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

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.

First-in-human trial of blood–brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound

“…MRgFUS blood-spinal cord barrier opening has not yet been developed in humans, but has been performed safely in the spinal cord of non-ALS rodent models 42,43 . An early study demonstrated enhanced chemotherapy delivery using MRgFUS blood-spinal cord barrier opening in rodents 44 . However, the bony vertebrae of the spinal column in primates present a technical challenge for focusing the ultrasound and further validation and optimization studies are necessary before translation to humans 45 .…”

Characterization of ultrasound-mediated delivery of trastuzumab to normal and pathologic spinal cord tissue

“…The issue of target motion due to breathing is reduced by placing the animals supine so that the chest can expand freely however, the posterior elements of the vertebral bone are highly irregular especially in comparison to the skull surface. In rats, an average of about a 33% signal loss is expected from bone attenuation, although with large spatial variations 21 , but large focal distortions are not expected since the vertebrae are thin. It was expected that using the same controller for this study as used in the small animal BBB studies would provide similar opening.…”

“…Pressure values were based off of calibrations performed in water and were not de-rated for attenuation through tissue. Mean transmission in rat spines at 0.5 MHz has previously been reported as 67 ± 15% (range: 45–92%) and is subject to large local variations due to the bony anatomy of the spine 21 . The signal level to trigger the controller was calculated as the baseline signal plus 10 times the standard deviation of the baseline signal.…”

“…We have previously investigated FUS-induced drug delivery as a means for treating LM in a rat model and a preliminary study showed a potential therapeutic response 21 . It was reported that although there was no statistical difference in survival between the control groups and the FUS + drug treated group, FUS + trastuzumab was effective in reducing the overall tumour burden.…”

Focused Ultrasound and Microbubbles-Mediated Drug Delivery to Brain Tumor

“…FUS has been used to increase the vascular permeability and deliver a variety of therapeutics in different types of preclinical disease models. To date, the application of FUS-mediated BBB modulation for drug delivery against tumors has been applied across many locations in the CNS such as cerebrum, brain stem, and spine [ 81 , 82 , 83 ]. This technique has been used to enhance the delivery of a wide range of chemotherapeutic agents such as doxorubicin, carboplatin, and temozolomide across the BBB/BBTB.…”