A drug/carrier dual redox-responsive system based on 6-mercaptopurine dimer-loaded cysteine polymer nanoparticles for enhanced lymphoma therapy

Many anticancer drugs have limited clinical applications owing to their unsatisfactory therapeutic efficacy or side effects. This situation can be improved by drug delivery systems or drug modification strategies. Herein, to improve the therapeutic efficacy and safety of the traditional anticancer drug 6-mercaptopurine (6-MP), we dimerized 6-MP to form a disulfide bond-containing drug dimer and prepared a cysteine-based poly (disulfide amide) with redox-responsive capability as a drug carrier. Briefly, dimeric 6-MP (DMP) was synthesized via the oxidization of iodine and self-assembled with the poly (disulfide amide) to form dual redox-responsive DMP-loaded NPs (DMP-NPs). The 6-MP itself could hardly be loaded into nanoparticles (NPs) owing to its hydrophobicity, while the DMP-NPs showed a higher drug loading capacity over 6-MP, small particle size, and favorable stability. With abundant disulfide bonds in polymer backbones and drug payloads, DMP-NPs could rapidly respond to high levels of glutathione (GSH) and release drugs in a controllable manner. More importantly, both cellular and animal experiments demonstrated the enhanced anticancer efficacy of DMP-NPs against lymphoma and their high safety. Overall, this drug dimer-loaded dual redox-responsive drug delivery system provides new options for improving the applications of traditional drugs and developing drug delivery systems with enhanced drug effects and high safety.