Ultrasound-mediated destruction of oxygen and paclitaxel loaded dual-targeting microbubbles for intraperitoneal treatment of ovarian cancer xenografts

Abstract

Folate receptor (FR) is overexpressed in many epithelial cancers and tumor-associated macrophages (TAMs), which enable it to function as an appropriate target for cancer treatment. We have successfully synthesized multifunctional folate-targeted and oxygen/paclitaxel loaded microbubbles (TOPLMBs) for ultrasound (US) mediated delivery for combination therapy in an intraperitoneal ovarian cancer xenograft model. The TOPLMBs target both ovarian cancer cells and TAMs and provide a promising drug delivery strategy for the combination treatment of ovarian cancer and tumor microenvironment. Microscopic imaging and flow cytometric analysis showed that TOPLMBs significantly penetrated into ovarian cancer cells and tumor-associated macrophages (TAMs) within tumor ascites fluid and the tumor nodules. Immunohistochemical analyses of dissected tumor tissue confirmed the increased tumor apoptosis, the reduced expression of vascular endothelial growth factor (VEGF) and microvascular density (MVD), and the reduced expression of CD68 after treatment (P < 0.05). Our experiment results suggest that intraperitoneal injection of dual-targeting TOPLMBs followed by US mediation provide a promising drug delivery strategy for combination treatment of ovarian cancer and tumor microenvironment with the therapeutic outcome superior to that of conventional therapeutic options.

Keywords: Folate; Macrophages; Microbubbles; Ovarian cancer; Ultrasound.