Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Stem Cells. 2010 Apr;28(4):832-41. doi: 10.1002/stem.313.
Stem cells are promising therapeutic delivery vehicles; however pre-clinical and clinical applications of stem cell-based therapy would benefit significantly from the ability to simultaneously determine therapeutic efficacy and pharmacokinetics of therapies delivered by engineered stem cells. In this study, we engineered and screened numerous fusion variants that contained therapeutic (TRAIL) and diagnostic (luciferase) domains designed to allow simultaneous investigation of multiple events in stem cell-based therapy in vivo. When various stem cell lines were engineered with the optimized molecule, SRL(O)L(2)TR, diagnostic imaging showed marked differences in the levels and duration of secretion between stem cell lines, while the therapeutic activity of the molecule showed the different secretion levels translated to significant variability in tumor cell killing. In vivo, simultaneous diagnostic and therapeutic monitoring revealed that stem cell-based delivery significantly improved pharmacokinetics and anti-tumor effectiveness of the therapy compared to intravenous or intratumoral delivery. As treatment for highly malignant brain tumor xenografts, tracking SRL(O)L(2)TR showed stable stem cell-mediated delivery significantly regressed peripheral and intracranial tumors. Together, the integrated diagnostic and therapeutic properties of SRL(O)L(2)TR answer critical questions necessary for successful utilization of stem cells as novel therapeutic vehicles.
干细胞是很有前途的治疗性输送载体；然而，基于干细胞的治疗的临床前和临床应用将大大受益于能够同时确定通过工程化干细胞输送的治疗的疗效和药代动力学。在这项研究中，我们设计并筛选了许多融合变体，其中包含治疗（TRAIL）和诊断（荧光素酶）结构域，旨在允许同时研究体内基于干细胞治疗的多个事件。当用优化的分子 SRL(O)L(2)TR 对各种干细胞系进行工程化时，诊断成像显示干细胞系之间分泌水平和持续时间存在明显差异，而分子的治疗活性表明不同的分泌水平导致肿瘤细胞杀伤的显著变异性。在体内，同时进行诊断和治疗监测表明，与静脉内或肿瘤内给药相比，基于干细胞的输送显著改善了治疗的药代动力学和抗肿瘤效果。作为对高度恶性脑肿瘤异种移植物的治疗，跟踪 SRL(O)L(2)TR 显示稳定的干细胞介导的输送显著使外周和颅内肿瘤消退。总之，SRL(O)L(2)TR 的综合诊断和治疗特性回答了成功利用干细胞作为新型治疗载体所需的关键问题。
