Multifunctional Nanoparticles in Diagnosis and Therapy of Pancreatic Cancer

描述(由申请人提供)： 胰腺导管腺癌是美国癌症相关死亡的第四大常见原因，每年有近3.1万人死亡。绝大多数患者患有局部晚期或无法切除的疾病，目前可用的传统治疗方法在改善这种恶性肿瘤的悲惨预后方面取得了最小的成功。纳米生物技术为解决目前胰腺癌诊断和治疗中的许多陷阱提供了前所未有的机会。目前的提案代表了在纳米材料合成和交付、胰腺癌生物学和小动物成像方面拥有广泛专业知识的团体之间的多机构平台合作伙伴关系。多功能复合陶瓷-聚合物纳米粒子，特别是磷化铟量子点(InP Q-dots)和有机修饰二氧化硅(ORMOSIL)纳米粒子已被开发出来用于胰腺癌模型的全面临床前评估。这项建议的具体目标1包括合成长循环(聚乙二醇化)、表面功能化的Q点和含有PET探针的染料掺杂ORMOSIL纳米颗粒(“NanPET”)，用于改进体内早期和转移胰腺癌的成像。这项建议的具体目标2需要合成长循环、表面功能化的ORMOSIL纳米颗粒，包裹小分子抑制剂雷帕霉素(纳米雷帕霉素)，用于全身给药治疗胰腺癌。我们提出了一套系统的方法，包括“优化”阶段，包括使用人胰腺癌细胞系进行体外实验和使用常规皮下移植进行体内研究；然后，这些研究将进入“应用”阶段，利用两个忠实地概括人类胰腺癌生物学的临床前模型，包括腹内转移的发展：第一，新型KRAS驱动的转基因小鼠胰腺癌模型，第二，在无胸腺小鼠中建立的人胰腺癌自发转移的原位异种移植模型。预计这些“智能”纳米材料的临床转化将改善胰腺癌确诊时的分期，“高危”患者的早期发现，以及对晚期疾病患者更有效的治疗益处。这项建议的长期目标仍然是改善具有接近一致致死率的恶性肿瘤的患者预后。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma is the fourth most common cause of cancer-related mortality in the United States, accounting for nearly 31,000 deaths each year. The vast majority of patients present with locally advanced or unresectable disease, and currently available conventional therapeutic approaches have been minimally successful in ameliorating the dismal prognosis of this malignancy. Nanobiotechnology provides unprecedented opportunities for addressing many of the current pitfalls in the diagnosis and therapy of pancreatic cancer. The current proposal represents a multi-institutional platform partnership between groups with extensive expertise in nanomaterial synthesis and delivery, pancreatic cancer biology, and small animal imaging. Multifunctional hybrid ceramic-polymeric nanoparticles, specifically indium phosphide quantum dots (InP Q-DOTS) and organically modified silica (ORMOSIL) nanoparticles have been developed for comprehensive preclinical evaluation in pancreatic cancer models. Specific Aim 1 of this proposal entails the synthesis of long-circulating (PEGylated), surface-functionalized Q-DOTS and dye-doped ORMOSIL nanoparticles incorporating PET probes ("nanoPET"), for improved imaging of early and metastatic pancreatic cancer in vivo. Specific Aim 2 of this proposal entails synthesis of long-circulating, surface-functionalized ORMOSIL nanoparticles encapsulating the small molecule inhibitor rapamycin (nanorapamycin) for systemic drug delivery to pancreatic cancer. A systematic approach is proposed, including an "optimization" phase comprised of in vitro experiments using human pancreatic cancer cell lines and in vivo studies using conventional subcutaneous xenografts; these studies will then lead into an "application" phase utilizing two preclinical models that faithfully recapitulate human pancreatic cancer biology, including the development of intra-abdominal metastases: first, a novel KRAS-driven transgenic mouse model of pancreatic cancer and second, a spontaneously metastasizing orthotopic xenograft model of human pancreatic cancer established in athymic mice. It is anticipated that clinical translation of these "smart" nanomaterials will lead to improved staging of pancreatic cancer at diagnosis, early detection in "at risk" individuals, and more potent therapeutic benefits for patients with advanced disease. The long-term goal of this proposal remains improvement in patient outcome for a malignancy with near-uniform lethality.