Drug Delivery Systems in the Development of Novel Strategies for Glioblastoma Treatment

Abstract

Glioblastoma multiforme (GBM) is a grade IV glioma considered the most fatal cancer of the central nervous system (CNS), with less than a 5% survival rate after five years. The tumor heterogeneity, the high infiltrative behavior of its cells, and the blood–brain barrier (BBB) that limits the access of therapeutic drugs to the brain are the main reasons hampering the current standard treatment efficiency. Following the tumor resection, the infiltrative remaining GBM cells, which are resistant to chemotherapy and radiotherapy, can further invade the surrounding brain parenchyma. Consequently, the development of new strategies to treat parenchyma-infiltrating GBM cells, such as vaccines, nanotherapies, and tumor cells traps including drug delivery systems, is required. For example, the chemoattractant CXCL12, by binding to its CXCR4 receptor, activates signaling pathways that play a critical role in tumor progression and invasion, making it an interesting therapeutic target to properly control the direction of GBM cell migration for treatment proposes. Moreover, the interstitial fluid flow (IFF) is also implicated in increasing the GBM cell migration through the activation of the CXCL12-CXCR4 signaling pathway. However, due to its complex and variable nature, the influence of the IFF on the efficiency of drug delivery systems is not well understood yet. Therefore, this review discusses novel drug delivery strategies to overcome the GBM treatment limitations, focusing on chemokines such as CXCL12 as an innovative approach to reverse the migration of infiltrated GBM. Furthermore, recent developments regarding in vitro 3D culture systems aiming to mimic the dynamic peritumoral environment for the optimization of new drug delivery technologies are highlighted.

Tyrosine Kinase Inhibitors for Glioblastoma Multiforme: Challenges and Opportunities for Drug Delivery

“…This makes drug delivery to tumor sites challenging, necessitating innovative approaches to overcome the barriers. Moreover, novel drug delivery strategies are also required to target and treat the parenchyma-infiltrating GBM cells which remain after the surgical resection, invade the surrounding brain parenchyma, and are resistant to chemotherapy and radiotherapy [ 109 ]. Several approaches are being investigated to increase transport of drugs and overcome the BBB in treatment of brain tumors.…”

“…Hydrogels are 3-dimensional polymeric hydrophilic networks in an aqueous medium that can encapsulate different drugs and provide controlled release. They can prove to be more beneficial than the Gliadel wafers because of their similarity with brain tissue in terms of mechanical properties and softness [ 109 ]. Bastiancich et al have provided in-depth discussion on anticancer drug loaded hydrogels for local treatment of GBM [ 127 ].…”

ABCG2 Expression as a Potential Survival Predictor in Human Gliomas

“…The exploration of ABCG2 inhibitors used in conjunction with traditional chemotherapy represents a promising approach to surmount drug resistance in gliomas. The advancement of novel drug delivery systems capable of circumventing ABCG2-mediated drug efflux at the BBB holds the potential to radically transform the treatment paradigm for brain tumors [ 45 , 46 ]. Furthermore, recent advancements in nanotechnology offer novel avenues for circumventing ABCG2-mediated drug resistance.…”

Recent advances in targeted drug delivery for the treatment of glioblastoma

“…However, the efficacy of systemic delivery is limited due to the low permeability of the BBB, which prevents the passage of anti-cancer drugs. 50,51 Traditional chemotherapy drugs have deficiencies in terms of their biological stability, low selectivity, and drug resistance, which exaggerates the limitations of systemic drug delivery in GBM. 51,52 To overcome these limitations, researchers have explored different strategies, including cell delivery systems, transient opening of the BBB, drug-loaded nanocarriers, and nanorobotic delivery systems.…”