Advances in Glioblastoma Multiforme Treatment: New Models for Nanoparticle Therapy

Abstract

The most lethal form of brain cancer, glioblastoma multiforme, is characterized by rapid growth and invasion facilitated by cell migration and degradation of the extracellular matrix. Despite technological advances in surgery and radio-chemotherapy, glioblastoma remains largely resistant to treatment. New approaches to study glioblastoma and to design optimized therapies are greatly needed. One such approach harnesses computational modeling to support the design and delivery of glioblastoma treatment. In this paper, we critically summarize current glioblastoma therapy, with a focus on emerging nanomedicine and therapies that capitalize on cell-specific signaling in glioblastoma. We follow this summary by discussing computational modeling approaches focused on optimizing these emerging nanotherapeutics for brain cancer. We conclude by illustrating how mathematical analysis can be used to compare the delivery of a high potential anticancer molecule, delphinidin, in both free and nanoparticle loaded forms across the blood-brain barrier for glioblastoma.

Keywords: blood-brain barrier modeling; cytoscape; delphinidin; glioblastoma; nanoparticle.

Figure 1

The cross-sectional view of the blood-brain barrier. The blood-brain barrier (BBB) is a physical interface formed by cerebral endothelial cells, separated from pericytes and astrocytic end-feet by the basal lamina. The interactions of the endothelial cells and astrocytes maintaining the integrity of the BBB. Routes for molecular transport across the BBB are not depicted except energy-dependent transport protein (p-glycprotein) which acts as an efflux transporter.

Figure 2

The timeline of glioblastoma therapy.

Figure 3

The protein expression levels of healthy cerebral cortex cells mapped onto the GBM pathway map from the TCGA data set. In this diagram, The Human Protein Atlas database was used to obtain protein expression levels of healthy cerebral cortex cells. Special shapes used in the map represent different types of molecules which are given in the legend of the figure as protein complex, protein family, protein or small molecule. Lines and arrows show the relationship of the molecules. Each protein symbol (circle) is divided into quarters to represent, in a clockwise order: endothelial cells, neuropil, neuronal cells, and glial cells. The corresponding protein expression levels are shown in different colors. Olive for not available, deep sky blue for not detected, green for low expression, medium orchid for medium expression, and deep pink for high expression. The original GBM pathway map in the Cytoscape format was downloaded from (“The Cancer Genomics at cBio—Glioblastoma (TCGA)” n.d.).

Figure 4

The protein expression levels of glioma cancer cells mapped onto the GBM pathway map from the TCGA data set. In this diagram, The Human Protein Atlas database were used to obtain protein expression levels of glioma cancer cells. Special shapes used in the map represent different types of molecules which are given in the legend of the figure as protein complex, protein family, protein and small molecule, respectively. Lines and arrows show the relationship of the molecules. Each protein symbol (circle) is shown as pie chart to represent different expression levels of glioma cancer cell which are depicted in different colors. Olive for not available, deep sky blue for not detected, green for low expression, medium orchid for medium expression, and deep pink for high expression. The original GBM pathway map in the Cytoscape format was downloaded from (“The Cancer Genomics at cBio—Glioblastoma (TCGA)” n.d.).

Figure 5

The schematic representation of our single-tube like capillary model. In this 1D model, the blood-brain barrier is simplified into a single blood vessel with a lumen inside and surrounding tissue outside. The wall of the vessel is represented as the endothelial side. The route for the transport of compound into the surrounding brain tissue by modulation of pgp-mediated efflux is shown in the schematic diagram.

Figure 6

Predictions of free and encapsulated delphinidin delivery to brain tissue (A) Free delphinidin concentration vs. time graph where y-axis 0–1.3. (B) Encapsulated delphinidin concentration vs. time graph where y-axis 0.95–1.01. CL, concentration in the lumen; CE, concentration in the endothelial cells of the barrier.