Unveiling the enigma of the blood–brain barrier in glioblastoma: current advances from preclinical and clinical studies

Abstract

Purpose of review Glioblastoma (GBM), the most prevalent primary brain malignancy in adults, poses significant challenges in terms of treatment. Current therapeutic strategies for GBM patients involve maximal safe resection, followed by radiotherapy with concurrent and adjuvant temozolomide. However, despite this multimodal approach for GBM, the prognosis of GBM patients remains dismal because of their inherent primary and secondary resistances to treatments. Recent findings Several molecular and cellular mechanisms, including the presence of the blood–brain barrier (BBB), contribute to these resistances. The BBB, comprising multiple layers surrounding brain vessels, acts as a barrier limiting effective drug delivery to the brain. Invasive and noninvasive tools to deliver drugs and pharmaceutical formulations locally or systemically are continuously evolving to overcome the BBB in GBM toward improving drug bioavailability in the brain and reducing systemic toxicities. Summary Preliminary studies utilizing these approaches have demonstrated promising results in terms of safety and signals of efficacy during early-phase clinical trials. However, further work through additional clinical trials is necessary to evaluate the potential clinical benefits for GBM patients.

Glioblastoma Therapy: Past, Present and Future

“…Only 20% of small molecules/therapeutics agents cross the BBB and reach tumor cells at an effective concentration. GSC or GB cells protected against therapeutic agents by an intact BBB are the source of tumor recurrence [ 23 ]. P-glycoprotein, multidrug resistance proteins, organic anion transporters and breast cancer resistance proteins are especially important efflux pumps within the BBB that limit the accumulation of small-molecule-targeted therapies [ 249 ].…”

“…Invasive (local administration) and noninvasive tools to deliver drugs are continuously evolving to overcome the BBB [ 23 ]. As reviewed in previous works [ 884 , 885 , 886 , 887 ], several nanostructures, including polymeric nanoparticles (NPs) (e.g., dendrimers, polymer micelles or nanospheres), inorganic NPs (e.g., silica, iron, gold or graphene NPs), lipid-based NPs (e.g., liposomes, emulsions), nanogels, carbon dots and nano-implants, have been developed as drug delivery systems and potential diagnostic agents for GB over the past decades.…”

“…As suggested by the moniker “multiforme”, GB has a widespread tumoral heterogeneity and plasticity at the cytopathological, transcriptional, and genomic levels [ 16 , 17 , 18 , 19 , 20 , 21 ]. Moreover, its highly infiltrative nature and the protection by the blood–brain barrier (BBB) have posed significant treatment challenges [ 9 , 22 , 23 ]. Glioma stem cells (GSCs) are a small subpopulation of cells within the GB, with genomic instability, self-renewal and tumor-initiating capacity, and the ability to differentiate into different GB subpopulations, being responsible for tumor heterogeneity [ 24 , 25 , 26 , 27 ].…”

Immunotherapeutic Strategies for the Treatment of Glioblastoma: Current Challenges and Future Perspectives

“…Tumor-induced BBB leakage may enhance therapeutic delivery to the tumor core, yet the intact BBB beyond it can impede drug distribution. As outlined in a recent review by [45], brain drug delivery can be enhanced through surgical interventions such as intrathecal drug administration and convection-enhanced delivery (CED) and/or with the use of implantable pharmaceutical formulations, including biodegradable wafers or gels. Alternatively, researchers are focusing on improving drug penetration into the brain by enhancing drug liposolubility (e.g., using liposomes) or by modulating the BBB (e.g., through the modulation of efflux pumps, tight junctions, or the use of receptor agonists) [45].…”