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

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 2

Ablation greatly enhances 64Cu-LCL accumulation in tumor rim and remaining viable tumor in the NDL tumor model.

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Ablation greatly enhances 64Cu-LCL accumulation in tumor rim and remaini...
(A–T) Comparison of H&E-stained frozen sections (A, F, K, and P), autoradiography (B, G, L, and Q), and PET image slices (C–E, H–J, M–O, R–T) acquired at 3 hours, 20 hours, and 48 hours from tumors sectioned 48 hours after MRgFUS treatment with grid, circle, single-point ablation, or no ultrasound. Grid and circle MRgFUS exposures increased accumulation of 64Cu-LCL in rims surrounding ablation (dark purple rim on A and F corresponds with black rim on B and G). Limited resolution of PET images blurs rim in C–E and H–J, but also shows blood and lymphatic radioactivity in C–E, H–J, and M–O. Single-point ablation also increased accumulation of liposomes (L–O). Accumulation in untreated tumor was homogeneous and low (Q–T). (U and V) Region of interest analysis of autoradiography (rectangular black box was plotted as line profile) demonstrating that central accumulation in tumors treated with (U) grid protocol and (V) circle protocol is comparable to that in untreated tumors in 5 of 6 tumors. n = 4, 3, 12, 19, and 6 mice for grid, circle, single point, contralateral tumors, and no treatment. Scale bars: 5 mm. Color bar scaled from 25%ID/cc to 0%ID/cc. Data are representative of 5 experiments.