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Ultrasound ablation enhances drug accumulation and survival in mammary carcinoma models
Andrew W. Wong, … , Alexander D. Borowsky, Katherine W. Ferrara
Andrew W. Wong, … , Alexander D. Borowsky, Katherine W. Ferrara
Published November 23, 2015
Citation Information: J Clin Invest. 2016;126(1):99-111. https://doi.org/10.1172/JCI83312.
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Technical Advance Oncology

Ultrasound ablation enhances drug accumulation and survival in mammary carcinoma models

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Abstract

Magnetic resonance–guided focused ultrasound (MRgFUS) facilitates noninvasive image-guided conformal thermal therapy of cancer. Yet in many scenarios, the sensitive tissues surrounding the tumor constrain the margins of ablation; therefore, augmentation of MRgFUS with chemotherapy may be required to destroy remaining tumor. Here, we used 64Cu-PET-CT, MRI, autoradiography, and fluorescence imaging to track the kinetics of long-circulating liposomes in immunocompetent mammary carcinoma–bearing FVB/n and BALB/c mice. We observed a 5-fold and 50-fold enhancement of liposome and drug concentration, respectively, within MRgFUS thermal ablation–treated tumors along with dense accumulation within the surrounding tissue rim. Ultrasound-enhanced drug accumulation was rapid and durable and greatly increased total tumor drug exposure over time. In addition, we found that the small molecule gadoteridol accumulates around and within ablated tissue. We further demonstrated that dilated vasculature, loss of vascular integrity resulting in extravasation of blood cells, stromal inflammation, and loss of cell-cell adhesion and tissue architecture all contribute to the enhanced accumulation of the liposomes and small molecule probe. The locally enhanced liposome accumulation was preserved even after a multiweek protocol of doxorubicin-loaded liposomes and partial ablation. Finally, by supplementing ablation with concurrent liposomal drug therapy, a complete and durable response was obtained using protocols for which a sub-mm rim of tumor remained after ablation.

Authors

Andrew W. Wong, Brett Z. Fite, Yu Liu, Azadeh Kheirolomoom, Jai W. Seo, Katherine D. Watson, Lisa M. Mahakian, Sarah M. Tam, Hua Zhang, Josquin Foiret, Alexander D. Borowsky, Katherine W. Ferrara

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Figure 1

MRgFUS ablation enhanced accumulation of 64Cu-LCL in NDL mammary carcinoma.

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MRgFUS ablation enhanced accumulation of 64Cu-LCL in NDL mammary carcino...
(A) Three weeks after tumor implantation, tumors were ablated and imaged with pre- and postablation T1w-MRI. Mice were then injected with i.v. 64Cu-LCL and imaged with PET-CT at 3, 20, and 48 hours after treatment. Control treatment was no ultrasound (no US). (B–J) MRgFUS protocols and temperature profiles. T1w images localize ultrasound for (B) single-point, (C) circle, and (D) grid protocols. MR thermometry images following (E) 20 seconds single-point or (F) 60 seconds circle protocol MRgFUS. Temperature of measured and simulated ultrasound focus is plotted after (G) 20 seconds single-point or (H) 60 seconds circle protocol. Temperature distribution was simulated following (I) 20 seconds single-point or (J) 60 seconds circle protocol. Grid protocol shown in D and M–O is equivalent to E and G repeated in grid pattern, due to sequential application of ablation points and cool-down period. (K) PET-CT maximum intensity projection images of 64Cu-LCL without ablation. White arrows indicate tumors; yellow arrowheads indicate jugular vein (JV), heart (H), and liver (L). (L) At 3, 20, and 48 hours following single-point ablation (blue arrows), liposome accumulation is enhanced as compared with that in contralateral tumors (white arrows) in PET-CT images. 64Cu-LCL PET image–derived volume of interest analysis plotted as (M) maximum voxel intensity, (N) average activity, and (O) AUC48. Significance is analyzed with 1-way ANOVA followed by Tukey’s test. For M–O, n = 4, 3, 12, 19, and 6 mice for grid, circle, single point, contralateral tumors (contra), and no treatment. Scale bars: 1 cm. Thermometry color bars range from 70°C to 40°C; PET color bar ranges from 25%ID/cc to 0%ID/cc. *P < 1 × 10–4 vs. untreated tumors; †P < 0.05 vs. single-point ablation. Data are pooled from 5 experiments.
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