Developments in Blood-Brain Barrier Penetrance and Drug Repurposing for Improved Treatment of Glioblastoma

Abstract

Glioblastoma (GBM) is one of the most common, deadly, and difficult-to-treat adult brain tumors. Surgical removal of the tumor, followed by radiotherapy (RT) and temozolomide (TMZ) administration, is the current treatment modality, but this regimen only modestly improves overall patient survival. Invasion of cells into the surrounding healthy brain tissue prevents complete surgical resection and complicates treatment strategies with the goal of preserving neurological function. Despite significant efforts to increase our understanding of GBM, there have been relatively few therapeutic advances since 2005 and even fewer treatments designed to effectively treat recurrent tumors that are resistant to therapy. Thus, while there is a pressing need to move new treatments into the clinic, emerging evidence suggests that key features unique to GBM location and biology, the blood-brain barrier (BBB) and intratumoral molecular heterogeneity, respectively, stand as critical unresolved hurdles to effective therapy. Notably, genomic analyses of GBM tissues has led to the identification of numerous gene alterations that govern cell growth, invasion and survival signaling pathways; however, the drugs that show pre-clinical potential against signaling pathways mediated by these gene alterations cannot achieve effective concentrations at the tumor site. As a result, identifying BBB-penetrating drugs and utilizing new and safer methods to enhance drug delivery past the BBB has become an area of intensive research. Repurposing and combining FDA-approved drugs with evidence of penetration into the central nervous system (CNS) has also seen new interest for the treatment of both primary and recurrent GBM. In this review, we discuss emerging methods to strategically enhance drug delivery to GBM and repurpose currently-approved and previously-studied drugs using rational combination strategies.

Monotherapy efficacy of BBB-permeable small molecule activators of PP2A in glioblastoma

“…Nevertheless, all tested kinase inhibitors have failed to prolong the overall survival of GB patients in clinical trials (Mooney et al, 2019;. One of the reasons is that the blood-brain barrier (BBB) prevents the otherwise potentially effective kinase inhibitors from reaching the brain at high enough concentrations (Harder et al, 2018). Another potential reason is non-mutational plasticity induced by kinase inhibitors in GB cells (van den Heuvel et al, 2017).…”

Revealing the epigenetic effect of temozolomide on glioblastoma cell lines in therapeutic conditions

“…Many strategies are taken to increase the temozolomide concentration in the CNS, overcoming the boundaries of BBB [64][65][66][67][68]. What was shown earlier, simple implementation of radiotherapy, which is the damaging factor of BBB [69], improves the efficacy of TMZ [70].…”

Non‐viral nucleic acid delivery to the central nervous system and brain tumors

“…Gene packing can be achieved using several patterns, such as electrostatically combining anionic gene molecules with positively charged vectors, introducing hydrophobic moieties to condense gene molecules, enhancing the interaction between the vectors and gene molecules by a hydrogen bond or coordination bond, wrapping gene molecules into biodegradable polymers, or adsorbing gene molecules on the surface of vectors. Furthermore, the ideal vectors utilized in CNS gene delivery must possess certain characteristics: (i) the masking of negative charges of gene molecules, thus facilitating cellular uptake; (ii) the compression of gene molecules to make them smaller, achieving excellent biofilm permeability in vivo ; (iii) the protection of gene molecules from enzymatic degradation; (iv) the efficient release of gene molecules after endocytosis; and (e) the overcoming of biological barriers, such as BBB. Based upon these basic elements, a large amount of non‐viral gene vectors, including liposomes, gold nanoparticles, cationic niosomes, PLGA nanoparticles, carbon‐based carriers, cationic dendrimers and other nanobiomaterials, have been developed for CNS gene delivery (Table ).…”

“…Gene packing can be achieved using several patterns, such as electrostatically combining anionic gene molecules with positively charged vectors, introducing hydrophobic moieties to condense gene molecules, enhancing the interaction between the vectors and gene molecules by a hydrogen bond or coordination bond, wrapping gene molecules into biodegradable polymers, or adsorbing gene molecules on the surface of vectors 84,85 . Furthermore, the ideal vectors utilized in CNS gene delivery must possess certain characteristics 84,86 ionic liposome to enhance survivin siRNA delivery across the BBB to glioma cells. RGD peptide is known to be a binding peptide of integrin αvβ3 receptors, which are highly expressed in brain tumor cells.…”