MRI Capable Receptor Targeted Drug Delivery for Pancreatic Cancer

描述（由申请人提供）：胰腺癌是美国癌症死亡的第四大原因，并且仍然是最难治疗的癌症类型，诊断后存活5年的患者不到5%。化疗和放疗是这些患者的唯一选择。然而，全身化疗的疗效受到递送效率差和全身毒性的限制。近年来，个性化肿瘤治疗的研究主要集中在肿瘤靶向给药和控制释放治疗药物，并借助非侵入性成像技术监测药物在肿瘤中的释放和蓄积，评价治疗效果。在这个项目中，我们建议开发和测试一种多功能成像-递送磁性纳米颗粒平台，该平台结合了经证实的磁共振成像（MRI）对比度增强、受体特异性肿瘤靶向和优化的药物装载和释放的能力，用于MRI引导的化疗药物吉西他滨全身递送到胰腺肿瘤中。我们的具体目标1专注于设计，制备和表征具有MRI功能的纳米颗粒，这些纳米颗粒涂覆有功能化的防污“隐形”聚合物，可以结合靶向配体，并可以减少正常组织对纳米颗粒的非特异性吸收，以提高肿瘤靶向效率。我们将开发能够将吉西他滨结合到肿瘤靶向纳米颗粒上用于酶激活的细胞内释放的方法。药物-纳米颗粒复合物将靶向尿激酶纤溶酶原激活物受体（uPAR），一种在胰腺癌和活性肿瘤基质细胞中高度表达的细胞受体，以促进吉西他滨的肿瘤内和亚细胞递送。为了将所提出的磁性纳米颗粒成像-递送平台转化为临床应用，我们将研究该递送平台在正常和荷瘤小鼠中的生物分布、全身毒性和药代动力学。在目标2中，我们将开发新的MRI方法，这些方法被设计用于体内磁性纳米颗粒递送载体的特异性和灵敏性检测。对于MRI引导的药物递送应用，我们的目标是设计和测试一组MRI方法，例如超短TE成像，其不仅使我们能够以高灵敏度和更好的可视化跟踪和跟随递送载体，而且还提供关于肿瘤内递送效率的定量信息。还将测试评估肿瘤对治疗反应的新MRI方法。在目标3中，我们将评估纳米颗粒的肿瘤内分布，研究其肿瘤靶向治疗效果，测试和优化跟踪和量化药物在靶向肿瘤中的递送和积累的成像能力，以及使用MRI监测胰腺癌动物模型对治疗的反应。 公共卫生相关性：全身化疗是许多癌症慢性管理的常用方法。然而，其功效受到将治疗剂递送至肿瘤的效率差和全身毒性的限制。在这个项目中，我们建议开发一种多功能成像-递送磁性纳米颗粒平台，该平台结合了磁共振成像（MRI）、受体特异性肿瘤靶向和优化的药物装载和释放的能力，用于MRI引导的化疗药物的全身递送，用于治疗胰腺癌。

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer death in the US and remains the most difficult cancer type to treat with less than 5% of patients surviving 5 years after diagnosis. Chemotherapy and radiotherapy are the only options for these patients. However, the efficacy of systemic chemotherapy is limited by poor efficiency in the delivery and systemic toxicity. Recent research in personalized oncology has concentrated on tumor targeted delivery and controlled release of therapeutic agents with assistances of non-invasive imaging methods to monitor the delivery and accumulation of the drugs in the tumor and to assess the therapeutic response. In this project, we propose to develop and test a multi-functional imaging- delivery magnetic nanoparticle platform that combines the capabilities of demonstrated magnetic resonance imaging (MRI) contrast enhancement, receptor specific tumor targeting and optimized drug loading and release for MRI-guided systemic delivery of chemotherapy drug, gemcitabine, into pancreatic tumors. Our Specific Aim 1 focuses on the design, preparation and characterization of MRI-capable nanoparticles coated with functionalized anti-fouling "stealth" polymers that can conjugate targeting ligands and may reduce non-specific uptake of nanoparticles by normal tissues for improved tumor targeting efficiency. We will develop methods that can conjugate gemcitabine onto the tumor targeting nanoparticles for enzyme-activated intracellular release. The drug-nanoparticle complex will target the urokinase plasminogen activator receptor (uPAR), a cellular receptor highly expressed in pancreatic cancer and active tumor stromal cells, to facilitate the intratumoral and subcellular delivery of gemcitabine. With the goal of translating the proposed magnetic nanoparticle imaging-delivery platform into clinical applications, we will investigate the biodistribution, systemic toxicity and pharmacokinetics of this delivery platform in normal and tumor bearing mice. In Aim 2, we will develop novel MRI approaches that are designed for specific and sensitive detection of magnetic nanoparticle delivery vehicles in vivo. For MRI guided drug delivery applications, our objective is to design and test a set of MRI methods, such as ultra-short TE imaging, that not only enable us to track and follow the delivery vehicles with a high sensitivity and better visualization but also provide quantitative information on intra-tumoral delivery efficiency. New MRI methods to assess the tumor response to treatment will also be tested. In Aim 3, we will evaluate intratumoral distribution of nanoparticles, investigate their tumor targeted therapeutic effect, test and optimize the imaging capabilities of following and quantifying the delivery and accumulation of the drug in the targeted tumors as well as monitoring response to therapy in pancreatic cancer animal models using MRI. PUBLIC HEALTH RELEVANCE: Systemic chemotherapy is a common approach to the chronic management of many cancers. However, its efficacy is limited by poor efficiency in delivery of the therapeutic agent to the tumor and systemic toxicity. In this project, we propose to develop a multi-functional imaging-delivery magnetic nanoparticle platform that combines capabilities of magnetic resonance imaging (MRI), receptor specific tumor targeting and optimized drug loading and release for MRI guided systemic delivery of chemotherapy drugs for the treatment of pancreatic cancer.