Theranostic Nano particles for Targeted Treatment of Pancreatic Cancer

描述（由申请人提供）：胰腺癌治疗是临床肿瘤学中最具挑战性的问题之一，因为大多数晚期胰腺癌患者对目前可用的化疗和放疗无反应，并且患者的预后是所有癌症类型中最差的。这项拟议研究的目的是开发一种多功能治疗诊断纳米颗粒平台，该平台将纳米颗粒的成像能力和受体特异性与药物递送的新设计相结合，以克服胰腺癌耐药性的物理和内在障碍。我们在NCI CCNE计划支持下进行的广泛研究开发了可生物降解且受体靶向的磁性氧化铁纳米颗粒（IONP），作为胰腺癌MRI的分子成像探针。在这个项目中，我们将进一步开发一种治疗诊断纳米颗粒平台，该平台结合了MRI和药物递送能力，具有克服胰腺癌组织中导致治疗耐药性的障碍的特殊能力，并有效地将单一或多种治疗药物（如化疗药物和siRNA表达DNA盒）递送到肿瘤细胞中（目标1）。药物-纳米颗粒复合物将靶向在胰腺癌细胞和活性肿瘤基质细胞中高度表达的细胞受体，例如尿激酶纤溶酶原激活物受体，以促进纳米颗粒的肿瘤内递送。我们将开发新的MRI方法，这些方法被设计和优化用于通过MRI对胰腺癌病变中的治疗诊断磁性纳米颗粒进行特异性和灵敏性检测（目的2）。我们将使用MRI和肿瘤组织的组织学分析来确定肿瘤靶向治疗效果、纳米颗粒的肿瘤内分布以及在原位人胰腺癌异种移植物和小鼠转基因肿瘤模型中监测对治疗的反应的成像能力（目的3和目的4）。为了将治疗诊断磁性纳米颗粒转化为临床应用，我们将在正常和荷瘤小鼠模型中进行生物分布、全身毒性和药代动力学研究（目标5）。开发能够将大量和多种药物靶向递送到胰腺癌细胞和肿瘤环境中，同时提供用于监测药物递送和反应的成像工具的所提出的治疗诊断纳米颗粒对于胰腺癌的有效治疗特别重要，因为癌症患者具有非常短的中位存活时间。相关性（参见说明）;该研究项目将开发新的肿瘤靶向纳米技术疗法，以改善胰腺癌的治疗。

DESCRIPTION (provided by applicant): Pancreatic cancer treatment presents one of the most challenges in clinical oncology as majority of the patients with advanced pancreatic cancer do not response to current available chemotherapeutic and radiotherapy and the prognosis of the patients is one of the worst among all cancer types. The objective of this proposed study aims at developing a multi-functional theranostic nanoparticle platform that combines demonstrated imaging capability and receptor specificity of the nanoparticles with novel designs for drug delivery to overcome physical and intrinsic barriers that confer drug resistance in pancreatic cancer. Our extensive research supported by NCI CCNE program led to the development of biodegradable and receptor targeted magnetic iron oxide nanoparticles (lONP) as a molecular imaging probe for MRI of pancreatic cancer. In this project, we will further develop a theranostic nanoparticle platform that combines MRI and drug delivery capabilities with special ability to overcome the barriers causing resistance to therapy in pancreatic cancer tissues and effectively deliver single or multiple therapeutic agents such as chemotherapy drugs and siRNA expressing DNA cassettes into the tumor cells (Aim 1). The drug-nanoparticle complex will be targeted to cellular receptors, such as urokinase plasminogen activator receptor, that are highly expressed in pancreatic cancer cells and active tumor stromal cells to facilitate the intratumoral delivery of the nanoparticles. We will develop novel MRI approaches that are designed and optimized for specific and sensitive detection of the theranostic magnetic nanoparticles in the pancreatic cancer lesions by MRI (Aim 2). We will determine the tumor targeted therapeutic effect, intratumoral distribution of the nanoparticles, and the imaging capability of monitoring response to therapy in orthotopic human pancreatic cancer xenograft and in a mouse transgenic tumor model using MRI and histological analysis of the tumor tissues (Aim 3 and Aim 4). To translate the theranostic magnetic nanoparticles into clinical applications, we will conduct biodistribution, systemic toxicity, and pharmacokinetic studies In normal and tumor bearing mouse models (Aim 5). The development of proposed theranostic nanoparticles that that are capable of targeted delivery of large amounts and multiple drugs into pancreatic cancer cells and tumor environment while providing imaging tools for monitoring drug delivery and response is particularly important for the effective treatment of pancreatic cancer since the cancer patients have a very short median survival time. RELEVANCE (See instructions); This research project will develop novel tumor targeted nanotechnology therapeutics for improving the treatment of pancreas cancer.