(PQC5)Early Detection Pancreatic Cancer by Hyperpolarized Silicon Nanoparticles

描述(申请人提供)：胰腺癌患者预后差的主要原因是80%-90%的患者在诊断时有不能切除的疾病。这项研究提案提供了一种策略，可以使MRI检测胰腺癌的能力比目前使用靶向特定超极化硅纳米颗粒检测的至少小两到三个数量级。这一策略一旦成功应用于临床，将提高胰腺肿瘤发展的早期阶段的总体可探测性，并有可能通过成功的手术干预来挽救生命。在胰腺组织产生的胰腺肿瘤生物标志物中，hepatocarcinoma-intestine-pancreas/pancreatitis-相关蛋白(HIP/PAP)在胰腺癌组织的腺泡细胞中过度表达，是正常胰腺组织的130多倍。相反，在慢性胰腺炎的腺泡细胞中，仅观察到HIP/PAP蛋白的表达增加9倍。这为成像胰腺癌中肿瘤和肿瘤间质的相互作用提供了一个独特的机会。这个探索性项目的目标是基于我实验室最近开发的一种新的硅超极化磁共振成像(MRI)技术，开发一种高灵敏度的HIP/PAP靶向分子显像剂。以往的生化研究表明，HIP/PAP蛋白是一种乳糖结合蛋白，与D-乳糖有很高的亲和力。我们打算使用乳糖功能化超极化硅纳米颗粒(SiNPs)来靶向胰腺肿瘤周围的腺泡细胞中的HIP/PAP蛋白。与常规MRI相比，超极化导致信号增强10,000倍以上。我们推测，乳糖功能化的SiNPs与胰腺癌周围的HIP/PAP结合的特异性，加上超极化带来的敏感性增加，将导致“有效的病变大小放大”，从而使活体MRI中胰腺癌的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，我们提出了以下三个具体目标：1.优化乳糖功能化硅纳米颗粒(SiNPs)的29Si自由基动态核极化所能实现的超极化水平，作为SiNP尺寸和体内靶向效率的函数。Ii.实时超极化磁共振成像在a)一个正交异性胰腺癌异种小鼠模型和b)两组患者来源的肿瘤移植到NOD/SCID小鼠中，其中一组是人胰腺肿瘤，另一组接受新辅助治疗，展示了“有效的病变大小放大”。III.将在AIMS II上获得的超极化~(29)Si磁共振数据与免疫组织化学和荧光标记的SiNPs在小鼠肿瘤模型中的光学成像数据进行关联，以证明该技术在检测胰腺癌方面的有效性，该技术至少比目前检测到的小两到三个数量级。

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.