(PQC5)Early Detection Pancreatic Cancer by Hyperpolarized Silicon Nanoparticles

描述（由申请人提供）：胰腺癌患者预后不良的主要原因是80-90%的患者在诊断时已经有不可切除的疾病。该研究方案提供了一种策略，可以通过MRI检测胰腺癌，比目前使用靶向超极化硅纳米颗粒检测的胰腺癌至少小两到三个数量级。这一策略如果成功地应用于临床，将提高胰腺肿瘤早期的整体可检出性，并有可能通过成功的手术干预挽救生命。在胰腺组织中产生的胰腺肿瘤生物标志物中，发现肝癌-肠-胰腺/胰腺炎相关蛋白（HIP/PAP）在胰腺癌的胰腺腺泡细胞中过度表达超过130倍，与正常胰腺相比。相比之下，慢性胰腺炎的腺泡细胞中HIP/PAP蛋白的表达仅增加了9倍。这为胰腺癌中肿瘤和肿瘤间质相互作用的成像提供了一个独特的机会。这个探索性项目的目的是基于我实验室最近开发的一种新型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。以往的生物化学研究表明，HIP/PAP蛋白是一种“乳糖结合蛋白”，对D-乳糖具有很高的亲和力。我们打算利用乳糖功能化的超极化硅纳米颗粒（SiNPs）靶向胰腺肿瘤周围腺泡细胞中的HIP/PAP蛋白。与传统的MRI相比，超极化导致超过10,000倍的信号增强。我们假设，乳糖功能化的SiNPs与胰腺癌周围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”，从而使胰腺癌在体内MRI中的可视化比目前检测到的至少小两到三个数量级。为了实现这一目标，我们提出了以下三个具体目标：1 .优化无自由基29Si动态核极化在乳糖功能化硅纳米颗粒（SiNPs）上实现的超极化水平，作为SiNP大小和体内靶向效力的函数。2。通过实时超极化MRI在a)一个正异性胰腺肿瘤异种移植小鼠模型和b)两组移植到NOD/SCID小鼠体内的患者源性肿瘤，其中一组是未发现的人类胰腺肿瘤，另一组接受新辅助治疗，证明“有效病变大小放大”。3。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SiNPs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有效性，至少比目前检测的胰腺癌小两到三个数量级。

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.