Pitt Shield

Remotely controlled drug release in deep brain regions of non-human primates.

Authors: Wilson MG, Webb TD, Odéen H, Kubanek J

Many areas of science and medicine would benefit from selective release of drugs in specific regions. Nanoparticle drug carriers activated by focused ultrasound-remotely applied, depth-penetrating energy-may provide such selective interventions. Here, we developed stable, ultrasound-responsive nanoparticles that can be used to release drugs effectively and safely in non-human primates. The nanoparticles were used to release propofol in deep brain visual regions. The release reversibly modulated the subjects' visual choice behavior and was specific to the targeted region and to the released drug. Gadolinium-enhanced MR imaging suggested an intact blood-brain barrier. Blood draws showed normal clinical chemistry and hematology. In summary, this study provides a safe and effective approach to release drugs on demand in selected deep brain regions at levels sufficient to modulate behavior.

Introduction

Purpose Drug delivery WITHOUT BBB opening
Study Objective To develop and demonstrate safe, effective ultrasound-responsive nanoparticles that enable targeted, on-demand release of drugs (propofol) in deep brain regions of non-human primates to modulate behavior.
Animal model / Human subject Rhesus macaque (Macaca mulatta); age: 8 years; sex: male
Disease model healthy
MRI or image guidance method MRI-guided
Targeted brain region(s) And Geniculate Nucleus
Cargo name and characteristics Propofol (small-molecule anesthetic)
Route of administration Intravenous

Outcomes and Safety

Summary of Outcomes Ultrasound-triggered release of propofol from PFOB-core nanoparticles in awake non-human primates produced reversible, side-specific (ipsilateral) neuroinhibitory effects on visual choice behavior without detectable BBB disruption or adverse hematology
Duration of biological effect 3 min
Safety-related matter No major safety concerns. Gadolinium enhanced MRI showed no BBB disruption or edema. Only mild transient ALT elevation observed

Brain Region

Ultrasound Parameters

Ultrasound instrument 256-element phased array (Guangzhou Doppler Electronic Technologies, China)
FUS Frequency 480 kHz
FUS Pressure 1.2 MPa; 1.5 MPa
FUS Mode pulsed
Pulse duration 10 ms (1.2 Mpa); 30 ms (1.5 Mpa)
Duration of a single FUS session 60 seconds
Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None
Treatment frequency single session

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