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

Abstract

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.

Minimally invasive delivery of peptides to the spinal cord for behavior modulation

“…One critical challenge in developing medicine for diseases/disorders in the spinal cord is the limited drug penetration due to the BSCB. Researchers have attempted to use focused ultrasound to open the BSCB and tested it in small and large animal models (6, 21). However, ultrasound waves will need to travel through and penetrate the solid bone and soft tissue to reach the spinal cord.…”

“…There are several methods to overcome the BSCB (8). Transient opening of the BSCB mediated by focused ultrasound (FUS) following intravenous administration of gas-filled microbubbles (MBs) is currently an area of intense interest in improving spinal cord drug delivery (6,(9)(10)(11)(12), as encouraged by promising results in the brain (6,13). However, this technology may face many challenges in forming a tight ultrasound focus within the spinal canal, mainly due to the standing waves created by the reflective walls of the spinal canal, acoustic-thermal deposition in the bone (14), and complicated spine geometry (7).…”

Pretargeted Imaging Beyond the Blood-Brain-Barrier

“…Penetration of the blood-brain-barrier (BBB) can be achieved by several methods such as active transport, for example by utilizing the transferrin transporter, or by opening the BBB, for example by using focused ultrasound (FUS) based strategies. [15][16][17][18][19][20] Despite these advances, the use of mAbs for diagnostic brain imaging is still in its infancy as imaging is hindered by the slow pharmacokinetics of mAbs. Although there are long-lived radionuclides compatible with these pharmacokinetics, [21][22][23][24] respective radionuclides provide inferior image quality and result in high radiation burden for the patient.…”

Establishing density-dependent longitudinal sound speed in the vertebral lamina

“…This technology shows promise for improving drug delivery to the spinal cord in small animal models. [1][2][3][4][5][6][7] However, focusing ultrasound through human vertebrae is a challenge due to their larger dimensions and higher densities. The spine aberrates the incident ultrasound wavefront and distorts the intended focus.…”