Bioresponsive MR probes for imaging pancreatic cancer

胰腺癌是所有癌症中预后最差的，发病率几乎与死亡率持平。 费率。虽然在治疗许多其他癌症方面取得了重大进展，但 胰腺癌只有轻微的改善。目前的诊断方法只能检测到 晚期疾病，此时原发肿瘤通常太过晚期而不能进行根治性手术 转移的。通过能够检测到胰腺癌的早期阶段，患者的结果可能是 有了显著的改进。通过专门检测局部生物化学和细胞生物学的变化 环境和分子肿瘤标记物，有可能在肿瘤形成之前就发现它。 足以引起解剖或功能紊乱的。增生性肿瘤的关键环境标记物 包括高还原潜能，诱导肿瘤缺氧和胶原丰富的结缔组织增生。胰腺 侵袭性疾病类型的癌症分子标志物包括高水平的αvβ6整合素受体和 基质金属蛋白酶9(MMP9)活性升高。这些分子标记可以通过 以肿瘤标志物为靶点的生物响应性磁共振(MR)造影剂。 临床批准的Gd(III)磁共振造影剂(CA)提供了一个通用的开发平台 从环境和分子检测看胰腺癌的分子成像探针 记号笔。Meade实验室继续开发具有各种激活的响应性Gd(III)CA 根据特定条件改变探测器信号的机制。电子自旋弛豫时间(T1e) 调制分子成像探针为基于Gd(III)的CA提供了一种很有前途的生物活化平台 低R1，关，亮R1，开。由于T1e是影响CA的所有配位域的唯一参数，因此其 调制可以建立比调制T1参数更低的背景信号。氧化还原敏感型T1e- 调制的探针将使用胶原靶向环肽在促结缔组织中积聚 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 基于比率成像的区分肿瘤组织和健康组织的可生物激活的方法，其中 探头的信号会随着环境条件的变化而变化。利用环状RGD靶向整合素 受体在胰腺癌中的过度表达和被基质金属蛋白酶-9切割的短肽，该探针将 在胰腺肿瘤中积累，并提供关于基质金属蛋白酶-9活性的比率数据。新款汽车的性能 这些探针将在体内使用健康的小鼠和胰腺癌的原位模型进行评估。 这项提议符合NCI的使命声明和资金计划。该项目涉及 用于胰腺癌分子检测的新型成像探针的开发。环境和 胰腺癌的分子标志物为早期发现提供了靶点。因为预后不佳 与胰腺癌相关的疾病检测的进步可以极大地改善患者的预后。

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.