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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 5

Single-point MRgFUS ablation continues to enhance tumor accumulation of liposomes in the NDL tumor model after treatment for 2 weeks with MRgFUS ablation and therapeutic doxorubicin liposomes (Dox-LCL).

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Single-point MRgFUS ablation continues to enhance tumor accumulation of ...
(A) Mice were treated with weekly ablation (single-point protocol) or control (no ultrasound) and biweekly Dox-LCL (i.v., 6 mg/kg) for 2 weeks, then treated with ablation or control (no ultrasound) and injected with 64Cu-LCL. (B) PET-CT MIP images of mice treated only with repeated Dox-LCL (LCL) demonstrate heterogeneous tumor accumulation of 64Cu-LCL (white arrows). (C) PET-CT MIP images of mice treated with ablation plus Dox-LCL (US + LCL) reveal enhanced accumulation in ultrasound-treated tumors (blue arrows). PET image–derived tumor activity of 64Cu-LCL was obtained by manual segmentation with data plotted as (D) maximum pixel intensity within volume of interest, (E) activity averaged over volume of interest, and (F) AUC48. n = 3 each for US + LCL, contralateral tumors, and LCL. Scale bar: 1 cm. PET color bar ranges from 25%ID/cc to 0%ID/cc.
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