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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