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

Abstract

Gastric cancer (GC) is the most lethal malignancy in the digestive system. This study investigated an antibodynanoparticle conjugate (ANC) constructed with trastuzumab (Herceptin ®) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel, Abraxane ®) (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 ®), 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 (IC 50) for NCI-N87 cells was 0.24±0.08, 0.13±0.03 and 0.048±0.01 µg/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.

Molecular Characterization of Gastric Carcinoma: Therapeutic Implications for Biomarkers and Targets

“…These data suggest considerable heterogeneity among patients with HER2-positive GEJC/GC, possible treatment resistance, and need to refine and optimize biomarker selection criteria for future clinical trials. A recent report shows that trastuzumab conjugated with nanoparticle albumin-bound paclitaxel produced enhanced anti-tumor effect in a mouse xenograft of HER2-positive gastric cancer cells [ 27 ]. Further investigation of this antibody-nanoparticle conjugate in patients may raise hope for a novel form of targeted therapy in HER2-positive GC.…”

Recent trends in protein and peptide-based biomaterials for advanced drug delivery

“…Cellular uptake of the nanoparticles in cancer cell lines increased with albumin content [ 120 ]. Additionally, albumin nanoparticles can be decorated with targeting ligands, such as mannose [ 181 ], folic acid [ 182 ], antibodies [ 183 , 184 ], and aptamers [ 185 ], to provide greater receptor specificity.…”

Antibody‐Incorporated Nanomedicines for Cancer Therapy

“…Besides PLGA nanoparticles, EDC/NHS chemistry can be generally applicable to various other types of nanoparticles. [24,[113][114][115][116] For example, Xiong et al conjugated trastuzumab (Herceptin) and Abraxane via a one-step synthetic approach, utilizing the amine groups in the antibody and the carboxyl groups in Abraxane. [115] Trastuzumab-functionalized Abraxane could actively target human epidermal growth factor receptor-2 (HER2)-positive gastric cancer cells contributing to the enhanced anticancer efficacy of paclitaxel.…”