Magnetic Resonance Imaging-Guided Focused Ultrasound-Based Delivery of Radiolabeled Copper Nanoclusters to Diffuse Intrinsic Pontine Glioma

Abstract

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 (⁶⁴Cu-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 ⁶⁴Cu-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 ⁶⁸Ga-DOTA-ECL1i radiotracer and PET/CT before and after treatment. We then compared the delivery efficiency of ⁶⁴Cu-CuNCs to DIPG tumor with and without FUS treatment and demonstrated the FUS-enhanced delivery and time-dependent diffusion of ⁶⁴Cu-CuNCs within the tumor.

Keywords: diffuse intrinsic pontine glioma; focused ultrasound; magnetic resonance imaging; nanoclusters; positron emission tomography.

Figure 1.

(a) In vivo PET/CT images of ⁶⁴Cu-CuNCs without FUS treatment and under 0.28 and 0.61 MPa FUS pressure in WT mice at 24 h post IV injection. (b) Quantitative analysis of ⁶⁴Cu-CuNCs uptake in FUS treated left pons and non-treated right pons of WT mice under 0.28, 0.61, 0.72, and 0.85 MPa FUS pressures and the pons without FUS treatment in WT mice. (c) the uptake ratios of treated sites vs non-treated sites of the FUS treated mice under different pressures (*** p<0.001, **** p<0.0001, n = 4–5).

Figure 2.

Comparison of contrast enhanced T₁ and T₂ weighted MRI images of (a) 3-week-old DIPG mouse and related (b) H&E staining with MRI images at (c) 4-week-old DIPG mice and (d) H&E staining.

Figure 3.

(a) In vivo PET/CT images and (b) the quantitative tumor uptake of ⁶⁸Ga-DOTA-ECL1i in 3-week-old DIPG tumor mice with and without FUS treatment at 1 h post IV injection (** p<0.01, n = 4).

Figure 4.

In vivo PET/CT images, quantification of tumor uptake and intra-tumoral distribution volumes of ⁶⁴Cu-CuNCs at 24 h and 48 h post IV injection in (a, b, and c) 3-week-old and (d, e, and f) 4-week-old DIPG mice. (*** p<0.001, **** p<0.0001, n = 3–6).