Nanotechnology Platforms for the Prevention and Personalized Therapy of Pancreati

项目概述 本项目将致力于将纳米技术应用于解决胰腺癌(PAC)的独特问题。与在其他实体瘤中观察到的不同，胰腺癌细胞以病灶的形式存在，镶嵌在丰富的致密的低血管纤维间质中。这种致密间质的发展始于早期癌前疾病(胰腺上皮内瘤变(Panin))，并持续到肿瘤的进展。该项目的主要目标将是开发能够穿透或积聚在丰富的间质中的纳米技术，这是胰腺癌的特征。专门为胰腺肿瘤提供治疗的能力也将允许针对个别患者的适当靶点使用治疗，从而打开个性化治疗的大门。不幸的是，目前的PAC临床前肿瘤模型没有形成间质，因此不能准确地反映人类疾病中发现的微环境。最近，我们开发了新的临床前小鼠模型，包括异种移植和遗传，它准确地模拟了这种纤维状微环境。我们将使用这些新颖和独特的模型系统来开发优化的纳米技术，这些技术针对并积累在胰腺基质网络中进行治疗。PAC的成像和预防。因此，我们将有效地将治疗提供的障碍变成预防和治疗药物的储藏库。或者，我们将抑制间质细胞的生物活性，以防止癌症进展或使癌症更容易接受癌细胞导向的治疗。总而言之，这些研究将首次利用纳米载体穿透屏障 以达到临床上有意义的目标，

PROJECT OVERVIEW This project will focus on the application of nanotechnology to the unique problems of pancreatic adenocarcinoma (PAC). Unlike what is observed in other solid tumors, pancreafic cancer cells exist as foci embedded in an abundant dense hypovascular fibrofic stroma. Development of this dense stroma begins with eariy premalignant disease (pancreatic intraepithelial neoplasia (PanIN)) and continues through tumor progression. A primary goal of this project will be to develop nanotechnologies that can either penetrate or accumulate in the abundant stroma that characterizes pancreafic cancer. The ability to specifically deliver therapies to the pancreafic tumors will also allow the use of therapies directed at appropriate targets in individual patients, opening the door to individualized therapies. Unfortunately, the current preclinical tumor models for PAC do not develop stroma and thus do not accurately represent the microenvironment found in the human disease. Recentiy, we have developed novel preclinical mouse models, both xenografts and genetic, which accurately mimic this fibrofic microenvironment. We will use these novel and unique model systems to develop optimized nanotechnologies that target and accumulate within pancreafic stromal networks for therapy. Imaging, and prevenfion of PAC. Thus, we will effectively turn what was a barrier to therapeutic delivery into a reservoir for preventive and therapeutic agents. Alternatively, we will suppress the biological activity of the stromal cells to prevent cancer progression or to render the cancer more amenable to cancer cell directed therapies. Together these studies will, for the first fime, ufilize nanocarriers to penetrate the barrier surrounding pancreafic tumors to achieve clinically significant goals,