CPP-Based Bioactive Drug Delivery to Penetrate the Blood-Brain Barrier: A Potential Therapy for Glioblastoma Multiforme

Background: A large number of studies have been conducted on the treatment of glioblastoma multiforme (GBM). Chemotherapeutic drugs cannot penetrate deeply into the brain parenchyma due to the presence of the blood-brain barrier (BBB). Hence, crossing BBB is a significant obstacle in developing new therapeutic methods for GBM. Objective: Cell-penetrating peptides (CPPs) have emerged as new tools that can efficiently deliver various substances across BBB. CPPs beneficial properties, such as BBB penetration capacity, low toxicity, and the ability to achieve active targeting and controllable drug release, have made them worthy candidates for GBM treatment. However, their application is limited by several drawbacks, including lack of selectivity, insufficient transport efficacy, and low stability. In order to overcome the selectivity issue, tumor targeting peptides and sequences that can be activated at the target site have been embedded into the structure of CPPs. To overcome their insufficient transport efficacy into the cells, which is mostly due to endosomal entrapment, various endosomolytic moieties have been incorporated into CPPs. Finally, their instability in blood circulation can be solved through different modifications to their structures. As this field is moving beyond preclinical studies, the discovery of new and more efficient CPPs for GBM treatment has become crucial. Thus, by using display techniques, such as phage display, this encouraging treatment strategy can be developed further. Conclusion: Consequently, despite several challenges in CPPs application, recent progress in studies has shown their potential for the development of the next generation GBM therapeutics.