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  • br d Department of Pathology West China

    2022-05-20


    d Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, 610041, PR China
    • PEG-PCL-PEG and DOTAP could assembly into nanomicelles.
    • MP/DPPP could inhibited cancer proliferation in vitro.
    • MP/DPPP could induced cancer apoptosis in vitro.
    • MP/DPPP could inhibit cancer growth in vivo.
    Keywords:
    Matrix protein
    Cancer
    PEG-PCL-PEG 
    The matrix protein (MP) is the core structure of the oncolytic vesicular stomatitis virus (VSV) and it played a vital role during the process of VSV infection and corresponding cytopathic effects in cancer treatment. In this study, a novel delivery synthesized by PEG-PCL-PEG and DOTAP (PPPD) was applied to encapsulate MP plas-mids to derive the advantage and overcome the drawback of VSV platform in the treatment of colon cancer. The MP/DPPP micelles were stable in physiological solution, with an average diameter of 102 nm and zeta potential of 5.4 mV. This delivery system has a high encapsulation rate of 96% and transfection efficiency of 36%. A prominent anti-cancer activity of MP/DPPP was found both in Ct26 PSB 1115 and animal models. The mechanisms of antitumor were further explored in this research. Our results indicated that MP/DPPP micelles were promising agents for future clinical application in the treatment of colon cancer.
    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 hypothesis 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.