Design of Dual-Targeted pH-Sensitive Hybrid Polymer Micelles for Breast Cancer Treatment: Three Birds with One Stone

Breast cancer has a high prevalence in the world and creates a substantial socio-economic impact. Polymer micelles used as nano-sized polymer therapeutics have shown great advantages in treating breast cancer. Here, we aim to develop a dual-targeted pH-sensitive hybrid polymer (HPPF) micelles for improving the stability, controlled-release ability and targeting ability of the breast cancer treatment options. The HPPF micelles were constructed using the hyaluronic acid modified polyhistidine (HA-PHis) and folic acid modified Plannick (PF127-FA), which were characterized via (1)H NMR. The optimized mixing ratio (HA-PHis:PF127-FA) was 8:2 according to the change of particle size and zeta potential. The stability of HPPF micelles were enhanced with the higher zeta potential and lower critical micelle concentration compared with HA-PHis and PF127-FA. The drug release percents significantly increased from 45% to 90% with the decrease in pH, which illustrated that HPPF micelles were pH-sensitive owing to the protonation of PHis. The cytotoxicity, in vitro cellular uptake and in vivo fluorescence imaging experiments showed that HPPF micelles had the highest targeting ability utilizing FA and HA, compared with HA-PHis and PF127-FA. Thus, this study constructs an innovative nano-scaled drug delivery system, which provides a new strategy for the treatment of breast cancer.