pH/GSH Dual-Responsive Core-Cross-Linked Copolyprodrug Nanoparticles via Cross-Linking-Induced Self-Assembly of Copolymer with Doxorubicin-Based Dimer for Precise Tumor Chemotherapy.

The drug release performance of polymer-based nanoscale drug delivery systems (nano-DDSs) is determined by the carrier configurations and the drug-loading modes. Here, to integrate the merits of the polyprodrugs and cross-linked copolymer nanoparticles, pH/glutathione (GSH) dual-responsive core-cross-linked copolyprodrug nanoparticles (PEG-cPMN) were designed as a drug self-delivery system for precise tumor chemotherapy, by facile cross-linking-induced self-assembly of diblock copolymer PEG-PMN with a pH/GSH dual-triggered doxorubicin (DOX)-based dimeric prodrug as a cross-linker, via acid-labile acylhydrazone bond. The optimized copolyprodrug nanoparticles, possessing a DOX content of 24.1% and average hydrodynamic diameter (Dh) of 159 nm, exhibited an excellent pH/GSH dual-triggered drug release, with accumulative DOX release of 45.5% in 105 h in the simulated tumor intracellular microenvironment, while a negligible premature drug leakage of 2.5% in the simulated normal physiological medium. This feature endowed the proposed core-cross-linked copolyprodrug nanoparticles an outstanding tumor-specific on-demand DOX release without obvious cytotoxicity on the normal cells in the in vitro experiments.