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 Wu 1, 9, * , Jian Zhang 2, * , Wei Li 3, * , Bao-Xiang Bian 1 , Yi-Dong Hong 4 , Zi-Yan Song 1 , Hui-Yu Wang 5 , Fang-Bo Cui 6 , Ru-Tian Li 7 , Qin Liu 7 , Xiao-Dong Jiang 1 , Xiao-Min Li 8 and Jun-Nian Zheng 9 1 Department of Onology, Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu 222000, China 2 Department of General Surgery, Huai'an First People's Hospital, Nanjing Medical University, Huai’an, Jiangsu 223000, China 3 Center of Research Laboratory, Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu 222000, China 4 Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212001, China 5 Department of Oncology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214000, China 6 Department of Oncology, The People’s Hospital of Ma’anshan, Ma’anshan, Anhui 243000, China 7 The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 210008, China 8 Department of Emergency, Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu 222000, China 9 Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China * These are the corporate first authors Correspondence to: Jun-Nian Zheng, email: zhengjunnian1968@126.com Xiao-Min Li, email: lyglxm1@163.com Keywords: microRNA, gastric cancer, HER2, trastuzumab, nanoparticles Received: January 25, 2017 Accepted: April 12, 2017 Published: May 22, 2017 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.