Time Domian Electron Paramagnetic Resonance Imaging

a）TH-302作为体内辐射敏化剂的评价。TH-302是一种缺氧激活的前药，其具有与氮芥共价连接的硝基咪唑触发剂。在缺氧条件下，在硝基咪唑部分的氧化还原活化后，TH-302片段化并释放氮芥部分，产生显著的缺氧特异性细胞毒性。由于硝基咪唑部分本身可以作为放射增敏剂，我们检查了TH-302和辐射在体外和体内的联合作用。我们使用了两种肿瘤模型：小鼠SCCVII肿瘤和HT 29肿瘤。体外研究表明，这些细胞与TH-302在10 M水平下孵育导致与众所周知的放射增敏剂米索硝唑类似的放射增敏作用。体内研究表明，与单独的TH-302或单独的辐射相比，组合的TH-302 + 3戈伊辐射导致显著的肿瘤生长延迟。这些结果表明，联合化疗和放疗与TH-302的好处。B）抗肿瘤剂CG-0321作用模式的机理研究：CG-0321是一种磺基糖脂，已显示其使肿瘤对电离辐射敏感。然而，机制细节尚未明确，一些研究指出给药后肿瘤氧合短暂增加。体外研究表明，在几种检测的细胞系中没有放射增敏的证据。体内成像研究表明，CG-0321给药后30 - 60分钟存在肿瘤pO 2升高的时间窗。肿瘤pO 2的增加幅度具有肿瘤类型依赖性。另外的成像研究表明，给药后肿瘤灌注增加。监测SCCVII和A549细胞中的治疗反应的体内肿瘤生长动力学研究显示，当在CG-0321施用后约30分钟施用放射治疗时，存在显著的生长延迟。这些研究显示了分子成像技术探测肿瘤微环境在理解药物作用机制方面的价值，以及使用这种成像方式来计划治疗。

a) Evaluation of TH-302 as an in vivo radiation sensitizer. TH-302 is a hypoxia activated prodrug which has a nitroimidazole trigger linked to a nitrogen mustard covalntly. Upon redox-activation of the nitroimidazole moiety, in hypoxic conditions, TH-302 fragments and releases the nitrogen mustard moiety exerting significant hypoxia specific cytotoxicity. Since the nitroimidazole moiety can itself act as a radiosensitizer, we examined the combined effect of TH-302 and radiation in vitro and in vivo. We used the two tumor models: The SCCVII tumor and the HT29 tumor in mice. In vitro studies show that incubation of these cells with TH-302 at 10 M level results in radiosensitzation similar to the well-known radiosensitizer, misonidazole. In vivo studies show that, the combined TH-302 + 3 Gy radiation resulted in a significant tumor growth delay compared to ether TH-302 alone or radiation alone. These results suggest the benefits of combination chemoradiation therapy with TH-302. b) Mechanistic studies of the mode of action of the anti-tumor agent CG-0321: CG-0321 is a sulfoglycolipid which has been shown to sensitize tumors to ionizing radiation. However the mechanistic details are not clearly established with some studies pointing to transient increases in tumor oxygenation after drug administration. In vitro studies show no evidence of radiosensitization in several cell lines tested. In vivo imaging studies show that there is a time window of increased tumor pO2 30 - 60 mins after CG-0321 administration. The magnitude increase in tumor pO2 was tumor type dependent. Additional imaging studies show that there is increased tumor perfusion after drug administration. In vivo tumor growth kinetics studies monitoring treatment response in SCCVII and A549 cells show that there is a significant growth delay when radiation treatment was administered at about 30 mins after CG-0321 administration. These studies show the value of molecular imaging techniques probing the tumor microenvironment in understanding the mechanistic aspects of drug action and also the use of such imaging modalities to plan treatments.