Multidrug resistance (MDR) is an important hindrance to efficient cancer chemotherapy. Cancer cell lysosomes play an important role in intrinsic MDR by accumulating chemotherapy drugs and deactivating their therapeutic action. The cationic polymer polyethyleneimine (PEI) can disrupt the endosomal/lysosomal membrane via the proton-sponge effect (PSE). However, its positive charge makes it toxic and so it cannot be used in vivo. Here, linear PEI (LPEI) is used to demonstrate that a pH-triggered charge-reversal carrier can solve this problem. The imines are amidized by masking a lysosomal pH-active agent. LPEI regenerates its positive charge in the acidic endosomal/lysosomal cell compartments and disrupts the endosomal/lysosomal membrane, resulting in delivery of the drugs into the cytoplasm and nuclei where they exert their pharmacologic activity. Folic acid targeting groups are introduced into the polymer to increase its cancer-cell targeting capability. An anticancer drug camptothecin (CPT) conjugated to the carrier by intracellular cleavable disulfide bonds shows improved cytotoxicity over free CPT. (C) 2015 Elsevier Ltd. All rights reserved.