Development of Surfactant-Modified Liposomal Lomustine to Improve Blood-Brain Barrier Transport and Therapeutic Outcomes in Glioblastoma.

Effective chemotherapy for glioma remains limited by the restrictive nature of the blood-brain barrier (BBB). In this work, a pH-responsive polysorbate 80-coated liposomal nanocarrier loaded with lomustine (CCNU@T80-LIP) was developed to enhance the delivery and therapeutic efficacy of lomustine (CCNU) against glioma. The liposomes exhibited spherical morphology, uniform size distribution, and high encapsulation efficiency. The formulation demonstrated pH-triggered drug release under acidic conditions, supporting its potential for endosomal escape and controlled intracellular delivery. In vitro studies revealed that CCNU@T80-LIP exhibited strong, dose-dependent cytotoxicity against U87-MG glioma cells while maintaining minimal toxicity toward hCMEC/D3 endothelial cells. In 3D tumor spheroids, the formulation achieved enhanced penetration and reduced cell viability to 76.81 ± 14.29%, compared with 92.32 ± 9.79% for free CCNU. Furthermore, in a coculture BBB model in a transwell system, coumarin-6 loaded T80-LIP displayed approximately 1.5-fold higher permeability than the uncoated formulation (Cou6@LIP) and significantly decreased glioma viability (64.37 ± 3.54%) without compromising endothelial integrity. Overall, CCNU@T80-LIP demonstrates efficient BBB translocation, pH-responsive release, and potent tumor-selective cytotoxicity, highlighting its potential as an effective nanocarrier for glioma chemotherapy.