Graduate Institute of Cancer Biology, China Medical University, Taichung 40447, Taiwan.
Mol Pharm. 2012 May 7;9(5):1396-408. doi: 10.1021/mp200649g. Epub 2012 Apr 16.
Cell-based carriers were recently exploited as a tumor-targeting tool to improve systemic delivery of oncolytic viruses for cancer therapy. However, the slow clearance of carrier cells from normal organs indicates the need for a controllable system which allows viral delivery only when the carrier cells reach the tumor site. In this study, we sought to develop a pharmaceutically inducible cell-based oncolytic adenovirus delivery strategy for effective targeting and treatment of renal cell carcinoma (RCC), which is one of the most malignant tumor types with an unfavorable prognosis. Herein, we demonstrated the intrinsic tumor homing property of human bone marrow-derived mesenchymal stem cells (hMSCs) to specifically localize primary and metastatic RCC tumors after systemic administration in a clinically relevant orthotopic animal model. The platelet derived growth factor AA (PDGF-AA) secreted from RCC was identified as a chemoattractant responsible for the recruitment of hMSCs. Like endogenous osteocalcin whose barely detectable level of expression was dramatically induced by vitamin D(3), the silenced replication of human osteocalcin promoter-directed Ad-hOC-E1 oncolytic adenoviruses loaded in hMSCs was rapidly activated, and the released oncolytic adenoviruses sequentially killed cocultured RCC cells upon vitamin D(3) exposure. Moreover, the systemic treatment of RCC tumor-bearing mice with hMSC cell carriers loaded with Ad-hOC-E1 had very limited effects on tumor growth, but the loaded hMSCs combined with vitamin D(3) treatment induced effective viral delivery to RCC tumors and significant tumor regression. Therapeutic effects of hMSC-based Ad-hOC-E1 delivery were confirmed to be significantly greater than those of injection of carrier-free Ad-hOC-E1. Our results presented the first preclinical demonstration of a novel controllable cell-based gene delivery strategy that combines the advantages of tumor tropism and vitamin D(3)-regulatable human osteocalcin promoter-directed gene expression of hMSCs to improve oncolytic virotherapy for advanced RCC.
细胞载体最近被用作肿瘤靶向工具，以改善溶瘤病毒的全身递送，用于癌症治疗。然而，载体细胞从正常器官中的清除缓慢表明需要一种可控的系统，该系统仅在载体细胞到达肿瘤部位时才允许病毒递送至载体细胞。在这项研究中，我们试图开发一种基于药物诱导的细胞溶瘤腺病毒递药策略，用于有效靶向和治疗肾细胞癌（RCC），RCC 是预后不良的最恶性肿瘤类型之一。在此，我们证明了人骨髓间充质干细胞（hMSC）的内在肿瘤归巢特性，在临床相关的原位动物模型中，hMSC 经全身给药后可特异性定位于原发性和转移性 RCC 肿瘤。从 RCC 分泌的血小板衍生生长因子 AA（PDGF-AA）被鉴定为负责招募 hMSC 的趋化因子。与内源性骨钙素一样，其表达水平几乎检测不到，但维生素 D（3）可显著诱导其表达，负载于 hMSC 中的人类骨钙素启动子指导的 Ad-hOC-E1 溶瘤腺病毒的沉默复制被迅速激活，并且释放的溶瘤腺病毒在暴露于维生素 D（3）后相继杀死共培养的 RCC 细胞。此外，用负载 Ad-hOC-E1 的 hMSC 细胞载体对 RCC 荷瘤小鼠进行全身治疗对肿瘤生长的影响非常有限，但负载 hMSC 并联合维生素 D（3）治疗可有效将病毒递送至 RCC 肿瘤，并显著抑制肿瘤生长。基于 hMSC 的 Ad-hOC-E1 递药的治疗效果明显优于注射无载体的 Ad-hOC-E1。我们的结果首次展示了一种新型的、基于细胞的、可控制的基因递药策略的临床前验证，该策略结合了肿瘤趋向性和维生素 D（3）调控的 hMSC 中人类骨钙素启动子指导的基因表达的优势，以改善晚期 RCC 的溶瘤病毒治疗。
