Etoposide-Bound Magnetic Nanoparticles Designed for Remote Targeting of Cancer Cells Disseminated Within Cerebrospinal Fluid Pathways

Abstract

Magnetic nanoparticles (MNPs) have potential for enhancing drug delivery in selected cancer patients, including those which have cells that have disseminated within cerebrospinal fluid (CSF) pathways. Here, we present data related to the creation and in vitro use of new two-part MNPs consisting of magnetic gold-iron alloy cores which have streptavidin binding sites, and are coated with biotinylated etoposide. Etoposide was chosen due to its previous use in the CSF and ease of biotinylation. Etoposide magnetic nanoparticles (“Etop-MNPs”) were characterized by several different methods, and moved at a distance by surface-walking of MNP clusters, which occurs in response to a rotating permanent magnet. Human cell lines including D283 (medulloblastoma), U138 (glioblastoma), and H2122 (lung adenocarcinoma) were treated with direct application of Etop-MNPs (and control particles), and after remote particle movement. Cell viability was determined by MTT assay and trypan blue exclusion. Results indicated that the biotinylated etoposide was successfully bound to the base MNPs, with the hybrid particle attaining a maximum velocity of 0.13 ± 0.018 cm/sec. Etop-MNPs killed cancer cells in a dose-dependent fashion, with 50 ± 6.8% cell killing of D283 cells (for example) with 24 h of treatment after remote targeting. U138 and H2122 cells were found to be even more susceptible to the killing effect of Etop-MNPs than D283 cells. These findings indicate that the novel Etop-MNPs have a cytotoxic effect, and can be moved relatively rapidly at physiologic distances, using a rotating magnet. While further testing is needed, intrathecal administration of Etop-MNPs holds promise for magnetically-enhanced eradication of cancer cells distributed within CSF pathways, particularly if given early in the course of the disease.

Parallel Multichannel Assessment of Rotationally Manipulated Magnetic Nanoparticles

“…Five different types of MNPs were used in these studies, including graphene-coated cobalt MNPs (TurboBeads™-Carboxy, TurboBeads GMBH, Zurich, Switzerland), 29 nickel nanorods (NiNRs), gold-iron alloy MNPs (Fe 0.5 Au 0.5 MNPs), 25 gold-coated Fe 3 O 4 @Au MNPs, 5 and uncoated Fe 3 O 4 MNPs. 5 MNP characteristics are given in Table 1 .…”

“… 30–32 Fe 0.5 Au 0.5 alloy MNPs with streptavidin surface coatings were supplied by IMRA America, Inc. (Ann Arbor, Michigan, USA). 25 Gold-coated Fe 3 O 4 @Au MNPs and uncoated Fe 3 O 4 MNPs were synthesized in our laboratory as previously described. 5 TurboBeads™ and NiNRs were ferromagnetic, while the other MNPs were paramagnetic.…”

“…Past experiments on a similar scale have used a rotating permanent magnet, not an electric system. 5 , 6 , 25 , 28 The MMS was used for simultaneous velocity testing of multiple MNPs in response to a rotating magnetic field, i.e., “racing” MNPs in real time. Experiments consisted of placing five different MNPs into parallel channels (lanes) of the tray, exposing them to the rotating field, and capturing video recordings of the motion of the MNP clusters along the lengths of the channels.…”

Leptomeningeal disease in glioblastoma: endgame or opportunity?

“…Effective administration of chemotherapy to the CSF could be useful in treatment of LMD. In vitro magnetic nanoparticles have been used to deliver chemotherapy agents such as etoposide to CSF pathways; glioblastoma cells were particularly susceptible to this method of delivery [33]. Immunotherapy has also been considered in treatment of LMD.…”

Soft Capsule Magnetic Millirobots for Region-Specific Drug Delivery in the Central Nervous System

“…The cortex and the spinal cord are potential targets for therapeutic delivery using magnetically guided microrobots. Both tissues are bathed in low viscosity cerebrospinal fluid, meaning that treatment of the tissues does not necessarily require microrobots to traverse dense tissues (Engelhard et al, 2020). Additionally, these tissues are not deep inside the body, making it easier to apply strong magnetic fields sufficient for manipulation.…”