To create a novel vector for specifically delivering anticancer therapy to solid tumors, we used diafiltration to synthesize pH-sensitive polymeric micelles. The micelles, formed from a tetrablock copolymer [poly(ethylene glycol)-b-poly(L-histidine)-b-poly(L-lactic acid)-b-poly(ethylene glycol)] consisted of a hydrophobic poly(L-histidine) (polyHis) and poly(L-lactic acid) (PLA) core and a hydrophilic poly(ethylene glycol) (PEG) shell, in which we encapsulated the model anticancer drug doxorubicin (DOX). The robust micelles exhibited a critical micellar concentration (CMC) of 2.1–3.5 µg/ml and an average size of 65–80 nm pH 7.4. Importantly, they showed a pH-dependent micellar destabilization, due to the concurrent ionization of the polyHis and the rigidity of the PLA in the micellar core. In particular, the molecular weight of PLA block affected the ionization of the micellar core. Depending on the molecular weight of the PLA block, the micelles triggering released DOX at pH 6.8 (i.e. cancer acidic pH) or pH 6.4 (i.e. endosomal pH), making this system a useful tool for specifically treating solid cancers or delivering cytoplasmic cargo in vivo. Copyright © 2008 John Wiley & Sons, Ltd.