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Doxorubicin (DOX) was conjugated to polyethylenimine (PEI) in several synthetic ways and created PEI-succinic anhydride (SUC)-DOX, PEI-N-succinimidyl 3-maleimidopropionate (SMP)-DOX and PEI-3-maleimidopropionic acid hydrazide (MPH)-DOX conjugates using pH-insensitive linkage (amide bond) or pH-sensitive linkage (hydrazone bond). The effects of the conjugates on anticancer therapy against human breast cancer cells were investigated for in vitro release under different pH, cellular uptake, intracellular localization and antiproliferative activity. DOX release from PEI-MPH-DOX formed via hydrazone bonds occurred in an acid-triggered manner and increased with decreasing pH. But PEI-SUC-DOX and PEI-SMP-DOX formed via amide bonds were quite stable and released negligible DOX under both neutral and acidic conditions. The results from flow cytometry and confocal laser scanning microscopy analysis showed that conjugates uptakes were PEI-SUC-DOX > PEI-SMP-DOX > PEI-MPH-DOX, which was consistent with the primary amine content and more efficient than free DOX due to the intense nonspecific interaction between the positively charged conjugates and the negatively charged cell surface proteoglycans. PEI-MPH-DOX showed higher antiproliferative activity than that of PEI-SUC-DOX and PEI-SMP-DOX. The antiproliferative activity of PEI-MPH-DOX was achieved through the endocytosis, nuclear entry of released DOX and interaction with the DNA. However, PEI-SUC-DOX and PEI-SMP-DOX showed more endocytosis but less nuclear entry leading to lower antiproliferative activity. According to the measurements, we determined that enhanced endocytosis and pH-sensitive drug release were the critical processes in determining anticancer therapy of drug-polymer conjugate. The PEI-MPH-DOX conjugate could be sifted to use as a prodrug for cancer therapy and also as a novel delivery carrier to codelivery DOX and gene in further research.