Biodegradation and Toxicity of Protease/Redox/pH Stimuli-Responsive PEGlated PMAA Nanohydrogels for Targeting Drug delivery

The application of nanomaterials in intelligent drug delivery is developing rapidly for treatment of cancers. In this paper, we fabricated a new kind of protease/redox/pH stimuli-responsive biodegradable nanohydrogels with methacrylic acid (MAA) as the monomer and N,N-bis(acryloyl)cystamine (BACy) as the cross-linker through a facile reflux-precipitation polymerization. After that, the polyethylene glycol (PEG) and folic acid (FA) were covalently grafted onto the surface of the nanohydrogels for enhancement of their long in vivo circulation lifetime and active targeting ability to the tumor cells and tissues. This kind of nanohydrogels could be disassembled into short polymer chains (Mn<1140; PDI<1.35) both in response to glutathione (GSH) through reduction of the sensitive disulfide bonds and protease by breakage of the amido bonds in the cross-linked networks. The nanohydrogels were utilized to simultaneously load both hydrophilic drug doxorubicin (DOX) and hydrophobic drug paclitaxel (PTX) with high drug loading efficiency. The cumulative release profile showed that the drug release from the drug-loaded nanohydrogels was significantly expedited by weak acidic (pH 5.0) and reducing environment (GSH), which exhibited an distinct redox/pH dual stimuli-responsive drug release to reduce the leakage of drugs before they reach tumor site. In addition, the in vitro experiment results indicated that the multidrug-loaded system had synergistic effect on cancer therapy. Meanwhile, the acute toxicity and intravital fluorescence imaging studies were adopted to evaluate the biocompatibility and biotoxicity of the nanohydrogels, the experimental results showed that the PEG modification could greatly enhance the long in vivo circulation lifetime and reduce the acute toxicity (LD50: from 138.4 mg/kg to 499.7 mg/kg) of the nanohydrogels.