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. 2018 Jun 13;8(1):9013.
doi: 10.1038/s41598-018-27335-y.

Preliminary Investigation of Focused Ultrasound-Facilitated Drug Delivery for the Treatment of Leptomeningeal Metastases

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Free PMC article

Preliminary Investigation of Focused Ultrasound-Facilitated Drug Delivery for the Treatment of Leptomeningeal Metastases

Meaghan A O'Reilly et al. Sci Rep. .
Free PMC article

Abstract

Leptomeningeal metastases (LM) are a serious complication of cancer in the central nervous system (CNS) and are diagnosed in approximately 5% of patients with solid tumors. Effective treatment using systemically administered therapeutics is hindered by the barriers of the CNS. Ultrasound can mediate delivery of drugs through these barriers. The goal of this study was to test the feasibility of using ultrasound-mediated drug delivery to improve the treatment of LM. LM was induced in the spinal cord of athymic rats by injecting HER2-expressing breast cancer cells into the subarachnoid space of the thoracic spine. Animals were divided into three groups: no treatment (n = 5), trastuzumab only (n = 6) or trastuzumab + focused ultrasound + microbubbles (FUS + MBs) (n = 7). Animals in groups 2 and 3 were treated weekly with intravenous trastuzumab +/- FUS + MBs for three weeks. Suppression in tumor growth was qualitatively observed by MRI in the group receiving ultrasound, and was confirmed by a significant difference in the tumor volume measured from the histology data (25 ± 17 mm3 vs 8 ± 5 mm3, p = 0.04 in the trastuzumab-only vs trastuzumab + FUS + MBs). This pilot study demonstrates the potential of ultrasound-mediated drug delivery as a novel treatment for LM. Future studies will extend this work to larger cohorts and the investigation of LM arising from other cancers.

Conflict of interest statement

M.A. O’Reilly and K. Hynynen are listed as co-inventors on a patent application related to the ultrasound methods used in this study. M.A. O’Reilly, G.J. Czarnota and K. Hynynen have commercial research grants with FUS Instruments. K. Hynynen has ownership interest (including patents) in Sunnybrook Research Institute and Brigham and Women’s Hospital, and FUS Instruments, and is a member of the FUS Instruments Board of Directors. The other authors have no conflicts to disclose.

Figures

Figure 1
Figure 1
(A) Mean days to onset and initial volume measured by MRI. (B) Weekly normalized tumor volume (top: mean ± S.D., bottom: individual data points), normalized to the initial tumor volume. (C) Example image series (contrast-enhanced T1weighted MRI) for each of the three groups. The white arrowheads show the tumor regions. *Data from the No Treatment group shown in A and B excludes one animal.
Figure 2
Figure 2
Survival curves for the three groups.
Figure 3
Figure 3
(A) Representative histology sections from animals in the trastuzumab only and trastuzumab + FUS + MBs groups illustrating reduced tumor burden in the animal treated with trastuzumab + FUS + MBs compared to that receiving the drug alone. (B) Tumor volume based on quantification of the histology data for the three groups. Error bars indicate one standard deviation.
Figure 4
Figure 4
(A,B) Study design and treatment timeline; (C) Illustration of the FUS experimental setup; (D) Example T1weighted sagittal MR images showing the tumor location (grey arrowheads) before FUS + MB and the enhancement of the cord indicating BSCB opening (white arrows) post-FUS + MB.

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