Integrated Metalloproteinase, pH and Glutathione Responsive Prodrug-Based Nanomedicine for Efficient Target Chemotherapy.

Prodrug self-assembled nanomedicines with cleavable moieties sensitive to intracellular stimuli have attracted great interest to pharmacists. In this paper, a docetaxel-hyaluronic acid (DTX-HA) conjugate with peptide, hydrazone bonds and disulfide in sequence, which were cleavable catalyzed by metalloproteinase (MMP), weak acidity and glutathione (GSH), respectively, were involved in a moiety as the linker to immobilize DTX on HA chains, the prodrugs were self-assembled into nanoparticles and utilized for cancer chemotherapy. The synthesis of conjugate was characterized by H-1 NMR, ESI-TOF and GPC. The self-assembly of the conjugates was investigated via DLS and TEM. The release profiles revealed that the nanomedicine was disassociated to trigger the drug release in the simulated intracellular conditions of MMP, pH value and GSH, respectively. The in vitro anticancer activity of the nanomedicine with IC50 test, cytometry and confocal laser scanning microscopy exhibited efficient cellular uptake and apoptosis of cancer cells. The in vivo anticancer study of the nanomedicine in tumor-bearing nude mice showed promising therapeutic efficacy in magnificent inhibition tumor growth, long circulation time in pharmacokinetic and low toxicity to organs.