(PQC5)Early Detection Pancreatic Cancer by Hyperpolarized Silicon Nanoparticles

(PQC5)超极化硅纳米颗粒早期检测胰腺癌

• 批准号: 8687422
• 负责人: Pratip K. Bhattacharya
• 金额: $ 20.88万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687422
• 关键词: Accounting; Acinar Cell; Affinity; Avidity; Binding; Binding Proteins; Biochemical; Biological Markers; Cancer Etiology; Cancer Model; Cell Nucleus; Cessation of life; Characteristics; Clinic; Coupled; Data; Decision Making; Defect; Detection; Development; Diagnosis; Diagnostic Imaging; Disease; Disease-Free Survival; Early Diagnosis; Environment; Excision; Feedback; Free Radicals; Goals; Hour; Human; Image; Imagery; Imaging Device; Imaging Techniques; Immunohistochemistry; Intestines; Laboratories; Lactose; Lead; Lesion; Life; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Microscopic; Monitor; Mus; NOD/SCID mouse; Neoadjuvant Therapy; Nuclear; Operative Surgical Procedures; Outcomes Research; Pancreas; Pancreatic carcinoma; Patient Selection; Patients; Process; Proteins; Research; Research Proposals; Resolution; Sensitivity and Specificity; Signal Transduction; Silicon; Site; Specificity; Staging; Stromal Neoplasm; Surface; Techniques; Time; Tissues; Translating; Tumor-Derived; United States; Unresectable; analog; base; chronic pancreatitis; cohort; cold temperature; imaging modality; improved; in vivo; in vivo imaging; molecular imaging; mouse model; nanoparticle; neoplastic cell; novel; optical imaging; outcome forecast; pancreatic neoplasm; pancreatitis-associated protein; public health relevance; tumor; tumor xenograft; virtual

DESCRIPTION (provided by applicant): The primary reason for a poor prognosis for patients with pancreatic cancer is because 80-90% of patients have unresectable disease at the time of diagnosis. This research proposal offers a strategy that may enable the detection of pancreatic cancer by MRI with at least two to three orders of magnitude smaller than those currently detected by employing target specific hyperpolarized silicon nanoparticles. This strategy when successfully introduced in the clinic will improve the overall detectability of pancreatic tumors a early stages of their development and could potentially save lives by successful surgical interventions. Among pancreatic tumor biomarkers produced in pancreatic tissue, the hepatocarcinoma-intestine-pancreas/pancreatitis- associated protein (HIP/PAP) was found to be over-expressed more than 130-fold in pancreatic acinar cells in pancreatic cancer, as compared to normal pancreas. In contrast, only a 9-fold increased expression of HIP/PAP protein was observed in acinar cells in chronic pancreatitis. This offers a unique opportunity to image the tumor and tumor stromal interaction in pancreatic cancer. The objective of this exploratory project is to develop a highly sensitive HIP/PAP targeted molecular imaging agent based on a novel silicon hyperpolarized Magnetic Resonance Imaging (MRI) technique recently developed in my laboratory. Previous biochemical studies demonstrated that HIP/PAP protein is a "lactose binding protein" which has a very high affinity to D- lactose. We intend to employ lactose-functionalized hyperpolarized Silicon nanoparticles (SiNPs) to target HIP/PAP protein in the acinar cells surrounding the pancreatic tumor. Hyperpolarization leads to over 10,000 fold signal enhancement compared to conventional MRI. We hypothesize that the specificity of lactose- functionalized SiNPs binding to HIP/PAP surrounding the pancreatic cancer coupled with the sensitivity gain due to hyperpolarization will lead to an "effective lesion size amplification", thereby, enabling the visualization of pancreatic carcinoma in in vivo MRI with at least two to three orders of magnitude smaller than those currently detected. Towards this goal, we propose the following three specific aims: I. Optimize the levels of hyperpolarization achievable by radical-free 29Si Dynamic Nuclear Polarization on lactose-functionalized silicon nanoparticles (SiNPs) as a function of SiNP size and in vivo targeting efficacy. II. Demonstrate "effective lesion size amplification" with real-time hyperpolarized MRI in a) one orthotropic pancreatic tumor xenograft mouse model and in b) two cohorts of patient derived tumor engrafted into NOD/SCID mice one of which is na¿ve human pancreatic tumor and the other exposed to neoadjuvant therapy. III. Correlate hyperpolarized 29Si MR data acquired in Aims II with immunohistochemistry and optical imaging data of fluorescently-tagged SiNPs in the murine cancer models demonstrating efficacy of this technique on the detection pancreatic carcinoma with at least two to three orders of magnitude smaller than those currently detected.

描述（申请人提供）：胰腺癌患者预后不良的主要原因是80-90%的患者在诊断时患有不可切除的疾病。该研究提案提供了一种可能能够检测胰腺癌的策略。通过 MRI 检测到的结果至少比目前使用目标特异性超极化硅纳米颗粒检测到的结果小两到三个数量级。当该策略成功引入临床时，将提高胰腺的整体可检测性。在胰腺组织产生的胰腺肿瘤生物标志物中，肝癌-肠-胰腺/胰腺炎相关蛋白（HIP/PAP）被发现过度表达。与正常胰腺相比，胰腺癌的胰腺腺泡细胞中 HIP/PAP 蛋白的表达仅增加了 9 倍。该探索性项目的目标是开发一种基于新型硅超极化的高灵敏度 HIP/PAP 靶向分子成像剂。我的实验室最近开发的磁共振成像 (MRI) 技术之前的生化研究表明，HIP/PAP 蛋白是一种“乳糖结合蛋白”，与 D-乳糖具有非常高的亲和力。我们打算采用乳糖功能化的超极化硅纳米粒子 (SiNP) 来靶向胰腺肿瘤周围腺泡细胞中的 HIP/PAP 蛋白，与传统 MRI 相比，超极化导致信号增强超过 10,000 倍。 SiNP 与胰腺癌周围的 HIP/PAP 结合，再加上超极化带来的敏感性增益，将导致“有效病灶大小”放大”，从而使体内 MRI 中的胰腺癌可视化至少比目前检测到的小两到三个数量级。为了实现这一目标，我们提出以下三个具体目标： I. 优化可通过以下方式实现的超极化水平乳糖功能化硅纳米颗粒 (SiNP) 上的无自由基 29Si 动态核极化与 SiNP 尺寸和体内靶向功效的关系 II。在 a) 一种正交异性胰腺肿瘤异种移植小鼠模型和 b) 两组刻入 NOD/SCID 小鼠的患者源性肿瘤中使用实时超极化 MRI 进行扩增，其中一组是 na¿将 Aims II 中获得的超极化 29Si MR 数据与小鼠癌症模型中荧光标记的 SiNP 的免疫组织化学和光学成像数据相关联，证明该技术在检测胰腺癌方面的功效。比目前检测到的至少小两到三个数量级。