Systemic administration of mesenchymal stem cells loaded with a novel oncolytic adenovirus carrying IL-24/endostatin enhances glioma therapy
Systemic administration of mesenchymal stem cells loaded with a novel oncolytic adenovirus carrying IL-24/endostatin enhances glioma therapy
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全身给药装载有携带 IL-24/内皮抑素的新型溶瘤腺病毒的间充质干细胞可增强神经胶质瘤治疗
DOI：
10.1016/j.canlet.2021.03.027
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发表时间：
2021-04-10
期刊：
影响因子：
9.7
通讯作者：
Xia, Haibin
中科院分区：
文献类型：
--
作者：
Zhang, Junhe;Chen, Hao;Xia, Haibin
溶瘤腺病毒介导的基因治疗在癌症治疗中显示出希望；然而，溶瘤腺病毒系统地递送到肿瘤仍然具有挑战性。最近，间充质干细胞(MSCs)已成为改善转运的潜在载体。然而，由于溶瘤腺病毒在MSCs中复制，平衡MSC活性和病毒载量是实现最佳治疗效果的关键。因此，我们开发了一种Allin-one Tet-on系统，可以调控溶瘤腺病毒的复制。然后，我们将携带IL-24和/或内皮抑素的新型溶瘤腺病毒负载到人脐血-间充质干细胞(hUCB-MSCs)中，用于胶质瘤的治疗。体外实验表明，这种新型的溶瘤腺病毒可以有效地复制和杀死胶质瘤细胞，而不影响正常细胞。此外，多西环素可有效调控溶瘤腺病毒在人脐血间充质干细胞中的复制。在人脑胶质瘤移植瘤模型中，同时表达IL24和内皮抑素的多西环素诱导组的抗肿瘤作用明显强于其他组。因此，这种由Tet-On系统控制的溶瘤腺病毒系统递送策略是一种很有前途的抗胶质瘤疗效的方法，尤其是对转移性肿瘤。
Oncolytic adenovirus-mediated gene therapy shows promise for cancer treatment; however, the systemic delivery of oncolytic adenovirus to tumors remains challenging. Recently, mesenchymal stem cells (MSCs) have emerged as potential vehicles for improving delivery. Yet, because the oncolytic adenovirus replicates in MSCs, balancing MSC viability with viral load is key to achieving optimal therapeutic effect. We thus developed an allin-one Tet-on system that can regulate replication of oncolytic adenovirus. Then, we loaded the novel oncolytic adenovirus carrying interleukin (IL)-24 and/or Endostatin in human umbilical cord blood-mesenchymal stem cells (hUCB-MSCs) for glioma therapy. In vitro assays demonstrated that this novel oncolytic adenovirus could efficiently replicate and kill glioma cells while sparing normal cells. Moreover, doxycycline effectively regulated oncolytic adenovirus replication in the hUCB-MSCs. The doxycycline induction group with dual expression of IL24 and Endostatin exhibited significantly greater antitumor effects than other groups in a xenograft model of glioma. Thus, this strategy for systemic delivery of oncolytic adenovirus with its oncolytic activity controlled by a Tet-on system is a promising method for achieving antitumor efficacy in glioma, especially for metastatic tumors.