Abstract: OBJECTIVE To prepare redox-responsive mPEG-S-S-C18 nanoparticles loaded with hydroxycamptothecin (HCPT) and optimize preparation process of the nanoparticles by central composite design-response surface methodology. METHODS HCPT/mPEG-S-S-C18 nanoparticles were prepared by emulsifying-solvent evaporation method. The influence of the drug dosage, water phase/oil phase volume ratio, ultrasonic power and ultrasonic time on the entrapment efficiency and drug loading capacity of HCPT/mPEG-S-S-C18 nanoparticles were investigated respectively by single factor mwthod. Then, with the entrapment efficiency and drug loading capacity as the indexes, the preparation process of HCPT/mPEG-S-S-C18 nanoparticles was optimized by central composite design-response surface method with Design-Expert V8.0.6 software. RESULTS The optimal preparation process of HCPT/mPEG-S-S-C18 nanoparticles was as followed:the drug dosage of 1.0 mg, water phase/oil phase volume ratio of 4.56:1, ultrasonic power of 562.5 W. The entrapment efficiency, drug loading capacity of HCPT/mPEG-S-S-C18 nanoparticles prepared by the optimal process were (58.14±1.04)% and (3.46±0.22)%, respectively, with average particle size of (322.9±9.52)nm, polydispersity index of 0.195±0.05 and Zeta potential of (-17.5±2.11)mV.CONCLUSION The emulsifying-solvent evaporation method is feasible to prepare HCPT/mPEG-S-S-C18 nanoparticles. The central composite design-response surface method is suitable for optimization of the preparation of HCPT/mPEG-S-S-C18 nanoparticles with high entrapment efficiency and drug loading capacity. The established mathematical model is predictive.