Enhanced antiproliferative activity of antibody-functionalized polymeric nanoparticles for targeted delivery of anti-miR-21 to HER2 positive gastric cancer
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Feng-Lei Wu1,9,*, Jian Zhang2,*, Wei Li3,*, Bao-Xiang Bian1, Yi-Dong Hong4, Zi-Yan Song1, Hui-Yu Wang5, Fang-Bo Cui6, Ru-Tian Li7, Qin Liu7, Xiao-Dong Jiang1, Xiao-Min Li8 and Jun-Nian Zheng9
1Department of Onology, Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu 222000, China
2Department of General Surgery, Huai'an First People's Hospital, Nanjing Medical University, Huai’an, Jiangsu 223000, China
3Center of Research Laboratory, Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu 222000, China
4Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212001, China
5Department of Oncology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214000, China
6Department of Oncology, The People’s Hospital of Ma’anshan, Ma’anshan, Anhui 243000, China
7The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 210008, China
8Department of Emergency, Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu 222000, China
9Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
*These are the corporate first authors
Jun-Nian Zheng, email: [email protected]
Xiao-Min Li, email: [email protected]
Keywords: microRNA, gastric cancer, HER2, trastuzumab, nanoparticles
Received: January 25, 2017 Accepted: April 12, 2017 Published: May 22, 2017
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.
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