Development of Targeted Nanotechnology Platform for Pancreatic Cancer

由于对胰腺癌的反应极差，胰腺癌（PanCa）的治疗异常困难。 可用的治疗方式。生存率低主要是由于药物输送和化疗不理想 由于胰腺肿瘤中过度纤维化和细胞外基质沉积（结缔组织形成）而产生的抵抗力。 NF-κB、Wnt 和 Sonic Hedgehog (SHH) 是 PanCa 中涉及的关键致癌信号通路 进展和对吉西他滨等药物的化疗耐药性。有针对性地抑制这些行为的策略 PanCa 肿瘤中的关键致癌途径（包括转移）尚未充分发育。最近的研究 证明姜黄素对上述途径具有有效的抑制作用并诱导化疗 PanCa 细胞的致敏作用。然而，姜黄素的药代动力学较差，对姜黄素的修饰 成功临床使用所需的。最近，我们设计了一种独特的姜黄素负载多层 用于磁共振成像 (MRI) 和治疗的磁性纳米颗粒 (MNP-CUR) 制剂 应用（专利号PCT/US2011/063723）。我们的总体目标是针对有针对性的制定新战略 通过利用新型靶向磁性抑制 PanCa 中这些关键的致癌信号通路 纳米颗粒（MNP）配方。最近，我们发现了一种新型跨膜粘蛋白，MUC13，它是 在 PanCa 中高表达，但在正常胰腺中不表达。此外，我们还生成了新型单克隆 和人源化抗 MUC13 抗体，可用于靶向肿瘤特异性载药递送 纳米颗粒。基于这一令人信服的证据，我们假设我们的新型抗体引导 MNP 将增强姜黄素在肿瘤中的生物利用度，从而减弱肿瘤生长并使胰腺敏感 癌细胞通过抑制 NF-κB、Wnt、SHH 信号通路转化为吉西他滨并减少 促纤维增生反应。最近的研究表明肿瘤间质（旁分泌）串扰在 PanCa 的病理学。抗体引导的MNP-CUR（靶向纳米技术）的积累 肿瘤/转移瘤内的平台）将持续释放姜黄素，从而调节自分泌 PanCa 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标是：1） 研究 MNP-CUR 制剂对体内发生的分子相互作用调节的影响 胰腺肿瘤微环境； 2) 评估MNP-CUR的治疗和影像学效果 PanCa 异种移植和转基因 (PDA.MUC1) 小鼠模型中的配方； 3) 确定 抗体引导的 MNP-CUR 制剂联合吉西他滨在临床中的治疗诊断效果 相关鼠标型号。该项目的总体目标是开发一种创新的靶向治疗方法 PanCa 的成像方法。该项目的研究结果将推动 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。

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.