It was widely accepted that polymeric nanodrugs held superiority in enhancing antitumor efficacy, reducing side effect and achieving better long-term prognosis. However, there still existed disputes that whether their therapeutic efficiency was closely related to insure effective release of hydrophobic drug located in their hydrophobic core in tumor site. In order to investigate this controversy, we constructed two polymeric nanodrugs (pH-activatable sLMWH-UOA and non-sensitive LMWH-UOA) with low molecular weight heparin (LMWH) and ursolic acid (UOA) for chemo-and anti-angiogenic combination therapy in hepatocellular carcinoma. The degradation ratio of pH-activatable sLMWH-UOA increased by 33% compared with non-sensitive LMWH-UOA in in vitro degradation study. Besides, confocal microscopy captured that sLMWH-UOA could effectively release drug in acidic microenvironment of lysosome while LMWH-UOA nearly could not. More importantly, in contrast with LMWH-UOA, sLMWH-UOA presented pH-dependent cytotoxicity, indicating that promoting drug release played a key role in enhancing the cytotoxicity of polymeric nanodrugs. Additionally, in vivo pharmacodynamic evaluation showed that although non-sensitive LMWH-UOA had benefited from enhanced tumor targeting drug delivery ability to achieve absolute advantage over free drug combination therapy in antitumor combination therapy, sLMWH-UOA could acquire further optimized combined therapeutic effect with better drug release in tumor. All above, application of tumor-triggered chemical bonds to construct polymeric nanodrugs held vast prospect for improving the therapeutic efficiency for tumor cells. (C) 2018 Elsevier Inc. All rights reserved.