Magnetic Resonance Imaging-Guided Focused Ultrasound-Based Delivery of Radiolabeled Copper Nanoclusters to Diffuse Intrinsic Pontine Glioma.
Authors: Zhang X, Ye D, Yang L, Yue Y, Sultan D, Pacia CP, Pang H, Detering L, Heo GS, Luehmann H, Choksi A, Sethi A, Limbrick DD, Becher OJ, Tai YC, Rubin JB, Chen H, Liu Y
Diffuse intrinsic pontine glioma (DIPG) is an invasive pediatric brainstem malignancy exclusively in children without effective treatment due to the often-intact blood-brain tumor barrier (BBTB), an impediment to the delivery of therapeutics. Herein, we used focused ultrasound (FUS) to transiently open BBTB and delivered radiolabeled nanoclusters (<sup>64</sup>Cu-CuNCs) to tumors for positron emission tomography (PET) imaging and quantification in a mouse DIPG model. First, we optimized FUS acoustic pressure to open the blood-brain barrier (BBB) for effective delivery of <sup>64</sup>Cu-CuNCs to pons in wildtype mice. Then the optimized FUS pressure was used to deliver radiolabeled agents in DIPG mouse. Magnetic resonance imaging (MRI)-guided FUS-induced BBTB opening was demonstrated using a low molecular weight, short-lived <sup>68</sup>Ga-DOTA-ECL1i radiotracer and PET/CT before and after treatment. We then compared the delivery efficiency of <sup>64</sup>Cu-CuNCs to DIPG tumor with and without FUS treatment and demonstrated the FUS-enhanced delivery and time-dependent diffusion of <sup>64</sup>Cu-CuNCs within the tumor.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To evaluate whether MRI-guided focused ultrasound can transiently open the blood-brain tumor barrier to enhance delivery and PET imaging of radiolabeled 64Cu nanoclusters in a mouse model of diffuse intrinsic pontine glioma.
Animal model / Human subject
Mice (wildtype), strain: wildtype (specific strain not specified), age: not specified, sex: not specified
Disease model
Diffuse intrinsic pontine glioma (DIPG)
MRI or image guidance method
MRI-guided focused ultrasound (FUS) targeting, with PET/CT confirmation using the low-molecular-weight, short-lived 68Ga-DOTA-ECL1i radiotracer (PET/CT before and after treatment)
Targeted brain region(s)
Pons
Target coordinates
Not provided in the paper text.
Cargo name and characteristics
64Cu-CuNCs: radiolabeled copper nanoclusters (nanoparticle PET imaging agent, 64Cu-labeled) used to quantify delivery and diffusion in DIPG; 68Ga-DOTA-ECL1i: low-molecular-weight, short-lived 68Ga-labeled DOTA-conjugated PET radiotracer used to demonstrate FUS-induced BBTB opening
Route of administration
Intravenous injection (systemic) with MRI-guided focused ultrasound (FUS)-mediated blood–brain tumor barrier opening
Outcomes and Safety
Summary of Outcomes
MRI-guided focused ultrasound transiently opened the blood-brain tumor barrier in a mouse DIPG model, significantly enhancing delivery and time-dependent intratumoral diffusion of radiolabeled 64Cu nanoclusters for improved PET imaging.
Duration of biological effect
not reported
Safety-related matter
No safety issues or adverse effects were reported or mentioned in the provided text.
Brain Region
Ultrasound Parameters
Ultrasound instrument
Imasonics, Voray sur 1'Ognon, France
FUS Frequency
1.5 MHz
FUS Intensity
Not specified in provided text
FUS Pressure
0.28, 0.61, 0.72, and 0.85 MPa
FUS Mode
pulsed
Pulse duration
6.7 ms
Duration of a single FUS session
1 min
Focal Characteristics
Not reported
Treatment frequency
single session
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