Self-Assembled Honokiol-Loaded Microbubbles in the Treatment of Ovarian Cancer by Ultrasound Irradiation.

Abstract

To observe the growth inhibition of subcutaneous ovarian cancer xenografts in nude mice and mechanisms by ultrasound irradiation with honokiol-loaded poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, PCEC) microbubbles (HK-PCEC-MB) as a promising therapeutic approach to ovarian tumor. HK-PCEC-MB were prepared using the double-emulsion solvent evaporation technique. Particles were characterized with regard to shape, size, distribution and surface potential using dynamic light scattering and the Malvern Zetasizer ZS90 system. Entrapment efficiency and loading amounts of honokiol were determined via high-performance liquid chromatography (HPLC). Pharmacological activity and optimal mode of action were examined using MTT assay. Nude mice were sorted into five groups of cisplatin-sensitive (A2780s) and cisplatin-resistant (A2780cp) ovarian cancer cell subcutaneous xenograft models: (1) HK-PCEC-MB+ultrasound; (2) HK; (3) PCEC-MB+ultrasound; (4) HK-PCEC-MB; (5) controls. We observed rates of growth inhibition, necrosis, and apoptosis, as well as microvessel density (MVD) changes. Physical properties of HK-PCEC-MB followed the normal pattern. The drug entrapment efficiency of HK-PCEC-MB was 65.08±2.31% and drug loading amount was 6.51±0.23%. Cancer cell survival rate was lowest in vitro at a drug concentration of 10 μg/mL with exposure to 2.58 W ultrasonic wave. In ultrasound irradiation combined with HK-PCEC-MB group, rates of necrosis and apoptosis were the highest, while the number of microvessel was the least. We have successfully prepared self-assembled HK-PCEC-MB that inhibits resistant human ovarian tumor growth by ultrasound irradiation.