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

摘要

Gastric cancer (GC) is the most lethal malignancy in the digestive system. This study investigated an antibody-nanoparticle conjugate (ANC) constructed with trastuzumab (Herceptin (R)) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel, Abraxane (R)) (trastuzumab/nab-paclitaxel) as a novel strategy of targeted therapy for human epidermal growth factor receptor 2 (HER2) positive GC. The ANC was fabricated with trastuzumab and nab-paclitaxel by a 'one-step' synthesis using EDC/NHS. In vitro antitumor efficacy was evaluated by cell viability, apoptosis rate and cell cycle of HER2-positive GC NCI-N87 cells and compared with paclitaxel (Taxol (R)), nab-paclitaxel and trastuzumab/nab-paclitaxel. In addition, GC xenograft models were established to evaluate antitumor efficacy in vivo. These results demonstrated that trastuzumab/nab-paclitaxel was spherical with a suitable size (139.18 +/- 32.06 nm). The half-maximal inhibitory concentration (IC50) for NCI-N87 cells was 0.24 +/- 0.08, 0.13 +/- 0.03 and 0.048 +/- 0.01 mu g/ml of paclitaxel, nab-paclitaxel and trastuzumab/nab-paclitaxel, respectively. Compared with paclitaxel and nab-paclitaxel, trastuzumab/nab-paclitaxel could induce a higher rate of apoptosis and significant G2/M arrest. At 4 weeks after treatment, tumor-bearing mice had a mean tumor volume of 233 +/- 24 mm(3) treated by trastuzumab/nab-paclitaxel, 559 +/- 97 mm(3) by nab-paclitaxel, 871 +/- 94 mm(3) by paclitaxel and 1,576 +/- 190 mm(3) by PBS as control, respectively, which showed that trastuzumab/nab-paclitaxel could surpass nab-paclitaxel and paclitaxel in antitumor effect. Furthermore, the NIR imaging indicated that trastuzumab/nab-paclitaxel labeled by NIR-797 could more precisely focus on tumor regions. In conclusion, trastuzumab/nab-paclitaxel could mediate targeted therapy and enhance antitumor efficacy, which could represent a novel therapeutic agent for HER2-positive GC.