To integrate the two advantages of upregulated stability during blood circulation and site-specific drug release in cancer cells, pH/reduction dual-responsive prodrug microspheres with high drug content were designed by conjugating doxorubicin (DOX) onto aldehyde-functionalized disulfide-crosslinked copolymer microspheres via acid-labile imine linkage, where the copolymer microspheres were synthesized by facile emulsion copolymerization of poly(ethylene glycol) methyl ether methacrylate (PEGMA) and 4-formylphenyl acrylate (FPA) with N,N-bis(acryloyl)cystamine (BACy) as crosslinker. Their particle size and average hydrodynamic diameter were 150 nm and 205 nm respectively, with high DOX content of 44.4%. The DOX release ratio reached 73% within 60 h and the prodrug microspheres decrosslinked into water soluble copolymers within 72 h in the simulated tumor microenvironment (pH 5.0 with 10 mM GSH), while only 16% of DOX was released in physiological medium (pH 7.4 with 10 pM GSH), demonstrating their good tumor intracellular triggered release performance. Furthermore, the disintegration of the copolymer microspheres into water soluble copolymers in simulated tumor microenvironment would favor the metabolism of drug carriers. The MTT assay demonstrated that the prodrug microspheres exhibited the enhanced inhibitory efficiency against HepG2 cells in comparison with free DOX, while the bare polymer microspheres were cytocompatible.