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，每年约有31，000例死亡。绝大多数患者存在局部晚期或不可切除的疾病，目前可用的常规治疗方法在改善这种恶性肿瘤的不良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递送、胰腺癌生物学和小动物成像方面具有广泛专业知识的团体之间的多机构平台伙伴关系。多功能混合陶瓷-聚合物纳米颗粒，特别是磷化铟量子点（InP Q-DOTS）和有机改性二氧化硅（ORMOSIL）纳米颗粒已被开发用于胰腺癌模型的综合临床前评价。该提案的具体目标1需要合成长循环（PEG化）、表面官能化的Q-DOTS和掺入PET探针的染料掺杂的ORMOSIL纳米颗粒（“nanoPET”），用于改善早期和转移性胰腺癌的体内成像。该提案的具体目标2需要合成长循环、表面官能化的ORMOSIL纳米颗粒，其包封小分子抑制剂雷帕霉素（纳米雷帕霉素），用于全身性药物递送至胰腺癌。提出了一种系统性方法，包括“优化”阶段，包括使用人胰腺癌细胞系的体外实验和使用常规皮下异种移植物的体内研究;然后，这些研究将进入“应用”阶段，利用两种临床前模型忠实地概括人胰腺癌生物学，包括腹腔内转移的发展：第一，一种新的KRAS驱动的胰腺癌转基因小鼠模型，第二，在无胸腺小鼠中建立的人胰腺癌自发转移原位异种移植模型。预计这些“智能”纳米材料的临床转化将导致胰腺癌诊断阶段的改善，“风险”个体的早期检测，以及晚期疾病患者更有效的治疗益处。该提案的长期目标仍然是改善恶性肿瘤的患者结局，其致死率几乎一致。

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.