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Doxorubicin (DOX) is a widely used anticancer agent, but its clinical use is hampered by its natural features, such as low selectivity to tumor tissue, and dose-dependent heart toxicity.To overcome these limits, more effective and active targeting systems are needed to enhance intracellular drug uptake by cancerous cells at the tumor sites.A PEG based folate mediated active tumor targeting drug delivery system DOX-hyd-PEG-FA nanoparticles (NPs) was prepared.DOX-hyd-PEG-FA NPs showed a significantly faster DOX release at pH 5.0 than at pH 7.4.Compared with DOX-hyd-PEG NPs, DOX-hyd-PEG-FA NPs increased the intracellular accumulation of DOX and showed a DOX translocation from lysosomes to nucleus.Compared with DOX-hyd-PEG NPs, DOX-hyd-PEG-FA NPs delivered more DOX into the nuclear of KB cells.The cytotoxicity of DOX-hyd-PEG-FA NPs on KB cells was much higher than that of free DOX, DOX-ami-PEG-FA NPs and DOX-hyd-PEG NPs.The cytotoxicity of DOX-hyd-PEG-FA NPs on KB cells was attenuated in the presence of exogenous folate acid.The IC50 of DOX-hyd-PEG-FA NPs and DOX-hyd-PEG NPs on A549 cells showed no significant difference.Compared with free DOX, the IC50 of DOX-hyd-PEG-FA NPs on KB cells significantly decreased.After DOX-hyd-PEG-FA NPs was intravenously administered, the amount of DOX distributed in tumor tissue was significantly increased, while the amount of DOX distributed in heart and other normal organ was greatly decreased.DOX-hyd-PEG-FA NPs improved survival rate, prolonged life span, and inhibited tumor growth in tumor bearing mice model.Meanwhile, it markedly reduced the cardiotoxicity of DOX.These results indicated that the acid sensitivity, passive and active tumor targeting abilities were likely to act synergistically to enhance the drug delivery efficiency of DOX-hyd-PEG-FA NPs.Therefore, DOX-hyd-PEG-FA NPs is a promising drug delivery system for targeted cancer therapy.