Long-acting drug delivery systems (DDSs) have attracted interests for tumor chemotherapy. Here, novel reduction-triggered polymer prodrug was designed by conjugation of a high-performance thiolated doxorubicin (DOX-SH) onto the diblock copolymer PEG-PPDSMvia the bioreducible cleavable disulfide bond. The resultant polymer prodrug PEG-PPDSM-DOX with a DOX content of 33 % could be easily self-assembled into nanoparticles of 146 nm. They showed a slow solubility-controlled sustained drug release with a cumulative release of 30.13 % within 84 h in the simulated tumor intracellular microenvironment but an ultra-low premature drug leakage of 4.01 % in the simulated normal physiological media. Such slow sustained release is expected to prolong the action time of the active drug. The MTT assays demonstrated the tumor-selective killing performance of the proposed prodrug nanoparticles with an enhanced antitumor efficacy on the tumor HepG2 cells than the free DOX, but no obvious cytotoxicity on the normal L20 cells at the lower dosages.Copyright © 2020 Elsevier B.V. All rights reserved.