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Hao Zhang,1 Chen Liang,2 Xinxin Hou,3 Ling Wang,1 Dongsheng Zhang41Department of Imaging and Nuclear Medicine, Medical School of Southeast University, Nanjing, Jiangsu, 2Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 3Department of Pathology, Medical School of Henan Polytechnic University, Jiaozuo, Henan, 4Jiangsu Key Laboratory for Biomaterials andDevices, Medical School, Southeast University, Nanjing, People’sRepublicof ChinaAbstract: Combination therapy for lung cancer has garnered widespread attention. Radiation therapy, gene therapy, and molecular targeted therapy for lung cancer have certain effects, but the disadvantages of these treatment methods are evident. Combining these methods can decrease their side effects and increase their curative effects. In this study, we constructed a pYr-ads-8-5HRE-cfosp-iNOS-IFNG plasmid (a gene circuit that can express IFNγ), which is a gene circuit, and used that plasmid together with C225 (cetuximab) to prepare gene-loaded immunomagnetic albumin nanospheres (IMANS). Moreover, we investigated the therapeutic effects of gene-loaded IMANS in combination with radiation therapy on human lung cancer in vitro and in vivo. The results showed that this gene circuit was successively constructed and confirmed that the expression of INFγ was increased due to the gene circuit. Gene-loaded IMANS combined with radiation therapy demonstrated improved results in vitro and in vivo. In conclusion, gene-loaded IMANS enhanced the efficacy of combination therapy, solved problems related to gene transfer, and specifically targeted lung cancer cells.Keywords: gene circuit, combination therapy, magnetic albumin nanospheres

Hao Zhang,1 Xinxin Hou,2 Mei Lin,3 Ling Wang,1 Hongbo Li,4 Chenyan Yuan,1 Chen Liang,1 Jia Zhang,5 Dongsheng Zhang1,6 1Medical School of Southeast University, Nanjing, Jiangsu, People’s Republic of China; 2Medical School of Henan Polytechnic University, Jiaozuo, Henan, People’s Republic of China; 3Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu, People’s Republic of China; 4Department of Ultrasound in Medicine, The First Affiliated Hospital (Jiangsu Province Hospital of TCM), Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 5Jiangsu Cancer Hospital, Nanjing, Jiangsu, People’s Republic of China; 6Jiangsu Key Laboratory For Biomaterials and Devices, Nanjing, Jiangsu, People’s Republic of China Abstract: As one of the most common malignant tumors, the clinical and socio-economic consequences of lung cancer are significant. Currently, surgery is the main treatment strategy for this disease, but the survival rates of lung cancer patients are not ideal due to the high recurrence rate of the disease. Therefore, many researchers are exploring new specific therapeutic methods that are highly curative and minimally cytotoxic to healthy tissues. To this end, albumin nanospheres simultaneously were loaded with super-paramagnetic iron oxide nanoparticles (as gene vector and anticancer gene), and plasmid pDONR223-IFNG, and modified with anti-EGFR monoclonal antibody cetuximab as therapy. Targeting agents, namely gene-loaded immunomagnetic albumin nanospheres (cetuximab [C225]-IFNG-IMANS), were prepared for targeted lung carcinoma cells (GLC-82 cell lines). Transmission electron microscopy images showed that the C225-IFNG-IMANS were successfully prepared, and the ability of the nanospheres to target GLC-82 cells in vitro was confirmed by Prussian blue staining, immunofluorescence experiments, and magnetic resonance imaging. Transfection photographs and agarose gel electrophoresis proved that pDONR223-IFNG could be encased in the albumin nanospheres. A Cell Counting Kit-8 assay showed that the combination therapy group had significantly more therapeutic effects on GLC-82 cells than other therapy groups. A flow cytometry assay showed that the apoptotic index of the combined treatment group was 67.68%, whereas the indices of the C225 group, gene therapy group, and magnetic fluid hyperthermia group were 12.2%, 16.34%, and 20.04% respectively. Therefore, the combination of thermal treatment, molecular targeted treatment, and gene treatment synergistically targets GLC-82 cells, and the use of C225-IFNG-IMANS as a gene or drug carrier offers a novel and promising approach for the treatment of lung cancer. Keywords: targeting gene therapy, nano-drug, magnetic nanoparticles

Yijie Chen,1,2,* Xinran Wang,3,4,* Ting Liu,3,4 Ding Sheng-zi Zhang,1,2 Yunfei Wang,3,4 Hongchen Gu,1,2 Wen Di3,4 1State Key Laboratory of Oncogenes and Related Genes, Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, 2School of Biomedical Engineering and Med-X Research Institute, 3Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 4Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Therapeutic antiangiogenesis strategies have demonstrated significant antitumor efficacy in ovarian cancer. Recently, RNA interference (RNAi) has come to be regarded as a promising technology for treatment of disease, especially cancer. In this study, vascular endothelial growth factor (VEGF)-small interfering RNA (siRNA) was encapsulated into a magnetic mesoporous silica nanoparticle (M-MSN)-based, polyethylenimine (PEI)-capped, polyethylene glycol (PEG)-grafted, fusogenic peptide (KALA)-functionalized siRNA delivery system, termed M-MSN_VEGF siRNA@PEI-PEG-KALA, which showed significant effectiveness with regard to VEGF gene silencing in vitro and in vivo. The prepared siRNA delivery system readily exhibited cellular internalization and ease of endosomal escape, resulting in excellent RNAi efficacy without associated cytotoxicity in SKOV3 cells. In in vivo experiments, notable retardation of tumor growth was observed in orthotopic ovarian tumor-bearing mice, which was attributed to significant inhibition of angiogenesis by systemic administration of this nanocarrier. No obvious toxic drug responses were detected in major organs. Further, the magnetic core of M-MSN_VEGF siRNA@PEI-PEG-KALA proved capable of probing the site and size of the ovarian cancer in mice on magnetic resonance imaging. Collectively, the results demonstrate that an M-MSN-based delivery system has potential to serve as a carrier of siRNA therapeutics in ovarian cancer. Keywords: antiangiogenesis, small interfering RNA, mesoporous silica nanoparticles, vascular endothelial growth factor, ovarian cancer

Osteosarcoma is one of the most common primary bone tumors in children and young adults. In this study, we investigated the role of musculoaponeurotic fibrosarcoma oncogene homolog K (MAFK) in osteosarcoma cell proliferation in vitro and the possible pathways that contributed to MAFK-related osteosarcoma development. We first reported that MAFK was expressed at low levels in an osteosarcoma cell line. Furthermore, a significant correlation between MAFK and the Wnt signaling pathway was observed in osteosarcoma by using a gene microarray assay. We found that expression of MAFK could be induced by Wnt1 in a dose-dependent manner. Furthermore, Wnt1-induced MAFK expression caused a significant increase of cell viability, whereas a Wnt pathway inhibitor, IWR-1-endo, abolished Wnt1-induced effects on MAFK. Finally, cell cycle analysis showed that enhanced cell proliferation might be attributed to re-distribution of the cell cycle. Together, our results suggested that Wnt1-induced MAFK expression promoted cell proliferation in MG63 cells, and that the role of MAFK in osteosarcoma might be closely linked to the Wnt signaling pathway.