Poly-2-oxazoline nanoparticles potentiate effectiveness of vismodegib for breast cancer through improvement in pharmacokinetics and reduction in systemic toxicity

Abstract

Breast cancer is one of the most significant health challenges in the world. Vismodegib has been used for treatment of breast cancer limits the prescriptions of this drug. Therefore, it is of great significance to improve therapeutic effect of vismodegib therapy. This study modified the vismodegib with poly-2-oxazoline (POx) nanoparticles (POx-vismo) and examined the therapeutic potential of this approach for treating breast cancer. After preparation of POx-vismo micelles, they were characterized and loading efficiency, which was also measured by high performance liquid chromatography. The POx-vismo and vismodegib were administered to mice with breast cancer and healthy, respectively. Tumor, forebrain and blood samples were taken for analysis of pharmacokinetics and measurement of toxicity, where the concentration of POx was determined. Pharmacodynamic response was evaluated and Western blot analysis was used to determine the expression of retinoblastoma protein (pRB) and proliferating cell nuclear antigen (PCNA). Compared with traditional vismodegib, POx-vismo significantly improved the delivery efficiency of drugs in central nervous system accompanied with higher level of vismodegib. Administration with POx-vismo greatly improved the pharmacokinetics, diminished the toxicity, and strengthened the efficacy. POx-vismo therapy more effectively suppressed tumor cell growth and decreased pRB expression than oral administration of vismodegib. Collectively, the POx effectively served as a carrier of vismodegib in breast cancer and brain. POx-vismo micelles suppressed breast cell growth with low toxicity and addition of POx can enhance the efficacy of vismodegib for breast cancer and improves pharmacokinetics and pharmacodynamic response. These findings provide a novel insight into the drug therapy against the disorder.