Glutathione-Induced Structural Transform of Double-Cross-Linked PEGylated Nanogel for Efficient Intracellular Anticancer Drug Delivery.

A glutathione-sensitive poly[methacrylic acid- co-poly(ethylene glycol) methyl ether methacrylate] (PMAABACy- co-PEGMA) nanogel with tunable stability has been fabricated through covalent and metal double-cross-linking strategies in response to the differential change of GSH concentration between the inside and outside of tumor cells. Herein, the size-controlled PMAA- co-PEGMA that possessed unique core-shell structure was first obtained via adjusting the length of PEGMA. Furthermore, N, N-bis(acryloyl)cystamine was introduced to endow PMAA- co-PEGMA with glutathione-sensitive property. The PMAABACy- co-PEGMA950 nanogel exhibited reasonable particle size and desired hydrodynamic diameter that was further cross-linked by Fe(III) ions to obtain a double-cross-linked PMAABACy/Fe(III)- co-PEGMA950 vehicle. In this double-cross-linked vehicle, the existence of metal cross-linked structure made this vehicle possess favorable structural stability to restrict the premature leakage of therapeutic drug. The introduction of covalent cross-linked structure synchronously imparted the vehicle with glutathione-sensitive property in response to the high intracellular glutathione concentrations in tumor cells to induce its structural transform for realizing the release of drug. Additionally, a series of in vitro evaluations demonstrated that PMAABACy/Fe(III)- co-PEGMA950 displayed remarkable biocompatibility and glutathione-sensitive release toward anticancer drug in the simulated intracellular environment of tumor tissues. Notably, the drug-loaded PMAABACy/Fe(III)- co-PEGMA950 exhibited excellent anticancer activity against tumor cells. The double-cross-linked PMAABACy/Fe(III)- co-PEGMA950 nanogel therefore is expected to be a promising tumor microenvironment-sensitive platform for delivering chemotherapeutic drugs.