Bioresponsive MR probes for imaging pancreatic cancer

胰腺癌是所有癌症中预后最差的，其发病率几乎等于死亡率 率虽然许多其他癌症的治疗取得了重大进展，但 胰腺癌也只是轻微好转目前的诊断方法只能检测出 在晚期阶段的疾病，在这一点上，原发性肿瘤往往是太先进的根治性手术，并已 转移了通过能够检测胰腺癌的早期阶段，患者的结果可以 大幅改善。通过特异性检测局部生物化学和细胞生物学的变化， 环境和分子肿瘤标志物，有可能在新生肿瘤发展之前检测到它。 足以引起解剖或功能紊乱。增殖性肿瘤的关键环境标志物 包括由肿瘤缺氧和富含胶原纤维结缔组织增生诱导的高还原电位。胰腺 侵袭性疾病类型的癌症分子标志物包括高水平的αvβ6整联蛋白受体， 基质金属蛋白酶-9（MMP-9）活性升高。这些分子标记物可以通过 靶向肿瘤标志物的生物响应磁共振（MR）造影剂。 临床批准的Gd（III）MR造影剂（CA）为开发 胰腺癌的分子成像探针，通过检测环境和分子 标记。米德实验室继续开发具有各种活化的响应性Gd（III）CA 改变探针信号以响应特定条件的机制。电子自旋弛豫时间（T1 e） 调制的分子成像探针为基于Gd（III）的CA提供了一个有前途的生物活化平台， 因为T1 e是影响CA的所有配位球的唯一参数，所以其 调制可以建立比T1参数的调制更低的背景信号。氧化还原敏感T1 e- 调制的探针将使用胶原靶向环肽在促结缔组织增生中积累， 微环境，并将针对肿瘤特异性氧化还原电位进行调整。MR移位探头提供 一种基于比率成像区分肿瘤组织与健康组织的生物可激活方法，其中 探针的信号响应于环境条件而移动。使用环状RGD靶向整合素 受体在胰腺癌中过表达和MMP-9切割的短肽，该探针将 在胰腺肿瘤中积累，并提供MMP-9活性的比率数据。新的性能 将使用健康小鼠和胰腺癌的原位模型在体内评价探针。 该提案符合NCI的使命声明和供资计划。该项目涉及 开发用于胰腺癌分子检测的新型成像探针。环境和 胰腺癌的分子标记物提供了早期检测的目标。因为预后不佳 与胰腺癌相关，疾病检测的进步可以大大改善患者的预后。

Pancreatic cancer holds the poorest prognosis of any cancer with an incident rate nearly equal to its mortality rate. While significant advances in treatment have been made for many other cancers, the outcomes for pancreatic cancer have only marginally improved. Current diagnostic methods are only able to detect the disease at late stages, at which point the primary tumor is often too advanced for curative surgery and has metastasized. By enabling detection of early stages of pancreatic cancer, the outcome of patients could be drastically improved. By specifically detecting changes in local biochemistry and cell biology through environmental and molecular tumor markers, it is possible to detect a nascent tumor before it has developed enough to cause anatomical or functional disturbances. Key environmental markers of proliferating tumors include a high reduction potential, induced by tumor hypoxia, and collagen-rich desmoplasia. Pancreatic cancer molecular markers of aggressive disease types include high levels of αvβ6 integrin receptor and elevated matrix metalloproteinase-9 (MMP-9) activity. These molecular markers can be detected by bioresponsive magnetic resonance (MR) contrast agents that are targeted to tumor markers. Clinically-approved Gd(III) MR contrast agent (CAs) provide a versatile platform for developing molecular imaging probes for pancreatic cancer through the detection of environmental and molecular markers. The Meade lab has continued to develop responsive Gd(III) CAs with a variety of activation mechanisms that alter the probe's signal in response to specific conditions. Electronic spin relaxation time (T1e) modulated molecular imaging probes provide a promising bioactivatable platform for Gd(III)-based CA with a low r1,off and bright r1,on. Because T1e is the only parameter to affect all coordination spheres of the CA, its modulation can establish a lower background signal than modulation of T1 parameters. Redox-sensitive T1e- modulated probes will use a collagen-targeting cyclic peptide to accumulate in the desmoplastic microenvironment and will be tuned for a tumor specific redox potential. MR shift probes provide a bioactivatable method of distinguishing tumor tissue from healthy tissue based on ratiometric imaging, in which the signal of the probe shifts in response to environmental conditions. Using cyclic RGD to target integrin receptors overexpressed in pancreatic cancer and a short peptide cleaved by MMP-9, this probe will accumulate in pancreatic tumors and provide ratiometric data on MMP-9 activity. The performance of the new probes will be evaluated in vivo using healthy mice and an orthotopic model of pancreatic cancer. This proposal meets the mission statement and funding plans of the NCI. The project involves the development of new imaging probes for molecular detection of pancreatic cancer. Environmental and molecular markers of pancreatic cancer provide a target for early detection. Because of the poor prognosis associated with pancreatic cancer, advances in disease detection could drastically improve patient outcome.