Nanotechnology Platforms for the Prevention and Personalized Therapy of Pancreati

项目概况 该项目将重点关注纳米技术在胰腺癌（PAC）独特问题上的应用。与在其他实体瘤中观察到的不同，胰腺癌细胞作为包埋在丰富的致密低血管纤维化基质中的病灶存在。这种致密间质的发展始于早期癌前病变（胰腺上皮内瘤变（PanIN）），并持续到肿瘤进展。该项目的主要目标是开发纳米技术，这些技术可以渗透或积累在胰腺癌的丰富基质中。对胰腺肿瘤特异性递送治疗的能力也将允许在个体患者中使用针对适当靶点的治疗，从而为个体化治疗打开大门。不幸的是，目前PAC的临床前肿瘤模型不发育基质，因此不能准确地代表人类疾病中发现的微环境。最近，我们已经开发了新的临床前小鼠模型，异种移植和遗传，准确地模拟这种纤维化微环境。我们将使用这些新颖独特的模型系统来开发优化的纳米技术，这些技术可以靶向胰腺基质网络并在其中积累以用于治疗。PAC的影像学检查和预防。因此，我们将有效地把治疗传递的障碍变成预防和治疗剂的储存库。或者，我们将抑制基质细胞的生物活性以防止癌症进展或使癌症更适合于癌细胞定向疗法。这些研究将首次使纳米载体穿透屏障 胰腺肿瘤周围以实现临床上重要的目标，

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,