Herein, acid-degradable poly(ortho ester urethanes) (POEUs) were synthesized via polycondensation between an acid-labile ortho ester diamine and active esters of poly(e-caprolactone) (PCL) diols with different molecular weights. The POEUs nanoparticles were easily fabricated using an oil-in-water emulsion technique, whose ortho ester bonds in main-chains could be degraded at different rate in acidic pHs. DOX was loaded into the nanoparticles with high drug loading efficiency. In vitro release studies demonstrate that DOX is released in a pH-dependent manner. In vitro cellular uptake confirms that DOX-loaded POEUs nanoparticles can be more readily internalized by two-dimensional (2D) cells and three-dimensional (3D) multicellular tumor spheroids (MCTS), resulting in efficient antitumor efficiency of cancer cells. In vivo biodistribution and antitumor effect were evaluated by H22 tumorbearing mice. The results demonstrate that DOX-loaded POEUs nanoparticles show a prolonged blood circulation time and improved accumulation in solid tumor, leading to enhanced therapeutic efficacy. (C) 2017 Elsevier Ltd. All rights reserved.