Angiopep-2-Modified Carboxymethyl Chitosan-Based pH/Reduction Dual-Stimuli-Responsive Nanogels for Enhanced Targeting Glioblastoma

Glioblastoma (GBM) is a fatal brain tumor with poor prognosis. Blood-brain barrier (BBB) prevents the effective delivery of chemotherapeutic agents to GBM. Herein, we developed a pH/reduction-sensitive carboxymethyl chitosan nanogel (CMCSN) modified by targeting peptide angiopep-2 (ANG) and loaded with doxorubicin (DOX). The multifunctional nanogel (DOX-ANG-CMCSN) exhibited good pH and reduction sensitivity, ideal stability, and biocompatibility. Its hydrodynamic diameter was 190 nm, drug loading was 12.7%, and the cumulative release rate of 24 h was 82.3% under the simulated tumor microenvironment. More importantly, the modification of ANG significantly enhanced BBB penetration and tumor targeting ability both in vivo and in vitro. DOX-ANG-CMCSN achieved 2-3-fold higher uptake and an enhanced antitumor activity compared with nontargeted DOX-CMCSN. Therefore, the targeted nanogels with the pH/reduction dual-stimuli response may provide a promising platform for GBM-targeted chemotherapy.

Automated summary

A pH/reduction-sensitive carboxymethyl chitosan nanogel modified by targeting peptide angiopep-2 loaded with doxorubicin shows promising potential for targeted chemotherapy of glioblastoma. The targeted nanogel exhibited good stability, biocompatibility, and enhanced BBB penetration and tumor targeting ability, leading to higher drug uptake and stronger antitumor activity compared to nontargeted nanogels. This innovative nanogel platform with pH/reduction dual-stimuli response may hold great significance for GBM-targeted therapy.