BBB-Targeted Polymeric Nanocarriers for Paclitaxel Delivery in Glioblastoma Therapy: A Comprehensive Review on Polymeric Systems, Targeting Mechanisms, Clinical Challenges in Glioblastoma and Future Prospects

Abstract

Glioblastoma remains one of the most lethal brain malignancies, characterized by aggressive proliferation and high recurrence rates despite multimodal treatment approaches. While paclitaxel demonstrates potent anticancer activity, its clinical utility in glioblastoma management is severely hampered by its inability to cross the bloodbrain barrier, coupled with poor aqueous solubility and P-glycoprotein-mediated efflux. Current standard care, based on surgical resection combined with radiotherapy and chemotherapy, yields disappointing median survival rates of only 12-15 months, underscoring the urgent need for innovative therapeutic strategies. Nanotechnologybased drug delivery systems have emerged as a promising approach to circumvent these limitations. Polymeric nanoparticles, including PLGA, PLA, PCL, and chitosan-based formulations, can effectively encapsulate paclitaxel while protecting it from efflux mechanisms and enhancing cellular uptake through receptor-mediated pathways. Surface functionalization strategies such as PEGylation, peptide conjugation, and targeting ligand attachment significantly improve blood-brain barrier penetration and tumor-specific accumulation. Despite promising preclinical results demonstrating substantial improvements in brain drug concentrations and tumor growth suppression, several obstacles persist in advancing these systems to clinical practice. These include manufacturing scalability, formulation stability, regulatory requirements, and standardization of quality control parameters. Furthermore, tumor heterogeneity and variable receptor expression patterns necessitate personalized therapeutic approaches. This review highlights recent progress in BBB-targeted paclitaxel nanoparticle systems, outlines key technological advances, addresses current limitations, and identifies future research priorities essential for successful clinical translation in glioblastoma therapy.