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

in Biomacromolecules by Panpan Song, Nannan Song, Li Li, Minghao Wu, Zhongxia Lu, Xia Zhao

TLDR

  • A novel pH/reduction-sensitive nanogel modified with targeting peptide angiopep-2 and loaded with doxorubicin showed enhanced BBB penetration and tumor targeting ability, and demonstrated promising antitumor activity in GBM.

Abstract

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 bothand. 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.

Overview

  • The study developed a pH/reduction-sensitive carboxymethyl chitosan nanogel (CMCSN) modified with targeting peptide angiopep-2 (ANG) and loaded with doxorubicin (DOX) for the treatment of glioblastoma (GBM).
  • The nanogel, DOX-ANG-CMCSN, showed good stability, biocompatibility, and pH/reduction sensitivity, as well as efficient BBB penetration and tumor targeting ability.
  • The study aimed to investigate the efficacy of the targeted nanogels in GBM-targeted chemotherapy and its potential as a promising platform for GBM treatment.

Comparative Analysis & Findings

  • The study found that the modification of ANG significantly enhanced the BBB penetration and tumor targeting ability of DOX-ANG-CMCSN, leading to a 2-3-fold higher uptake and enhanced antitumor activity compared to nontargeted DOX-CMCSN.
  • The cumulative release rate of DOX from DOX-ANG-CMCSN was 82.3% under simulated tumor microenvironment conditions.
  • The hydrodynamic diameter of DOX-ANG-CMCSN was 190 nm, and the drug loading was 12.7%.

Implications and Future Directions

  • The study demonstrates the potential of targeted nanogels with pH/reduction dual-stimuli response as a promising platform for GBM-targeted chemotherapy.
  • The findings suggest the need for further studies to evaluate the safety and efficacy of DOX-ANG-CMCSN in clinical trials.
  • Future research directions may include exploring the optimal dosage and administration route of DOX-ANG-CMCSN, as well as investigating its potential application in combination with other chemotherapeutic agents or with immunotherapies.
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