Ho Chun-Te, Wu Mei-Hsuan, Chen Ming-Jen, Lin Shih-Pei, Yen Yu-Ting, Hung Shih-Chieh
Drug Development Center, Institute of New Drug Development, Institute of Biomedical Sciences, School of Medicine, China Medical University, Taichung 404, Taiwan.
Integrative Stem Cell Center, Department of Orthopaedics, China Medical University Hospital, Taichung 404, Taiwan.
Biomedicines. 2021 May 13;9(5):548. doi: 10.3390/biomedicines9050548.
Although oncolytic viruses are currently being evaluated for cancer treatment in clinical trials, systemic administration is hindered by many factors that prevent them from reaching the tumor cells. When administered systemically, mesenchymal stem cells (MSCs) target tumors, and therefore constitute good cell carriers for oncolytic viruses. MSCs were primed with trichostatin A under hypoxia, which upregulated the expression of CXCR4, a chemokine receptor involved in tumor tropism, and coxsackievirus and adenovirus receptor that plays an important role in adenoviral infection. After priming, MSCs were loaded with conditionally replicative adenovirus that exhibits limited proliferation in cells with a functional p53 pathway and encodes Escherichia coli nitroreductase (NTR) enzymes (CRAdNTR) for targeting tumor cells. Primed MSCs increased tumor tropism and susceptibility to adenoviral infection, and successfully protected CRAdNTR from neutralization by anti-adenovirus antibodies both in vitro and in vivo, and specifically targeted p53-deficient colorectal tumors when infused intravenously. Analyses of deproteinized tissues by UPLC-MS/QTOF revealed that these MSCs converted the co-administered prodrug CB1954 into cytotoxic metabolites, such as 4-hydroxylamine and 2-amine, inducing oncolysis and tumor growth inhibition without being toxic for the host vital organs. This study shows that the combination of oncolytic viruses delivered by MSCs with the activation of prodrugs is a new cancer treatment strategy that provides a new approach for the development of oncolytic viral therapy for various cancers.
尽管溶瘤病毒目前正在临床试验中评估用于癌症治疗，但全身给药受到许多因素的阻碍，这些因素使其无法到达肿瘤细胞。全身给药时，间充质干细胞（MSC）可靶向肿瘤，因此是溶瘤病毒的良好细胞载体。在缺氧条件下用曲古抑菌素A预处理MSC，这会上调CXCR4（一种参与肿瘤嗜性的趋化因子受体）以及在腺病毒感染中起重要作用的柯萨奇病毒和腺病毒受体的表达。预处理后，将条件性复制腺病毒加载到MSC中，该腺病毒在具有功能性p53途径的细胞中增殖受限，并编码用于靶向肿瘤细胞的大肠杆菌硝基还原酶（NTR）（CRAdNTR）。预处理的MSC增加了肿瘤嗜性和对腺病毒感染的敏感性，并在体外和体内成功保护CRAdNTR免受抗腺病毒抗体的中和，静脉注射时可特异性靶向p53缺陷型结直肠癌肿瘤。通过UPLC-MS/QTOF对脱蛋白组织的分析表明，这些MSC将共同给药的前药CB1954转化为细胞毒性代谢物，如4-羟胺和2-胺，诱导肿瘤溶解和肿瘤生长抑制，而对宿主重要器官无毒。这项研究表明，由MSC递送的溶瘤病毒与前药激活相结合是一种新的癌症治疗策略，为开发针对各种癌症的溶瘤病毒疗法提供了一种新方法。
