A Tumor-Specific Nanoimmunocomplex Markedly Improves MR Imaging

肿瘤特异性纳米免疫复合物显着改善 MR 成像

• 批准号: 7107574
• 负责人: Esther H Chang
• 金额: $ 47.89万
• 依托单位: SYNERGENE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-14 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7107574
• 关键词: carcinoma; neoplasm /cancer; pancreas; pancreas neoplasms; transferrin receptor

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.

描述(申请人提供)：胰腺癌治愈率低是一个重要的健康问题。美国癌症协会估计，2005年将有32,000名美国人被诊断出患有胰腺癌，其中31,800人将死亡。胰腺癌是美国癌症死亡的第四大原因。早期发现目前似乎是改善高死亡率的唯一方法，但由于胰腺位于腹膜后位置，以及早期疾病缺乏症状，因此很难做到这一点。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。每一种方法对于胰腺成像和胰腺肿瘤的分期都是中等到非常好的，但每一种都依赖于肿瘤的间接征象，基于对肿块、病变血管或其葡萄糖利用的识别。这些特征也存在于胰腺癌的主要模拟物--慢性胰腺炎的良性肿块中。抗转铁蛋白受体单链抗体片段(TfRscFv)免疫脂质体复合体是一种纳米结构(~lt；300 nm)，用于肿瘤的基因治疗。已经证明，当它作为异种移植到裸鼠体内时，它可以靶向体内的人胰腺癌细胞系。通过将Gad-d置入免疫脂质体纳米复合体中，新的和独特的功能导致Gad-d直接进入表达高水平转铁蛋白受体(TFR)的肿瘤细胞。大多数正常细胞很少或根本不摄取这种物质。大多数人胰腺癌细胞株都过度表达转铁蛋白受体。TfRscFv-免疫脂质体Gad-d纳米复合体(scl-Gad-d)是可生物降解的，残留成分由肾脏排泄(Gad-d)或分泌到胆道系统(脂质体)。Scl-Gad-d对肿瘤靶向具有很高的敏感性和高度的特异性，对小鼠正常组织的细胞摄取率很低。在我们对这种新型肿瘤靶向造影剂的初步研究中，我们发现携带胰腺癌的动物对肿瘤的背景摄取率非常高(是标准Gad-d的3倍)。在这个第一阶段的STTR项目中，我们将在动物模型中更好地描述这种药物的特性，确定最佳剂量、最佳成像时间，并在小鼠身上进行毒性研究，为未来的第二阶段STTR提交进行临床第一阶段剂量递增毒性研究做准备。