Mitoxantrone (DHAQ)-loaded poly (ethylene glycol)-poly (lactic acid-co-glycolic acid) -poly (ethyleneglycol) (PELGE) nanoparticles (NP) were fabricated using an emulsification/solvent evaporation technique. A central composite design (CCD) was applied to evaluate the joint influence of three formulation variables: the amounts of polymer, concentration of the DHAQ, and the ratio of the organic phase (inner-phase) and the aqueous phase (outer-phase). In this study, we optimize the preparation technology on the basis of the single factor evaluation. The optimal conditions for the preparation of DHAQ-loaded nanoparticle were found to be: the concentration of PELGE was 9 mg/mL, the concentration of inner-phase of DHAQ was 27.5 mg/L, and the ratio of inner-phase/outer-phase was 8.5/1. The results showed that CCD is an ideal technique for formulation studies. The entrapment efficiency ratio (ER) was 90% and particle sizes are less than 500 nm. The nanoparticles, as examined by transmission electron microscopy (TEM), have a smooth and spherical surface. The DHAQ could be loaded into PELGE copolymers. In this study, the DHAQ nanoparticle-polymer delivery system was established by using PELGE polymers as carrier material.