Synthesis of targeted ultrasound contrast agent containing chemotherapeutic drug and in vitro evaluation in HER2-positive gastric cancer cell line

Abstract

Introduction: Gastric cancer is one of the leading causes of cancer mortality. HER-2 is a well-established molecular target for treatment of advanced gastric cancer. For effective targeted delivery chemotherapeutic drug to HER2-positive gastric cancer, we aimed to synthesize and evaluate an ultrasound contrast agent conjugated with trastuzumab for targeted delivery of chemotherapeutic drug to HER2-positive gastric cancer in vitro.

Materials and Methods: Experiments involving animals were approved by the Institutional Animal Care and Use Committee. Human gastric cancer cell lines NCI-N87, SNU-216, SNU-484 and SNU-601 were obtained and incubated. We synthesized a HER2-targeted microbubble contrast material by forming a microbubble liposome complex (MLC) from mixing lipids and sulfur hexafluoride gas core. The MLC was conjugated with anti-HER2 antibody (trastuzumab, Herceptin®) to target Her2-positive gastric cancer cells. The MLC-HER2Ab was fluorescent-labeled, incubated with gastric cancer cells, and then evaluated under confocal laser scanning microscopy for cellular targeting. Next, cisplatin was conjugated with the MLC-HER2Ab, and incubated with NCI-N87 and SNU-484 gastric cancer cells to assess the cytotoxicity induced by the therapeutic agent. Ultrasound exposure was additionally performed to investigate the effect of ultrasound-mediated delivery of the complex.

Results: Under confocal microscopy, highly selective cell targeting for HER2-positive cell lines NCI-N87 and SNU-216 was observed. In NCI-N87 cells, cisplatin conjugated MLC-HER2Ab showed increase in cell death after the exposure of ultrasound. This effect was not observed in SNU-484 cells.

Conclusions: Microbubble liposome complex can specifically target HER2-positive gastric cancer cell lines by the conjugation of trastuzumab. It can also readily deliver cisplatin to target cells under ultrasound, resulting in effective cancer cell death. Therefore, MLC may provide a promising method for ultrasound-mediated targeted drug delivery.