Redox-responsive polymers with pendant quinone propionic acid groups as a redox trigger were optimized by computational modeling to prepare efficient redox-triggered polymer nanoparticles (NPs) for drug delivery. Lipophilicities at complete reduction of redox-responsive polymers (<5000 Da) constructed with adipic acid and glutaric acid were remarkably reduced to range from -6.29 to -0.39 compared with nonreduced state (18.87-32.46), suggesting substantial polymer solubility reversal in water. Based on this hypothesis, redox-responsive NPs were prepared from the synthesized polymers with paclitaxel as model cancer drug. The average size of paclitaxel-loaded NPs was 249.8 nm and their reconstitutions were stable over eight weeks. In vitro drug release profiles demonstrated the NPs to release >80% of paclitaxel over 24 h at a simulated redox-state compared with 26.5 to 41.2% release from the control. Cell viability studies revealed that the polymer was nontoxic and the NPs could release paclitaxel to suppress breast cancer cell growth. Copyright © 2014 Wiley Periodicals, Inc.