The linear-dendritic prodrug MPEG–b-PAMAM–LA/DOX was synthesized through modifying the linear methoxy poly(ethylene glycol)–block-dendritic poly(amidoamine) (MPEG–b-PAMAM) with lipoic acid (LA) and then conjugating doxorubicin (DOX) by an acid-labile hydrazone bond. The obtained amphiphilic prodrug self-assembled into nanosized spherically shaped micelles in deionized water, as characterized by transmission electron microscopy (TEM) and dynamic laser scattering (DLS). The micelles could be cross-linked using a catalytic amount of dithiothreitol (DTT). Compared with the non-cross-linked micellar nanoparticles (NPs) (NCL-NPs), the cross-linked NPs (CL-NPs) were more stable against dilution and high salt concentration. However, in the presence of 10 mM glutathione (GSH), the reducible CL-NPs swelled in a short time, as determined by DLS. In in vitro drug release experiments, the CL-NPs exhibited pH and reduction dual responsive DOX release behaviour. DOX was released slowly under physiological pH (7.4) and/or in the absence of reduced GSH, but was released quickly at endosomal pH (5.5) and in the presence of GSH (5 mM or 10 mM). Both the confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) studies indicated that CL-NPs could be effectively taken up by the HeLa cells, and the conjugated DOX was efficiently released in response to the intracellular environment (low pH and high GSH concentration). In the MTT assay, CL-NPs could effectively inhibit the proliferation of HeLa cells and A549 cells. Thus, CL-NPs with superior stability, pH and reduction dual responsive drug release behaviour and good anti-cancer capability showed promise for anti-cancer treatment in the future.