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

Extensive studies on focused ultrasound (FUS)-mediated drug delivery through the blood-brain barrier have been published, yet little work has been published on FUS-mediated drug delivery through the blood-spinal cord barrier (BSCB). This work aims to quantify the delivery of the monoclonal antibody trastuzumab to rat spinal cord tissue and characterize its distribution within a model of leptomeningeal metastases. 10 healthy Sprague-Dawley rats were treated with FUS + trastuzumab and sacrificed at 2-h or 24-h post-FUS. A human IgG ELISA (Abcam) was used to measure trastuzumab concentration and a 12 ± fivefold increase was seen in treated tissue over control tissue at 2 h versus no increase at 24 h. Three athymic nude rats were inoculated with MDA-MB-231-H2N HER2 + breast cancer cells between the meninges in the thoracic region of the spinal cord and treated with FUS + trastuzumab. Immunohistochemistry was performed to visualize trastuzumab delivery, and semi-quantitative analysis revealed similar or more intense staining in tumor tissue compared to healthy tissue suggesting a comparable or greater concentration of trastuzumab was achieved. FUS can increase the permeability of the BSCB, improving drug delivery to specifically targeted regions of healthy and pathologic tissue in the spinal cord. The achieved concentrations within the healthy tissue are comparable to those reported in the brain.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To quantify and characterize focused ultrasound-mediated delivery of the monoclonal antibody trastuzumab to rat spinal cord tissue and leptomeningeal metastases.

Animal model / Human subject Sprague-Dawley rat (10 animals), age not stated, sex not stated; Athymic nude rat (3 animals), age not stated, sex not stated

Disease model leptomeningeal metastases

Cargo name and characteristics Trastuzumab — a humanized monoclonal antibody (protein therapeutic, human IgG) targeting HER2 (used to treat HER2+ breast cancer), delivered to rat spinal cord and quantified by a human IgG ELISA.

Outcomes and Safety

Summary of Outcomes Focused ultrasound (FUS) with microbubbles transiently opened the blood–spinal cord barrier and increased delivery of trastuzumab to sonicated healthy spinal cord and leptomeningeal tumor deposits (≈12±5-fold increase at 2 h; 35±16 ng/mg protein), with concentrations returning to baseline in healthy tissue by 24 h. Successful FUS parameters were actively controlled exposures with peak negative pressures of ≈0.36±0.09 MPa in healthy rats and ≈0.46±0.09 MPa in tumor-bearing rats (producing BSCB opening volumes ≈6.4±2 mm3).

Duration of biological effect 2 h

Safety-related matter FUS with microbubbles was reported to safely and temporarily increase BSCB permeability with no observed hemorrhage or red blood cell extravasation; one animal showed possible mild off-target BSCB opening (disperse Evans blue) and was excluded, with no other adverse effects reported.

Brain Region

Visualization unavailable

Ultrasound Parameters

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

Treatment frequency single session

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