Anti-Tumor Study of H6, a 4-Substituted Coumarins Derivative, Loaded Biodegradable Self-Assembly Nano-Micelles In Vitro and In Vivo

作者：Zhu, Zejiang; Su, Zhengying; Yang, Jianhong; Liu, Huili; Tang, Minghai; Hu, Qiaoqiao; Bai, Peng; Wen, Jiaolin; He, Jun; Niu, Ting; Chen, Lijuan^*

来源：Journal of Biomedical Nanotechnology, 2019, 15(7): 1515-1531.

DOI：10.1166/jbn.2019.2797

• H6
• MPEG-PCL Micelles
• Anti-Tumor
• Pulmonary Metastatic B16/F10 Model
• Pulmonary Metastatic 4T1 Model

In our previous study, we identified a class of 4-substituted coumarins as a powerful microtubule inhibitors binding to the colchicine site of beta-tubulin. H6 showed potent anti-proliferative ability with IC50 values from 7 to 47 nM, and remarkable ability to reduce tumor growth in several xenograft models including taxol resistant tumor models. However, the extremely hydrophobicity limited its clinical application. In this study, to improve the anticancer activity and reduce the toxicity of H6, we successfully prepared MPEG-PCL with different proportions and H6-loaded polymeric micelles (H6/MPEG2k-PCL2k micelles) by a simple thin-film hydration method. The prepared H6/MPEG-PCL micelles had a drug loading of 3.79 +/- 0.001%, an encapsulation efficiency of 98.00 +/- 0.41%, a mean particle size of 30.45 +/- 0.18nm and a polydispersity index (PDI) of 0.096 +/- 0.009. Computer simulation results revealed a good compatibility of H6 and MPEG(2k)-PCL2k copolymer. In in vitro release study and pharmacokinetic study showed H6 micelles can release H6 over an extended period. Furthermore, H6 micelles possessed comparative effect as free H6 in inhibiting cell growth, preventing cell migration, and inducing apoptosis. Mechanism study identified that H6 is a novel reversible microtubule inhibitor. In in vivo studies, H6 micelles exhibited tumor growth inhibition on two pulmonary metastatic tumor models (B16/F10 and 4T1). Importantly, H6 micelles significantly improved the solubility, reduced the toxicity, extended the half-life of drugs, and augmented the therapeutic All these results imply that H6 micelles have great potential for suppression of tumor metastasis.

• 单位
  四川省医学科学院（四川省人民医院）; 四川大学