Dual-responsive nanoparticle system for enhanced blood-brain barrier crossing and glioblastoma penetration

Glioblastoma (GBM) is recognized as one of the most aggressive and devastating primary brain cancers, posing a significant clinical challenge. The blood-brain barrier (BBB) significantly impedes therapeutic drug delivery, contributing to treatment resistance and poor prognosis with GBM. As a choline analogue, 2-methylacryloxyethyl phosphocholine (MPC) has been identified to cross the BBB by binding to nicotinic acetylcholine receptors (nAChRs) and choline transporters (ChTs) on the surface of the brain endothelial cells. In this study, aiming at utilizing this unique property to realize targeted drug delivery to brain tumors, a novel poly(2-methylacryloxyethyl phosphocholine) (pMPC-CHO)-based pH-responsive nanoparticles (NPs) drug delivery system (DDS) was developed via a simple strategy. By copolymerizing MPC monomer and oligo-poly(ethylene glycol) monomer containing aldehyde group to form a hydrophilic shell and synthesizing amphiphilic chitosan polymer-paclitaxel conjugate as the core, pH-responsive nano DDS (PC/M NPs) were obtained. pMPC-CHO enhances biocompatibility and BBB crossing ability. In the tumor microenvironment, PC/M NPs release positively charged chitosan NPs due to the broken imine bond, promoting cancer cell uptake and transcytosis, and then intracellular glutathione (GSH) activates paclitaxel to kill tumor cells. This pH and GSH-dual-responsive nano DDS integrates BBB crossover and tumor penetration, presenting an innovative and promising drug delivery platform for GBM treatment, which can balance prolonged circulation time, efficient BBB crossover, and enhanced tumor infiltration.