A Tumor-Specific Nanoimmunocomplex Markedly Improves MR Imaging

描述（申请人提供）：胰腺癌的低治愈率是一个重要的健康问题。美国癌症协会估计，2005年将有32000名美国人被诊断出患有胰腺癌，31800人将死亡。胰腺癌是美国癌症死亡的第四大原因。早期发现似乎是目前改善高死亡率的唯一途径，但由于胰腺位于腹膜后且早期疾病缺乏症状，因此相当困难。我们建议进一步开发一种对进入癌细胞具有高亲和力的MR肿瘤靶向显像剂。目前胰腺的成像方法包括超声、CT、MRI和PET。每一种方法对胰腺成像和胰腺肿瘤分期都是中等到非常好的，但每一种方法都依赖于基于肿块、病变血管分布或其葡萄糖利用的间接癌征象。这些特征也存在于主要的胰腺癌模仿者中；慢性胰腺炎良性肿块。抗转铁蛋白受体scfv抗体片段（TfRscFv）免疫脂质体复合物是一种纳米结构（<300 nm），用于向肿瘤传递基因治疗。在裸鼠体内作为异种移植物植入后，它已被证明能靶向人胰腺癌细胞系。通过将gadenteate二聚氨基乙胺（“gadd”）放入免疫脂质体纳米复合物中，新的和独特的能力导致gadd直接递送到表达高水平转铁蛋白受体（TfR）的肿瘤细胞中。大多数正常细胞很少或没有摄取这种药物。大多数人胰腺癌细胞系过表达转铁蛋白受体。tfrscfv免疫脂质体gad-d纳米复合物（scL-gad-d）是可生物降解的，其残留成分可通过肾脏排出（gad-d）或分泌到胆道系统（脂质体）。scL-gad-d对肿瘤靶向具有高敏感性和高特异性，在小鼠正常组织中被细胞摄取的程度非常低。在我们对这种新型肿瘤靶向造影剂的初步研究中，我们发现胰腺癌动物对肿瘤背景的摄取非常高（是标准gad-d的3倍）。在这个1期STTR项目中，我们将在动物模型中更好地表征该药物，确定最佳剂量，最佳成像时间，并在小鼠中进行毒性研究，为未来2期STTR提交进行临床1期剂量升级毒性研究做准备。

DESCRIPTION (provided by applicant): The low rate of cure of pancreatic carcinoma is an important health problem. The American Cancer Society estimates that 32,000 Americans will be diagnosed with carcinoma of the pancreas in 2005, and 31,800 will die. Pancreatic cancer is the fourth leading cause of cancer death in the US. Early detection appears currently to be the only way of improving the high mortality rate, but is quite difficult because of the retroperitoneal location of the pancreas and the lack of symptoms in early disease. We are proposing to further develop a MR tumor targeting imaging agent with a high affinity for entering carcinoma cells. Current imaging methods for the pancreas include ultrasound, CT, MRI, and PET. Each of these is moderately to very good for imaging the pancreas and for staging pancreatic neoplasm, but each relies on indirect signs of carcinoma based on the identification of a mass, lesion vascularity, or its glucose utilization. These features are also present in the main mimicker of pancreatic carcinoma; benign masses from chronic pancreatitis. Anti-transferrin Receptor scFv-antibody fragment (TfRscFv) immunoliposome complex is a nano-construct (<300 nm) for delivery of gene therapy to tumors. It has been shown to target human pancreatic carcinoma cell lines in vivo when implanted as xenografts in athymic nude mice. By placing gadopentetate dimeglumine ("gad-d") into the immunoliposome nanocomplex, new and unique capabilities result in the delivery of gad-d directly into tumor cells which express high levels of the transferrin receptor (TfR). Most normal cells have little or no uptake of this agent. Most human pancreatic carcinoma cell lines overexpress the transferrin receptor. The TfRscFv-immunoiiposome gad-d nanocomplex (scL-gad-d) is biodegradable and the residual components are excreted by the kidney (gad-d) or secreted into the biliary system (liposome). The scL-gad-d demonstrates a high sensitivity for tumor targeting and high specificity having very low uptake into cells in the normal tissues of mice. In our preliminary work with this novel tumor targeting contrast media, we see very high tumor to background uptake in pancreatic carcinoma bearing animals (3 times that of standard gad-d). In this Phase 1 STTR project we will better characterize this agent in animal models, determine optimized dose, optimal time to imaging, and perform toxicity studies in mice in preparation for a future Phase 2 STTR submission to perform a Clinical Phase 1 dose escalation toxicity study.