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A promising avenue in cancer therapy using liposomal formulations is the combination of site-specific delivery with triggered drug release. The use of trigger mechanisms in liposomes could be relevant for drugs susceptible to lysosomal hydrolytic/enzymatic degradation. Here, we propose a polymeric pH-sensitive liposome system that is designed to release its content inside the endosomes through a polymer structural change following receptor-mediated internalization. Specifically, pH-sensitive immunoliposomes (ILs) were obtained by including a terminally alkylated copolymer of N-isopropylacrylamide (NIPAM) in the liposome bilayer and by coupling the anti-CD33 monoclonal antibody to target leukemic cells. In vitro release of encapsulated fluorescent probes and cytosine arabinoside (ara-C) revealed that pH-sensitivity of the vector was retained in the presence of the antibody upon incubation in plasma. Flow cytometry and confocal microscopy analyses demonstrated that the pH-sensitive ILs were efficiently internalized by various CD33+ leukemic cell lines while limited interaction was found for liposomes decorated with an isotype-matched control antibody. Finally, the pH-sensitive ILs-CD33 formulation exhibited the highest cytotoxicity against HL60 cells, confirming the role of the NIPAM copolymer in promoting the escape of intact ara-C in the endosomes. These results suggest that this pH-sensitive liposomal formulation could be beneficial in the treatment of acute myeloid leukemia.