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  • br Introduction br Colon cancer is

    2020-08-12


    1. Introduction
    Colon cancer is one of the most common cancer worldwide and the second leading cancer related cause in America [1]. Evidences show that diet, gut microbiota and gene mutation are closely related to colon progression and carcinogenesis [2–5]. Despite the development in surgical technique and traditional chemotherapy, the prevention of cancer relapse and metastasis, and extending of survival time are not satisfactory, especially for advanced colon cancer. Latest research showed cancer usually recurred in two years after treatment, and the system recurrence was approximate 25%, whereas the local recurrence rate was relative low, about 3%. The 5-year survival rate was only about 20% in patients with stage II or III colon cancer who accepted radical surgical resection accompanied by preoperative or post-operative chemotherapy [6]. It highlighted the deficiency of current
    adjuvant systemic treatment and other supplementary or alternative treatment for colon cancer is needed to improve the outcome of this notorious cancer.
    The immunotherapy of cancer, which obtained rapid development in recent years, has become an important therapeutic modality apart from surgery, chemotherapy and radiotherapy [7]. It started from a ABT 263 in 1909 that cancer progression was suppressed by immune system, and till now, various cancer immunotherapies have been proved to be effective to some extent, such as cancer vaccines, immune checkpoint inhibitors et al. [8–10]. Compared with traditional thera-pies, researches showed that cancer immunotherapy had unique ad-vantages. Immunotherapy agents suppress or eliminate cancer not de-pending on the tumor type. In a previous clinical trial, the immune cell co-receptor Programmed Death 1 (PD-1) blocker nivolumab demon-strated satisfactory anti-tumor activity against various advanced
    ∗ Corresponding author. Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second university Hospital, Sichuan University, Chengdu, 610041, PR China.
    malignant tumors [11]. In addition, patients who stopped im-munotherapy treatment, mainly due to immune-mediated side effects, could continue to benefit [12].
    Oncolytic viruses (OVs), have cause extensive concern due to their preferential killing of tumor cells, leaving normal cells intact, in cancer immunotherapy. They not only destroy tumor by direct lysis of tumor cells, but also brake the immune tolerance, which was created by tumor cells to escape immune surveillance, and activate immune responses against tumor cells in primary site and distant metastasis. The vesicular stomatitis virus (VSV), which consists of a negative-strand RNA, re-presents an excellent example of OVs based on its fast replication and specifically attack on tumor cells [13]. It can efficiently infect tumor cells, replicate rapidly in the cytoplasm, and prevent the synthesis of RNA and protein, causing the lysis of host cells. During this process, tumor-associated antigens were released from lysed cells, and activate immune responses against cancer cells, including the stimulation of dendritic cells, induction of tumor-specific CD8+ T cells, infiltration of natural killer cells et al. [14–16]. The core structure of VSV, matrix protein (MP), plays an important role in genome packaging and shut-ting down the transcription of cancer cells through a variety of me-chanisms. Suitable carriers should be chosen to deliver this key protein to target cells.
    The nanomedicine has got rapid development and wide concern in recent years. Various nanomaterials with different sizes, physico-chemical properties and surface morphologies were utilized to design proper delivery systems for compounds, antibodies, siRNAs and other agents in the treatment of cancer [17–20]. In this research, we plan to formulate a gene delivery system PPPD micelles with 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP) and poly (ethylene glycol)–poly (3-caprolactone)-poly (ethylene glycol) (PEG-PCL-PEG), and to re-search on therapeutic efficacy of MP on colon cancer and explore the mechanisms.
    2. Materials and methods
    Materials were purchased from standard sources: 1,2-dioleoyl-3-trimethylammonium-propane (chloride salt) (DOTAP) (Avanti Polar Lipids Inc., Alabaster, AL, USA); 3-(4,5-dimethylthiazol-2-yl)-2,5-di-phenyl tetrazolium bromide (MTT) (Sigma, USA); Dulbecco's Modified Eagle's Medium (DMEM) and fetal bovine serum (FBS) (Gibco BRL, USA); methanol and acetic acid (HPLC grade) (Fisher Scientific, UK); and dimethyl sulfoxide (DMSO) and acetone (KeLong Chemicals, China). Antibodies used include: rabbit anti-mouse Ki67 antibody (Abcam, USA) and rhodamine-conjugated secondary antibody (Abcam, USA).