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.
Highlights
Magnetic resonance–guided focused ultrasound (MRgFUS) provides completely noninvasive thermal therapy for cancer
Adequate treatment of the tumor margins can still be challenging near sensitive structures, such as nerves and blood vessels
We found that the circular ablation protocol leaving a thin (~200 μm) rim of viable tissue was locally curative when combined with liposomal therapy
Summary
Magnetic resonance–guided focused ultrasound (MRgFUS) provides completely noninvasive thermal therapy for cancer. To address systemic cancers, such local therapies are augmented with chemotherapy or immunotherapy. There are multiple motivations and precedents for combining systemic and local therapies; for example, radiation therapy combined with neoadjuvant chemotherapy reduces risk of local recurrence in breast-conserving surgery [1, 2]. The efficacy of radiofrequency (RF) ablation is improved by preablation thermosensitization [3] and coadministration of ablation and chemotherapy [4,5,6], suggesting that combining ablation with drug therapy may increase coagulation diameter and reduce recurrence using MRgFUS. The purpose of this study is to determine whether a practical ablation strategy in which the tumor margin is incompletely treated to preserve sensitive surrounding tissue can be locally curative in mammary carcinoma
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