Interfacing ReducedGraphene Oxide with Cationic Pillar[5]arenefor Doxorubicin Delivery: A Platform for Glioblastoma Treatment

Graphene-based materials are emerging as promising platforms in nanomedicine due to their high surface area and substantial drug-loading capacities. However, their clinical translation is hindered by challenges related to biocompatibility and the ability to cross physiological barriers, particularly the blood–brain barrier (BBB). In this study, we synthesized reduced graphene oxide (rGO) functionalized with quaternary ammonium pillar[5]arene (rGO-NMe₃P[5]A⁺) via noncovalent interactions, resulting in a positively charged surface (+28 mV). Doxorubicin (DOX) was loaded onto rGO-NMe₃P[5]A⁺ with a high efficiency of 99%, achieving a drug-loading capacity of 12.5% by weight. A pH-responsive drug release profile showed a cumulative release of 22% at pH 4.5 within 48 h, significantly higher than the 4% observed at pH 7.4. Cytotoxicity assays revealed that rGO-NMe₃P[5]A⁺-DOX reduced U251 Glioblastoma cell viability by 59% at a DOX concentration of 1 μg mL^–1, comparable to the 50% reduction observed with free DOX. Importantly, both unloaded and DOX-loaded rGO-NMe₃P[5]A⁺ demonstrated negligible toxicity to human brain microvascular endothelial cells (HBMEC), unlike free DOX, which reduced their viability by 60%. In vitro BBB model assays demonstrated the ability of rGO-NMe₃P[5]A⁺-DOX to cross the BBB and target Glioblastoma cells without compromising endothelial integrity. These findings highlight the potential of rGO-NMe₃P[5]A⁺-DOX as a biocompatible, efficient, and targeted platform for Glioblastoma treatment.