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)的治疗非常困难，因为对 现有的治疗方式。存活率低的主要原因是药物输送和化疗效果不佳。 胰腺肿瘤由于过度纤维化和细胞外基质沉积(促结缔组织增生)而产生的耐药性。 NF-κB、Wnt和Sonic Hedgehog(SHH)是参与PANCA的关键致癌信号通路 进展和对吉西他滨等药物的耐药性。有针对性地抑制这些问题的战略 Panca肿瘤的关键致癌途径，包括转移，还不是很发达。最新研究 证明姜黄素对上述途径有很强的抑制作用，并能诱导化疗。 潘卡细胞的敏化。然而，姜黄素的药代动力学很差，对姜黄素的修饰是 临床成功使用所需的药物。最近我们设计了一种独特的姜黄素多层负载 用于磁共振成像(MRI)和治疗的磁性纳米颗粒(MNP-CUR)配方 申请(专利号PCT/US2011/063723)。我们的总体目标是为目标客户制定新的战略 利用新型靶向磁场抑制PANCA中的这些关键致癌信号通路 纳米颗粒(MNP)配方。最近，我们发现了一种新的跨膜粘蛋白MUC13，它是 在胰腺组织中高表达，但在正常胰腺组织中不表达。此外，我们还产生了新的单克隆 和人源化的抗MUC13抗体，可用于靶向肿瘤特异性载药 纳米粒子。基于这一令人信服的证据，我们假设我们的新型抗体引导MNPs 将提高姜黄素在肿瘤中的生物利用度，以抑制肿瘤生长和增敏胰腺 癌细胞通过抑制NF-κB、WNT、SHH信号通路而降低吉西他滨 促结缔组织反应。最近的研究表明，肿瘤-间质(旁分泌)的串扰在 番茄病的病原学。抗体导向的MNP-CUR(靶向纳米技术)的积累 在肿瘤/转移中)将提供姜黄素的持续释放，从而调节自分泌 以及胰岛细胞和基质细胞之间的旁分泌信号。检验这一假设的具体目的是：1) 研究MNP-CUR制剂对体内分子相互作用的调节作用 胰腺肿瘤的微环境；2)评价MNP-CURR的疗效和影像效果 在Panca异种移植和转基因(PDA.MUC1)小鼠模型中的配方；以及3)确定 抗体导向的MNP-Cur制剂联合吉西他滨的临床疗效 相关的鼠标模型。该项目的总体目标是开发一种创新的靶向治疗方法 以及潘卡的成像方法。该项目的发现将促进对PANCA的诊断和治疗 减少这种毁灭性疾病造成的发病率和死亡率。