Targeting tumor and its microenvironment using nanotherapeutics for pancreatic cancer

使用纳米疗法治疗胰腺癌靶向肿瘤及其微环境

基本信息

批准号：
10223249
负责人：
Satyanarayana Rachagani
金额：
$ 37.23万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10223249
关键词：
Address Biodistribution CASP3 gene CASP7 gene Cancer cell line Cells Cleaved cell Clinic Clinical Clinical Trials Combined Modality Therapy Complex Cytotoxic agent Data Development Device Designs Devices Diagnosis Diagnostic Diffusion Disease-Free Survival Distant Dose Dose-Limiting Down-Regulation Drug Combinations Drug Kinetics Drug resistance Ectopic Expression Electrostatics Encapsulated Epithelial Extracellular Matrix Future Genes Goals Growth HIF1A gene Human In Vitro KPC model MUC4 mucin Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mesenchymal MicroRNAs Modeling Molecular Mus Nano delivery Neoplasm Metastasis Normal Cell Organ Organoids Pancreatic Intraepithelial Neoplasia Pathogenesis Pathologic Pathway interactions Patients Perfusion Pharmaceutical Preparations Play Prognosis Property Reporting Resistance Role SHH gene Signal Transduction Signaling Molecule Site Survival Rate System Temperature Testing Therapeutic Therapeutic Agents Tissues Toxic effect Treatment Efficacy Up-Regulation Vascular Endothelium Work Xenograft procedure aldehyde dehydrogenase 1 angiogenesis base beta catenin c-myc Genes cancer cell cancer stem cell cancer therapy cell motility cell stroma chemosensitizing agent chemotherapy clinical application cohort copolymer drug release kinetics drug sensitivity efficacious treatment epithelial to mesenchymal transition gemcitabine humanized mouse improved in vivo liposome vector lymph nodes mouse model nanoscale nanotherapeutic novel novel therapeutics pancreatic cancer cells pancreatic cancer patients pancreatic neoplasm pancreatic stellate cell pre-clinical prognostic restoration side effect stem cell survival success symptomatic improvement synergism therapeutic evaluation therapeutic miRNA therapeutic target therapy outcome therapy resistant tumor tumor growth tumor progression tumor xenograft

项目摘要

ABSTRACT Pancreatic cancer (PC) is lethal with a five-year survival rate of less than 9.2 % and a median survival of 5-6 months. The limited efficacy of mono-therapies has led to the exploration of combination therapies with limited success because of challenges associated with dose-limiting side effects, drug-associated toxicities, drug resistance, and poor pharmacokinetics. Importantly, these past approaches have not attempted the concurrent targeting of the pancreatic tumor and its stroma and PC stem cells. Our proposed work addresses these challenges by determining functional and clinic-pathological significance of miR-345 as well as developing a dual delivery nanoscale device (DDND) for combined delivery of miR-345 and GEM for the treatment of PC. Our preliminary studies have shown that miR-345 targets several important genes, including sonic hedgehog (Shh), Kras, MUC4 mucin and its downstream targets, genes-associated with cancer stem cells (ALDH1, ESA, Hif1α, and Oct/3/4), and causes up regulation of cleaved caspase-3, -7, and PARP. The Kras, Shh and MUC4-signaling play critical roles in tumor growth and metastasis by promoting epithelial to mesenchymal transition (EMT), PC stem cells, angiogenesis, desmoplasia, which limit the delivery and efficacy of chemotherapy. MiR-345 targeting Kras, Shh and MUC4, which makes miR-345 is an excellent candidate for diagnostic/prognostic and therapeutic targets in PC. We hypothesize that downregulation of miR-345 contributes to PC pathogenesis by upregulation of Kras, SHH, and MUC4; Its restoration, combination with GEM through the DDND, enhances GEM sensitivity in PC through modulation of SHH/Kras/MUC4 pathways, resulting in inhibition of desmoplasia, pancreatic stellate cells, and PC stem cells leading to an improved therapeutic outcome of GEM in PC through improving its tumor perfusion. The DDND is based on temperature and pH responsive pentablock copolymers electrostatically complexed with miR-345 and subsequently self-assembled with GEM encapsulated layers. The DDND design allows effective co-incorporation of miRNA/GEM combination; facilitates cellular entry; enhances stability compared to liposomal carriers; provides miRNA protection; allows targeting by selectively facilitating endosomal escape in cancer cells as opposed to normal cells by exploiting intracellular pH differences; and allows dose- sparing of the cytotoxic drugs. Aim 1 will focus to determine functional role and clinico-pathological significance of miR-345/Shh/Kras/MUC4 axis in highly aggressive and metastatic PC. Aim 2 will focus on the development of DDND loaded miR-345/GEM as a novel therapeutic agent against lethal PC by evaluating their therapeutic efficacy in vitro. In the final Aim 3, we will evaluate therapeutic efficacy of DDND loaded miR-345/GEM alone or in combination in mouse models. Altogether, the proposed work decipher the clinic-pathological significance of miR-345 and expected to significantly advance the goal of combining GEM and miR-345 delivery for treatment of PC patients, enhance understanding of the synergistic mechanisms involved, and will provide a novel DDND design for delivery of other therapeutics as well in the future.

