Bufalin-loaded vitamin E succinate-grafted chitosan oligosaccharide/RGD-conjugated TPGS mixed micelles inhibit intraperitoneal metastasis of ovarian cancer

Abstract

BackgroundIntraperitoneal metastasis is one of the major causes of the high mortality rate of ovarian cancer. Bufalin (BU) is an effective component of the traditional Chinese medicine Chansu that exerts antitumor effects, including metastasis inhibition. In our previous studies, we found that BU inhibited the migration and invasion of ovarian cancer cells. However, the application of BU is limited due to its insolubility, toxicity and imprecise targeting. The aim of this study was to use vitamin E succinate (VES)-grafted chitosan oligosaccharide (CSO)/arginine-glycine-aspartic acid peptide (RGD)-conjugated d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles (VeC/T-RGD MMs) to deliver BU to ovarian cancer cells to inhibit intraperitoneal metastasis. Moreover, the toxicity of BU was reduced by coating it with the mixed micelles to increase its biocompatibility for practical applications.ResultsThe BU-loaded VeC/T-RGD MMs (BU@MMs) had an average diameter of 161 ± 1.4 nm, a zeta potential of 4.49 ± 1.54 mV and a loading efficiency of 2.54%. The results showed that these micelles inhibited cell proliferation, induced apoptosis, and reduced the migration and invasion of A2780 and SKOV3 cells. Further studies indicated that BU@MMs enhanced the levels of e-cadherin and decreased the expression levels of N-cadherin, vimentin and Snail in vitro. In addition, the mixed micelles effectively enhanced the anticancer effect and inhibited intraperitoneal metastasis in intraperitoneal metastatic models. The BU@MMs exhibited fewer toxic side effects than BU, indicating better biocompatibility and biosafety for in vivo applications.ConclusionsOur studies show that BU@MMs are a potential multifunctional nano-drug delivery system that can effectively inhibit the intraperitoneal metastasis of ovarian cancer.