pH responsive prodrug nanoparticles (PEG-DOX) were prepared by attaching free Doxorubicin ( DOX) onto the amphipathic polyethylene glycol-aldehyde (PEG-CHO). The hydrophobic core of PEG-CHO enabled free DOX to be attached, while the hydrophilic outer layer of the carrier enabled the water solubility of the entire structure. This nanocarrier enabled a greater carrying capacity than free DOX, making its circulation time longer. The prodrug remained stable within neutral pH, ensuring its prolonged circulation time, but disassembled rapidly when reaching in the acidic environment of tumor tissues to release the free DOX. The newly designed nanocarriers have the potential to be applied clinically as a future DOX formulation in cancer chemotherapy.