Physicochemical characteristics and doxorubicin-release behaviors of pH/temperature-sensitive polymeric nanoparticles

In order to construct polymeric nanoparticles responsive to both temperature and pH, three different copolymers (PNDSP 1, 2 and 3), differing in their composition of a thermosensitive co-telomer of N-isopropylacrylamide and N,N-dimethylacrylamide (MNDT, Mn=4600, clouding temperature; 40 °C) and a pH-sensitive sulfamethoxypyridazine telomer (MSPT, Mn=3600, solubility transition; pH 7.4), were synthesized by radical polymerization. Each methacryloyl group terminated telomer was prepared in the presence of 2,2′-azobisisobutyronitrile and 2-aminoethanethiol as a chain transfer agent, followed by coupling with methacryloyl chloride. After the nanoparticles of the copolymers were prepared by diafiltration against the buffers of two different conditions (pH 7.0 and 35 °C (nanoparticle type I); pH 8.0 and 45 °C (nanoparticle type II)), their physicochemical properties in aqueous solutions were characterized by dynamic light scattering (DLS) and fluorescence spectroscopy. The diafiltration condition affected the physicochemical properties of the nanoparticles. The mean diameter of type I nanoparticles was <40 nm, while the diameter of type II ranged from 90 to 140 nm. The critical aggregation concentration (CAC) of type I nanoparticles(>1.2 mg/l) was higher than that of type II (<0.9 mg/l). The type II nanoparticle showed an increased loading efficiency of doxorubicin (DOX), a model anticancer drug. The DOX release rates were influenced by four combinatorial release conditions of two pH levels (7.0 and 7.5) and temperatures (37 and 42 °C). By converting the property of two graft chains (MNDT and MSPT) from hydrophilic (or phobic) to hydrophobic (or philic) simultaneously, the highest DOX release rate from both types of nanoparticles was achieved. The release condition of switching from hydrophilic to hydrophobic surface corresponded to local low tumor pH and hyperthermic conditions. The results indicate that the different types of nanoparticles responsive to local tumor pH, hyperthermic condition, or both can be prepared from the same polymer structure and composition depending on nanoparticle forming condition.