Abstract B026: Rotational magnetic drug targeting for leptomeningeal metastases
Authors: Engelhard Herbert , Willis Alexander , Shokuhfar Tolou , Mair Lamar 
Published: March 2024

Abstract
Background: Magnetic nanoparticles (MNPs) have potential for enhancing the delivery of therapeutic molecules to cancer cells and micronodules, including non-obstructing metastases within cerebrospinal fluid (CSF) pathways. Rotational magnetic drug targeting (rMDT) takes advantage of the surface-walking capability of clusters of MNPs, which can be activated remotely. Here, we present data related to 1) the creation, characterization, and in vitro testing of a variety of MNPs utilized with bound or unbound chemotherapeutic agents, and 2) the design and construction of four different magnetomotive systems used to propel MNPs at clinically-relevant distances. The goal was to create an in vitro model mimicking conditions found in patients with leptomeningeal metastases. Methods: Gold-iron alloy nanoparticles were combined with biotinylated etoposide via the streptavidin-biotin interaction. Unbound MNPs were tested with etoposide and doxorubicin. MNPs were characterized by techniques including electron microscopy, Zeta potential analysis, and dynamic light scattering. 3D-printed and acrylic trays were used as conduits for measuring translational motion over distances up to 30 cm through saline, culture media, and artifical CSF. MNP velocities were determined by videography. For propelling the MNPs, one electromagnetic system used a Helmholtz pair of coils on each side of an underlying perpendicular coil. The second electromagnetic system utilized 2 angled coils. Two rotating permanent magnet systems used neodymium-boron-iron magnets of different sizes and rotational speeds. Cultured cells included fibroblasts, lung cancer, glioblastoma, and medulloblastoma cell lines. Light microscopy and cytotoxicty assays (by MTT and trypan blue exclusion) were used to assess preservation of tumoricidal activity. Results: In unbound MNP studies, both etoposide and doxorubin could be dispersed over physiologic distances through saline and artificial CSF at velocities exceeding 1 cm/sec - much faster than by diffusion alone. Drugs conveyed in this manner could be transported at 37°C across cell surfaces and retain tumoricidal effect on cultured cells. With rotating magnets, MNPs could be moved against a saline flow rate of 1 cm/sec. In bound MNP studies, true rMDT was possible - all four magnetomotive systems could be shut off, depositing the MNP-drug conjugate at the desired location. Rotating permanent magnets were found to be advantageous for unilateral device design; electromagnetic devices, however, are more likely to be compatible with concurrent magnetic particle imaging (currently under development). Conclusions: These in vitro findings indicate that rMDT within CSF pathways is feasible and should advance to animal studies. Bound MNPs may prove to be more useful for intrathecal use (administered via lumbar puncture or Ommaya reservoir), considering dilutional effects and CSF flow. An improved ability to direct therapeutic agents within CSF would represent a major step forward in the treatment of patients with leptomeningeal metastases.
Citation Format: Herbert Engelhard, Alexander Willis, Tolou Shokuhfar, Lamar Mair. Rotational magnetic drug targeting for leptomeningeal metastases [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B026.