pH responsive intracellular tumor targeting is increasingly investigated as a pathway to trigger the release of anti-tumor drugs once the drug carrier reached the unique acidic environment of the solid tumors or after the drug carrier has been taken up by cells, resulting in the localization of the micelles in the acidic endosomes and lysosomes. Poly(itaconic acid)-poly(ethylene glycol)-folatepoly(L-histidine) (PIA-PEG-FA-PHIS) was synthesized as a carrier for tumor-targeted drug delivery. The micelles were internalized by receptor-mediated endocytosis, and the combination of active targeting and triggered release resulted in apparent cytotoxicity and antitumor activity. The MIT assay showed DOX-loaded micelles had higher and obvious cytotoxicity against Hela cells at pH 5.0 than that at pH 7.4. Cellular uptake experiments revealed that these pH-responsive PIA-PEG-FA-PHIS micelles were taken up in great amounts by receptor-mediated endocytosis and delivered to lysosomes, triggering release of DOX into the cytoplasm. These indicated that the PIA-PEG-FA-PHIS micelles could be a promising drug delivery system with preeminent stability for targeting the hydrophobic drugs to cancer cells and releasing DOX in to the cells by sensing the acidic environment of the endosomes for cancer therapy. (C) 2015 Elsevier Inc. All rights reserved.