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Abstract
MiR-21 is an oncogenic miR frequently elevated in gastric cancer. Overexpression of miR-21 decreases the sensitivity of gastric cancer cells to trastuzumab, which is a humanized monoclonal antibody targeting human epidermal growth factor receptor 2. However, optimization of miRNA or its anti-miRNA oligonucleotides (AMOs) for delivery is a challenge. Receptor-mediated endocytosis plays a crucial role in the delivery of biotherapeutics including AMOs. This study is a continuation of our earlier findings involving poly(ε-caprolactone) (PCL)-poly (ethylene glycol) (PEG) nanoparticles (PEG-PCL NPs), which were coated with trastuzumab to target gastric cancer cells with HER2 receptor over-expression using anti-miRNA-21 antisense oligonucleotides (AMO-21). The antibody conjugates (HER-PEG-PCL NPs) act against target cells via antibody-dependent mechanisms and also based on encapsutalated AMO-21. X-ray photoelectron spectroscopy validated the presence of trastuzumab on NP surface. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed a stable antibody expression. The cell line specificity, cellular uptake, AMO-21 delivery, and cytotoxicity of the HER-PEG-PCL NPs were investigated. We found that the antibody conjugates significantly enhanced the cellular uptake of NPs. The HER-PEG-PCL NPs effectively suppressed the target miRNA expression in gastric cancer cells, which further up-regulated phosphatase and tensin homolog (PTEN). As a result, the sensitivity of HER2-expressing gastric cancer cells to trastuzumab was enhanced. The approach enhances the targeting by trastuzumab as well as antibody-dependent cellular cytotoxicity of immune effector cells. The antitumor effects of AMO-21-HER-PEG-PCL NPs were compared with trastuzumab in xenograft gastric cancer mice. The results provide insight into the biological and clinical potential of targeted AMO-21 delivery using modified trastuzumab for gastric cancer treatment.
Highlights
Gastric cancer (GC) ranks fourth among all cancers in worldwide incidence
This study is a continuation of our earlier findings involving poly(ε-caprolactone) (PCL)-poly (PEG) nanoparticles (PEG-PCL NPs), which were coated with trastuzumab to target gastric cancer cells with human epidermal growth factor receptor 2 gene (HER2) receptor over-expression using anti-miRNA-21 antisense oligonucleotides (AMO-21)
7% to 34% of gastric cancers are characterized by poor prognosis associated with amplification of human epidermal growth factor receptor 2 gene (HER2) [4,5,6]
Summary
Gastric cancer (GC) ranks fourth among all cancers in worldwide incidence. It ranks second in cancerrelated deaths reported in China [1]. Most patients are diagnosed with surgically advanced or metastatic disease [2]. Despite the advantages of combination chemotherapy, the prognosis is poor. 7% to 34% of gastric cancers are characterized by poor prognosis associated with amplification of human epidermal growth factor receptor 2 gene (HER2) [4,5,6]. Treatment with a combination of trastuzumab, a humanized monoclonal antibody against HER2 and chemotherapy is indicated for HER2-positive advanced GC. Despite a significant survival advantage with the combination treatment, 12% of all HER2-positive GC cases show cancer progression [7]
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