Development of Targeted Nanotechnology Platform for Pancreatic Cancer

胰腺癌靶向纳米技术平台的开发

• 批准号: 9188609
• 负责人: Subhash C. Chauhan
• 金额: $ 34.77万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-19 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9188609
• 关键词: Antibodies; Antineoplastic Agents; Attenuated; Autocrine Communication; Binding; Biocompatible Materials; Biological Assay; Biological Availability; Cancer cell line; Cells; Clinical; Curcumin; Data; Deposition; Desmoplastic; Development; Diagnosis; Disease; Drug Delivery Systems; Drug Kinetics; Drug resistance; Engineering; European; Extracellular Matrix; Fibrosis; Formulation; Goals; Grant; Hyperthermia; Image; In Vitro; Incidence; Injection of therapeutic agent; Legal patent; Magnetic Resonance Imaging; Magnetic nanoparticles; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modality; Modeling; Modification; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mucin 1 protein; Mucins; Nanotechnology; Neoplasm Metastasis; Oncogenic; Outcome; Pancreas; Paracrine Communication; Pathway interactions; Peritoneal; Pharmaceutical Preparations; Regulation; Resistance; Resistance development; Role; SHH gene; Signal Pathway; Signal Transduction; Stromal Cells; Stromal Neoplasm; Technology; Testing; Therapeutic; Transgenic Organisms; Treatment Efficacy; Xenograft procedure; base; cancer cell; cancer imaging; clinically relevant; cost effective; gemcitabine; humanized monoclonal antibodies; improved; innovation; mortality; mouse model; nanoparticle; neoplastic cell; novel; outcome forecast; pancreatic cancer cells; pancreatic neoplasm; paracrine; response; smoothened signaling pathway; stellate cell; stem; targeted imaging; targeted treatment; theranostics; therapeutic target; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenic

The management of pancreatic cancer (PanCa) is exceptionally difficult due to the extremely poor response to available therapeutic modalities. Poor survival is primarily because of suboptimal drug delivery and chemo- resistance due to excessive fibrosis and extracellular matrix deposition (desmoplasia) in pancreatic tumors. NF-κB, Wnt and Sonic Hedgehog (SHH) are key oncogenic signaling pathways that are involved in PanCa progression and chemo-resistance to drugs such as gemcitabine. Strategies for targeted suppression of these key oncogenic pathways in PanCa tumors, including metastases, are not well developed. Recent studies demonstrate that curcumin has potent inhibitory effects on aforementioned pathways and induces chemo- sensitization in PanCa cells. However, curcumin has poor pharmacokinetics and modifications to curcumin are needed for successful clinical use. Recently we have engineered a unique curcumin loaded multi-layered magnetic nanoparticle (MNP-CUR) formulation for magnetic resonance imaging (MRI) and therapeutic applications (Patent # PCT/US2011/063723). Our overall goal is to develop new strategies for targeted suppression of these key oncogenic signaling pathways in PanCa by utilizing a novel targeted magnetic nanoparticle (MNP) formulation. Recently, we have identified a novel transmembrane mucin, MUC13, which is highly expressed in PanCa but not in the normal pancreas. Additionally, we have generated novel monoclonal and humanized anti-MUC13 antibodies that can be used for targeted tumor specific delivery of drug loaded nanoparticles. Based on this compelling evidence we hypothesize that our novel antibody guided MNPs will enhance bioavailability of curcumin in tumors to attenuate tumor growth and sensitize pancreatic cancer cells to gemcitabine via suppression of NF-κB, Wnt, SHH signaling pathways and decreased desmoplastic reaction. Recent studies suggest a major role for tumor-stromal (paracrine) cross-talk in the pathobiology of PanCa. The accumulation of antibody guided MNP-CUR (Targeted Nanotechnology Platform) within tumors/metastases will provide sustained release of curcumin which will regulate autocrine and paracrine signaling between PanCa cells and stromal cells. The specific aims to test this hypothesis are: 1) To investigate the effect of MNP-CUR formulation on the regulation of molecular interactions occurring within the pancreatic tumor microenvironment; 2) To evaluate therapeutic and imaging efficacy of MNP-CUR formulation in PanCa xenograft and transgenic (PDA.MUC1) mouse models; and 3) To determine the theranostic efficacy of antibody guided MNP-CUR formulation in combination with gemcitabine in clinically relevant mouse models. The overall objective of this project is to develop an innovative targeted therapeutic and imaging approach for PanCa. Findings of this project will advance diagnosis and therapy of PanCa to reduce the morbidity and mortality caused by this devastating disease.

胰腺癌（PANCA）的管理非常困难，因为对 可用的治疗方式。由于次优的药物递送和化学疗法，生存率不佳是主要的 由于纤维化过多和胰腺肿瘤中的细胞外基质沉积（脱木质）引起的抗性。 NF-κB，Wnt和Sonic刺猬（SHH）是涉及PANCA的关键致癌信号通路 对吉西他滨等药物的进展和化学抗性。针对性抑制这些的策略 包括转移酶在内的胰腺肿瘤中的关键致癌途径没有很好地发育。最近的研究 证明姜黄素对均等途径具有潜在的抑制作用，并诱导化学 panca细胞的敏化。但是，姜黄素的药代动力学不良，姜黄素的修饰是 成功使用临床所需。最近，我们设计了独特的姜黄素多层 用于磁共振成像（MRI）和治疗的磁性纳米颗粒（MNP-Cur）制剂 应用程序（专利＃PCT/US2011/063723）。我们的总体目标是制定针对目标的新策略 通过使用新型的靶向磁性，抑制panca中这些关键的致癌信号通路 纳米颗粒（MNP）公式。最近，我们确定了一种新型的跨膜粘蛋白MUC13，它是 在panca中高度表达，但在正常胰腺中不表达。另外，我们产生了新颖的单克隆 和人源化抗MUC13抗体，可用于靶向肿瘤特异性药物的递送 纳米颗粒。基于这个令人信服的证据，我们假设我们的新型抗体引导的MNP 将增强姜黄素在肿瘤中的生物利用度，以减轻肿瘤的生长和敏感性胰腺 癌细胞通过抑制NF-κB，Wnt，SHH信号通路并改善 去胶质反应。最近的研究表明，在 Panca病理生物学。抗体引导的MNP-Cur的积累（靶向纳米技术） 平台）在肿瘤/转移中将提供姜黄素的持续释放，这将调节自分泌 胰腺细胞和基质细胞之间的旁分泌信号传导。检验该假设的具体目的是：1） 研究MNP-cur公式对调节发生的分子相互作用的影响 胰腺肿瘤微环境； 2）评估MNP-Cur的治疗和成像效率 panca摄影和转基因（PDA.MUC1）小鼠模型中的形成； 3）确定 抗体指导MNP-Cur配方的疗法效率与吉西他滨在临床上结合使用 相关的鼠标模型。该项目的总体目的是开发一种创新的目标疗法 和panca的成像方法。该项目的发现将使Panca的诊断和治疗 降低这种毁灭性疾病引起的发病率和死亡率。