Antibody-nanoparticle conjugate constructed with trastuzumab and nab-paclitaxel for the targeted therapy of positive human epidermal growth factor receptor 2 gastric cancer.

Abstract

e15506 Background: Gastric cancer is the most lethal malignancies in the digestive system. This study was to investigate antibody-nanoparticle conjugate (ANC) constructed with Herceptin® and Abraxane® (Herceptin®/Abraxane®) as a novel strategy of targeted therapy for human epidermal growth factor receptor 2 (HER2) positive gastric cancer. Methods: Firstly, we fabricated the ANC with Herceptin and Abraxane by a “one-step” synthesis using EDC/NHS. In vitro study, the cell viability, apoptosis and cell cycle of the positive HER2 gastric cancer NCI-N87 cells were measured and compared in four groups of PBS, paclitaxel (Taxol), nano- paclitaxel (Abraxane) and ANC (Herceptin/ Abraxane). In addition, we constructed gastric cancer xenograft model in nude mice to evaluate the targeted antitumor effect in vivo. Furthermore, we chose the NIR797 to locate on the ANC and use the NIR imaging to demonstrate that the ANC could more precise target and delayed release of paclitaxel. Results: ANC of Herceptin/Abraxane was spherical in shape and in a suitable size (289.18 nm±102.6 nm). In vitro, the half-maximal inhibitory concentration (IC50), defined as the concentration of Taxol equivalent needed to kill 50% of cells, was found to be 0.24, 0.13 and 0.048 μg/ml for Taxol , Abraxane and ANC of Herceptin/Abraxane respectively for NCI-N87 cells with an excellent dose-effect relationship. Compared with Taxol and Abraxane, ANC of Herceptin/Abraxane could induce significant G2/M arrest. In vivo, at 4 weeks after treatment, mice treated by ANC of Herceptin/Abraxane had a mean tumor volume of 233±24 mm3, Abraxane of 559±97 mm3, Taxol of 871±94 mm3 and PBS as control of 1576±190 mm3. Obviously, the ANC could surpasses Abraxane and Taxol in reducing tumor volume with lesser side effects. Furthermore, NIRF imaging indicated a better targeting and sustained release of paclitaxel with ANC than that with Abraxane and Taxol. Conclusions: Antibody-nanoparticle conjugate of Herceptin/Abraxane could mediate targeted therapy and enhance antitumor activity, which could represent a novel targeted therapeutic agent for positive HER2 gastric cancer.