Multifunctional Nanoparticles in Diagnosis and Therapy of Pancreatic Cancer

多功能纳米粒子在胰腺癌诊断和治疗中的应用

• 批准号: 7678997
• 负责人: PARAS N. PRASAD
• 金额: $ 65.91万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678997
• 关键词: Accounting; Address; Animals; Antibodies; Antineoplastic Agents; Applications Grants; Area; Arts; Biocompatible; Biology; Biophotonics; Buffaloes; Cancer Biology; Cancer Etiology; Cancer Model; Cancer Patient; Cancer cell line; Ceramics; Cessation of life; Classification; Clinical; Collaborations; Comprehensive Cancer Center; Country; Development; Diagnosis; Diagnostic; Disease; Disease model; Distant; Drug Delivery Systems; Dyes; Early Diagnosis; Encapsulated; Ensure; Family; Funding; Gene Delivery; Genetic Predisposition to Disease; Genomics; Goals; Grant; Human; Hybrids; Image; In Vitro; Individual; Institutes; Institution; Intra-abdominal; Lasers; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Molecular; Monitor; Nanotechnology; Neoplasm Metastasis; Nude Mice; Oncogenic; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Positron-Emission Tomography; Pre-Clinical Model; Principal Investigator; Progress Review Group; Publishing; Quantum Dots; Radiation therapy; Research Infrastructure; Research Personnel; Research Priority; Risk; Role; Signal Pathway; Silicon Dioxide; Sirolimus; Small Animal Imaging Resource Programs; Solid; Specialized Center; Staging; Surface; Therapeutic; Time; Transgenic Mice; Transgenic Model; Translations; United States; Unresectable; Xenograft Model; Xenograft procedure; advanced disease; anticancer research; base; cancer cell; improved; in vivo; indium phosphide; inhibitor/antagonist; molecular/cellular imaging; mortality; mouse model; multidisciplinary; nanobiotechnology; nanoimaging; nanomaterials; nanoparticle; nanoparticulate; novel; novel diagnostics; optical imaging; outcome forecast; photonics; pre-clinical; preclinical evaluation; programs; research study; small molecule; subcutaneous; targeted delivery; therapeutic target; transcriptomics

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第四大癌症相关死亡原因，每年导致近 31,000 人死亡。绝大多数患者患有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收效甚微。纳米生物技术为解决当前胰腺癌诊断和治疗中的许多缺陷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输送、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。多功能杂化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全面临床前评估。该提案的具体目标 1 需要合成长循环（聚乙二醇化）、表面功能化的 Q-DOTS 和掺有染料的 ORMOSIL 纳米颗粒，并结合 PET 探针（“nanoPET”），以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、表面功能化的 ORMOSIL 纳米颗粒，该纳米颗粒封装了小分子抑制剂雷帕霉素（nanorapamycin），用于胰腺癌的全身药物输送。提出了一种系统方法，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传统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，利用两个忠实再现人类胰腺癌生物学的临床前模型，包括腹内转移的发展：首先是一种新型KRAS驱动的胰腺癌转基因小鼠模型，其次是在无胸腺小鼠中建立的自发转移的人类胰腺癌原位异种移植模型。预计这些“智能”纳米材料的临床转化将改善胰腺癌的诊断分期、“高危”个体的早期检测，以及为晚期疾病患者提供更有效的治疗益处。该提案的长期目标仍然是改善致死率接近均匀的恶性肿瘤的患者预后。