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 January 4, 2016; First 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

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 4

As compared with controls, grid and circular ablation protocols alter the tumor distribution of a single injection of gadoteridol contrast agent in the NDL tumor model.

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As compared with controls, grid and circular ablation protocols alter th...
Results were similar whether gadoteridol was injected before or after ablation. Columns represent the same tumor imaged at 5 minutes (A–E) and 3 hours (F–J) after ablation with the following protocols: (A and F) grid, (B and G) circle, (C and H) single point, (D and I) no ultrasound, gadoteridol before ablation, (E and J) circle ablation with no gadoteridol. (K) For gadoteridol injection after ablation, ratio of intensity in ablation region and quadriceps muscle reaches 3.2 ± 0.4 at 1.5 hours, n = 4. (A–J) Representative images with n = 4 each for grid, single-point ablation, no ultrasound plus gadoteridol (Gd), and circle no gadoteridol, n = 12 for circle plus gadoteridol. Scale bar: 5 mm. Data are pooled from 2 experiments.