

Disease model Healthy

MRI or image guidance method MRI-guided FUS: co-registered with a 7-Tesla MRI and targeted using axial T2-weighted images (MRI-guided targeting; coordinates provided)

Targeted brain region(s) Motor Cortex

Target coordinates Approximately RAS coordinates (-3.0, 2.0, 3.0 mm), (-4.0, 0.0, 3.0 mm), (-5.0, -2.0, 3.0 mm)

Cargo name and characteristics Pentobarbital sodium — small-molecule barbiturate anesthetic (lipophilic), loaded into lipid‑shelled decafluorobutane-core nanodroplets (~210 ± 80 nm diameter). Ultrasound-triggered release via acoustic vaporization of the nanodroplets. Study dosing: ~5 μg pentobarbital delivered in a 200 μL bolus (~2×10^10 nanodroplets).

Route of administration Intravenous (tail vein bolus injection)

Outcomes and Safety

Summary of Outcomes Ultrasound-triggered pentobarbital release from nanodroplets induced temporary localized motor impairment in the targeted motor cortex without detectable BBBO or tissue damage, with full recovery by 24 hour.

Duration of biological effect ≤24 hours

Safety-related matter MRI and histology showed no detectable BBB disruption, red blood cells extravasation, edema, or tissue damage. No signs of toxicity or necrosis were observed in the kidney, liver, heart, lung, or spleen, and animals showed no long-term motor deficits over weeks.

Brain Region

Ultrasound Parameters

Ultrasound instrument LP100 (FUS Instruments Inc., Toronto, ON, Canada); in-house manufactured prototype similar to the LP100. Transducer: spherically focused, 580 kHz center frequency; 60 mm radius of curvature; 75 mm external diameter with 20 mm central cut-out.

FUS Frequency 0.58 MHz (580 kHz)

FUS Pressure 0.76+-0.16 Mpa

FUS Mode pulsed

Pulse duration 10 ms

Duration of a single FUS session 180 s (3 minutes)

Focal Characteristics Focal depth: 20 mm; Focal length (radius of curvature): 60 mm; Aperture size (external diameter): 75 mm (20 mm central cut-out)

Treatment frequency Single session

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