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] (PMAA(BAcy)-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 PMAA(BAcy)-co-PEGMA(950) nanogel exhibited reasonable particle size and desired hydrodynamic diameter that was further cross linked by Fe(III) ions to obtain a double-cross-linked PMA(ABAcy/Fe(III))-co-PEGMA(950) 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 PMAA(BAcy/Fe(II))-co-PEGMA(950) displayed remarkable biocompatibility and glutathione-sensitive release toward anticancer drug in the simulated intracellular environment of tumor tissues. Notably, the drug-loaded PMAA(BAcy/Fe(III))-co-PEGMA(950) exhibited excellent anticancer activity against tumor cells. The double-cross-linked PMAA(BAcy/Fe(III))-co-PEGMA(950) nanogel therefore is expected to be a promising tumor microenvironment-sensitive platform for delivering chemotherapeutic drugs.