Multifunctional Nanoparticles in Diagnosis and Therapy

多功能纳米颗粒在诊断和治疗中的应用

• 批准号: 7127281
• 负责人: PARAS N. PRASAD
• 金额: $ 65.07万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7127281
• 关键词: athymic mouse; bioimaging /biomedical imaging; cell line; ceramics; clinical research; drug delivery systems; genetically modified animals; human tissue; image guided surgery /therapy; metastasis; nanotechnology; neoplasm /cancer chemotherapy; neoplasm /cancer diagnosis; neoplastic cell; nonhuman therapy evaluation; pancreas neoplasms; particle; positron emission tomography; silicates; sirolimus; technology /technique development; xenotransplantation

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.

描述（由申请人提供）： 胰腺导管腺癌是美国与癌症相关死亡率的第四大原因，每年造成近31,000人死亡。绝大多数患有局部晚期或不可切除的疾病的患者，目前可用的常规治疗方法在改善这种恶性肿瘤的惨淡预后方面取得了最小的成功。纳米生物技术为解决胰腺癌诊断和治疗中许多当前的陷阱提供了前所未有的机会。当前的提案代表了在纳米材料合成和分娩，胰腺癌生物学和小型动物成像方面具有广泛专业知识的群体之间的多机构平台伙伴关系。已经开发了多功能杂化陶瓷 - 陶瓷纳米纳米颗粒，特别是磷化物量子点（INP Q点）和有机修饰的二氧化硅（Ormosil）纳米颗粒，用于胰腺癌模型中的全面临床前评估。该提案的具体目的1需要合成长循环（pegypated），表面功能化的Q点和掺入PET探针的染料掺杂的Ormosil纳米颗粒，以改善生物中早期和转移性胰腺癌的早期和转移性胰腺癌的成像。该提案的特定目的2需要综合囊括小分子抑制剂雷帕霉素（纳米氨甲霉素）的长循环，表面官能化的Ormosil纳米颗粒，用于将全身药物递送至胰腺癌。提出了一种系统的方法，包括使用人胰腺癌细胞系的体外实验组成的“优化”相，并使用常规皮下异种移植物进行体内研究；然后，这些研究将利用两个临床前模型进入一个“应用”阶段，这些模型忠实地概括了人类胰腺癌生物学，包括腹腔内转移的发展：首先，一种新型的KRAS KRAS驱动的胰腺癌的转基因小鼠模型，其次，第二，一种自发地促进了矫形器型矫正型癌症良心良心的矫正型良好的良心，可以预计，这些“智能”纳米材料的临床翻译将导致诊断时胰腺癌的分期改善，对患有晚期疾病患者的“处于危险”患者的早期发现以及更有效的治疗益处。该提案的长期目标仍然可以改善患者结局的恶性肿瘤。