Development of Targeted Nanotechnology Platform for Pancreatic Cancer

胰腺癌（PanCa）的管理是非常困难的，因为对 可用的治疗方式。生存率低主要是因为次优的药物输送和化疗- 胰腺肿瘤中由于过度纤维化和细胞外基质沉积（结缔组织增生）导致的耐药性。 NF-κ B、Wnt和Sonic Hedgehog（SHH）是参与PanCa 疾病进展和对吉西他滨等药物的耐药性。有针对性地抑制这些 PanCa肿瘤（包括转移瘤）中的关键致癌途径尚未充分开发。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细胞中的致敏作用。然而，姜黄素具有差的药代动力学，并且对姜黄素的修饰是不安全的。 成功应用于临床。最近，我们设计了一种独特的姜黄素加载多层 用于磁共振成像（MRI）和治疗的磁性纳米颗粒（MNP-CUR）制剂 专利号PCT/US2011/063723）。我们的总体目标是制定新的战略， 通过利用一种新的靶向磁性抑制剂来抑制PanCa中这些关键的致癌信号通路， 纳米颗粒（MNP）制剂。最近，我们鉴定了一种新的跨膜粘蛋白MUC13， 在PanCa中高度表达，但在正常胰腺中不表达。此外，我们已经产生了新的单克隆抗体， 和人源化抗MUC13抗体，其可用于靶向肿瘤特异性递送载药的药物 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的MNP 将增强姜黄素在肿瘤中的生物利用度，以减弱肿瘤生长并使胰腺癌敏感化。 癌细胞通过抑制NF-κ B、Wnt、SHH信号通路对吉西他滨产生抑制作用， 结缔组织增生反应。最近的研究表明，肿瘤间质（旁分泌）串扰的主要作用， PanCa的病理生物学抗体引导的MNP-CUR（靶向纳米技术）的积累 平台）将提供姜黄素的持续释放，其将调节肿瘤/转移灶内的自分泌 以及PanCa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制剂对细胞内发生的分子相互作用的调节作用， 评价MNP-CUR的治疗和影像学效果 在PanCa异种移植物和转基因（PDA.MUC1）小鼠模型中的制剂;和3）为了确定 抗体引导的MNP-CUR制剂与吉西他滨组合在临床中的治疗诊断功效 相关小鼠模型。该项目的总体目标是开发一种创新的靶向治疗药物， 和成像方法。该项目的发现将促进PanCa的诊断和治疗， 减少这一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.