A patient-designed tissue-engineered model of the infiltrative glioblastoma microenvironment.

Glioblastoma is an aggressive brain cancer characterized by diffuse infiltration. Infiltrated glioma cells persist in the brain post-resection where they interact with glial cells and experience interstitial fluid flow. We use patient-derived glioma stem cells and human glial cells (i.e., astrocytes and microglia) to create a four-component 3D model of this environment informed by resected patient tumors. We examine metrics for invasion, proliferation, and putative stemness in the context of glial cells, fluid forces, and chemotherapies. While the responses are heterogeneous across seven patient-derived lines, interstitial flow significantly increases glioma cell proliferation and stemness while glial cells affect invasion and stemness, potentially related to CCL2 expression and differential activation. In a screen of six drugs, we find in vitro expression of putative stemness marker CD71, but not viability at drug IC50, to predict murine xenograft survival. We posit this patient-informed, infiltrative tumor model as a novel advance toward precision medicine in glioblastoma treatment.

Effect of inline filtration on the potency of low-dose drugs.

Simulating actual conditions of intravenous infusion, a number of routinely used additive drugs were tested for potential binding to an inline i.v. filter containing a cellulose ester membrane. Two infusion solutions, 5% dextrose and 0.9% sodium chloride, were used to deliver the drugs. Drug samples were assayed before and after passage through the filter by the following methods: bleomycin sulfate, cyanocobalamin, ergonovine maleate, mithramycin, vinblastine sulfate, and vincristine sulfate by direct spectrophotometry; oxytocin by biological assay; levarterenol by fluorescence; and folic acid, heparin, insulin, and digitoxin by radiotracer methods. Measurable reduction in potency occurred in both infusion solutions with digitoxin, insulin, mithramycin, and vincristine sulfate. No reduction in potency was observed in either infusion solution with bleomycin sulfate, cyanocobalamin, ergonovine maleate, folic acid, heparin, leverterenol bitartrate, oxytocin, and vinblastine sulfate. The study results indicate that the potency of drugs administered intravenously in small doses could be significantly reduced during inline filtration through a filter containing a cellulose ester membrane.