Li Fei, Yuan Yuan, Dai Yun, Cheng Teng, Cao Heng, Yan Danmei, Li Ying, Sun Qian, Huang Xiaoyuan, Gao Qinglei
Cancer Biology Research Center (Key Laboratory of the Ministry of Education); Departments of.
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Hum Gene Ther. 2022 Mar;33(5-6):262-274. doi: 10.1089/hum.2021.247.
Oncolytic adenoviruses (OAds) have shown great promise in cancer therapy, but their efficacy has been greatly limited by poor tumor selectivity and highly off-target liver sequestration. Herein, we generated a novel "stealth" and tumor-targeting OAd vector, M0-TMTP1, by inserting TMTP1 (NVVRQ), a tumor-homing peptide specifically targeting metastasis, into the hypervariable region 5 of hexon. M0-TMTP1 exhibits increased transduction of tumor cells . biodistribution of M0-TMTP1 in an intraperitoneal disseminated ovarian cancer model showed significantly reduced virus load in major organs but apparent aggregation in tumors. The tumor-to-liver ratio of M0-TMTP1 was nearly 5,000-fold higher than that of control adenovirus M0. Furthermore, we armed M0-TMTP1 with trunked BID, a mitochondrial apoptosis protein, to obtain M11. Combining M11 with cisplatin (DDP) could induce an intensive antitumor effect and . Moreover, this combination therapy showed higher biosafety. Taken together, our results suggest that M11 represents a tumor-targeting, efficacious, and relatively nontoxic virotherapeutic agent, and these findings might offer renewed hope for tumor management.
溶瘤腺病毒（OAds）在癌症治疗中显示出巨大的潜力，但其疗效因肿瘤选择性差和高度非靶向性的肝脏滞留而受到极大限制。在此，我们通过将特异性靶向转移的肿瘤归巢肽TMTP1（NVVRQ）插入六邻体的高变区5，构建了一种新型的“隐形”且靶向肿瘤的OAd载体M0-TMTP1。M0-TMTP1表现出对肿瘤细胞转导的增加。M0-TMTP1在腹膜播散性卵巢癌模型中的生物分布显示，主要器官中的病毒载量显著降低，但在肿瘤中明显聚集。M0-TMTP1的肿瘤与肝脏比值比对照腺病毒M0高出近5000倍。此外，我们用线粒体凋亡蛋白截短型BID武装M0-TMTP1，得到M11。将M11与顺铂（DDP）联合使用可诱导强烈的抗肿瘤作用，且这种联合疗法显示出更高的生物安全性。综上所述，我们的结果表明M11是一种靶向肿瘤、有效且相对无毒的病毒治疗剂，这些发现可能为肿瘤治疗带来新的希望。
