GSH-responsive nanofibrous prodrug formed by a short naphthylacetic acid-terminated peptide for 6-mercaptopurine delivery

As a purine analogue, 6-mercaptopurine (6-MP) is practical in treatment of leukemia and autoimmune diseases. Here, we connected 6-MP with a naphthylacetic acid-terminated short peptide (Nap-FFYE, NF) via disulfide bonds to form a novel prodrug Nap-FFYE–CO–NH–(CH 2 ) 2 –SS-6-MP (NF-SS-MP). NF-SS-MP can self-assemble to fibrous nanostructures with the diameter of ~50 nm in neutral aqueous solution. In vitro drug release experiments suggested that NF-6-MP showed sensitive GSH responsive and controlled releasing characteristics. 4-hour and 24-h cytotoxicity assay revealed that encapsulating 6-MP in NF-SS-MP nanofibers improved the killing ability of 6-MP to tumor cells in initial incubation time , and significantly reduced the toxicity of 6-MP on normal cells after 24 h incubation. From the results of cell uptake experiments, we found that NF-6-MP was easier to be absorbed by EC109 cells compared with free 6-MP, showing higher intracellular drug concentrations after incubation for 4 h, which confirmed the cytotoxicity result that nanofibrous NF-SS-MP has better ability to kill EC109 cells in a short incubation time. Thus, the developed NF-SS-MP can be used as an ideal delivery system for 6-MP in tumor treatment.