Polymer-linked Nitroxides Tumor-MRI Contrast Agents.

描述（由申请人提供）： 尽管在靶向药物递送方面取得了进展，但癌症治疗中持续存在的问题之一是除了监测肿瘤的大小和位置之外，化疗剂在肿瘤部位的定位。迄今为止，这些数据是从间接方法推断出来的，如动物模型中的分布研究和肿瘤大小的减小。同时监测递送系统的分布及其在减少肿瘤质量中的作用将是未来癌症治疗进展的主要兴趣。为了克服这一局限性，它提出了在这个小的赠款，开发聚合物导向的氮氧化物作为选择性磁共振造影剂的肿瘤成像。在制备聚合物导向的氮氧自由基后，将通过MRI测量兔肿瘤中的摄取来确定这些化合物的功效。具体而言，我们将合成并表征一系列N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物连接的氮氧自由基和HPMA共聚物连接的氮氧自由基。氮氧化物将通过不可生物降解的甘氨酰-甘氨酸间隔基连接到共聚物主链上。这些化合物将通过物理化学方法表征，以确定其平均分子量、分子量分布和连接的氮氧化物数量、稳定性和弛豫性。一旦完成，我们将确定HPMA共聚物连接的氮氧自由基和HPMA共聚物连接的氮氧自由基被兔模型中的肿瘤吸收的能力。将VX 2肿瘤细胞植入兔大腿肌肉中并进行MRI成像实验，此时肿瘤已达到5-10 mm大小。这些研究的结果将为开发新型HPMA共聚物连接的氮氧化合物用于实体瘤的MR成像和靶向癌症化疗的同步监测铺平道路。

DESCRIPTION (provided by applicant): Despite advances in targeted drug delivery, one of the continuing problems in cancer therapy is the localization of the chemotherapeutic agent at the tumor site, in addition to monitoring the size and location of the tumor. To date these data have been inferred from indirect methods such as distribution studies in animal models and reduction in tumor size. Concurrent monitoring of the distribution of the delivery system and its role in reduction of tumor mass will be of prime interest in future advances in cancer treatment. To overcome this limitation, it is proposed in this small grant to develop polymer-directed nitroxides as selective MR contrast agents for tumor imaging. Upon preparation of polymer-directed nitroxides, efficacy of these compounds will be determined, measuring uptake in rabbit tumors by MRI. Specifically, we will synthesize and characterize a series of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer linked-nitroxides and HPMA copolymer linked-nitroxide biradicals. Nitroxides will be attached to the copolymer backbone via a non-biodegradable glycyl-glycine spacer. These compounds will be characterized by physicochemical methods to determine their average molecular weight, molecular weight distribution, and number of nitroxides attached, stability and relaxivity. Once completed, we will determine the ability of HPMA copolymer linkednitroxides and HPMA copolymer linked-nitroxide biradicals to be taken up by a tumor in a rabbit model. VX2 tumor cells will be implanted into the rabbit thigh muscle and MRI imaging experiments performed, when the tumor has reached the size of 5-10 ram. Results from these studies will pave the way for the development of novel HPMA copolymer-linked nitroxides for MR imaging of solid tumors and concurrent monitoring of targeted cancer chemotherapy.