Theranostic Nano particles for Targeted Treatment of Pancreatic Cancer

描述（申请人提供）：胰腺癌的治疗是临床肿瘤学中最大的挑战之一，因为大多数晚期胰腺癌患者对目前可用的化疗和放疗没有反应，患者的预后是所有癌症类型中最差的之一。本研究的目的是开发一种多功能治疗纳米颗粒平台，将纳米颗粒的成像能力和受体特异性与新型药物递送设计相结合，以克服导致胰腺癌耐药的物理和内在障碍。在NCI CCNE项目的支持下，我们进行了广泛的研究，开发了可生物降解的受体靶向磁性氧化铁纳米颗粒（lONP），作为胰腺癌MRI的分子成像探针。在本项目中，我们将进一步开发一种治疗性纳米粒子平台，该平台将MRI和药物输送能力结合起来，具有克服胰腺癌组织中导致治疗耐药的障碍的特殊能力，并有效地将化疗药物和表达siRNA的DNA磁带等单一或多种治疗剂输送到肿瘤细胞中（Aim 1）。药物纳米颗粒复合物将靶向细胞受体，如尿激酶纤溶酶原激活剂受体，这些受体在胰腺癌细胞和活性肿瘤基质细胞中高度表达，以促进纳米颗粒在肿瘤内的传递。我们将开发新的MRI方法，设计和优化用于通过MRI特异性和敏感地检测胰腺癌病变中的治疗性磁性纳米颗粒（目的2）。我们将通过MRI和肿瘤组织组织学分析，确定原位人胰腺癌异种移植物和小鼠转基因肿瘤模型的肿瘤靶向治疗效果、纳米颗粒在肿瘤内的分布以及监测治疗反应的成像能力（Aim 3和Aim 4）。为了将治疗性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（目的5）。由于胰腺癌患者的中位生存时间非常短，因此开发出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，同时为监测药物递送和反应提供成像工具的治疗纳米颗粒对于有效治疗胰腺癌尤为重要。相关性（见说明书）；该研究项目将开发新的肿瘤靶向纳米技术治疗方法，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.