抽象的胰腺癌（PC）是致命的，五年生存率小于9.2％，中位存活率为5-6 月份。单性治疗的效率有限，导致对组合疗法的探索有限由于与剂量限制副作用相关的挑战，成功，药物相关的毒性，药物耐药性和药代动力学不良。重要的是，这些过去的方法尚未尝试并发靶向胰腺肿瘤及其基质和PC干细胞。我们提出的工作解决了这些通过确定miR-345的功能和临床病理学意义以及开发双重的挑战用于MiR-345和GEM用于处理PC的MiR-345和GEM的递送纳米级设备（DDND）。我们的初步研究表明，miR-345靶向几个重要基因，包括声波刺猬（SHH）， KRAS，MUC4粘蛋白及其下游靶标与癌症干细胞相关（Aldh1，ESA，HIF1α，，和OCT/3/4），并导致裂解的caspase -3，-7和PARP的调节。 KRAS，SHH和MUC4信号通过促进上皮过渡（EMT），PC，在肿瘤生长和转移中起关键作用干细胞，血管生成，脱木质，限制了化学疗法的递送和效率。 miR-345靶向 KRAS，SHH和MUC4，使MiR-345是诊断/预后和治疗的绝佳候选者 PC中的目标。我们假设miR-345的下调通过上调有助于PC发病机理 Kras，SHH和MUC4；它的恢复，通过DDN与宝石的结合增强了宝石灵敏度在PC中通过调节SHH/KRAS/MUC4途径，导致抑制脱发，胰腺星状静脉曲张细胞和PC干细胞通过改善其肿瘤，从而改善PC中宝石的治疗结果灌注。 DDND基于温度和pH响应pentablock共聚物静电与miR-345复合，随后与封装的层自组装。 DDND设计允许有效合并miRNA/gem组合；促进细胞进入；增强稳定性与脂质体载体相比；提供miRNA保护；通过选择性支持内体允许定位通过利用细胞内pH差异，癌细胞中的癌细胞逃脱；并允许剂量 - AIM 1将集中精力确定功能作用和临床病理意义高度攻击性和转移性PC中的miR-345/shh/kras/muc4轴。 AIM 2将专注于发展通过评估其治疗性的DDND LOACH MIR-345/GEM作为一种针对致命PC的新型治疗剂体外效率。在最终目标3中，我们将评估单独加载miR-345/gem的DDND的治疗效率或组合鼠标模型。总之，提议的工作解密了临床病理学意义 miR-345，预计将显着促进将GEM和MiR-345交付的目标促进治疗的目标 PC患者的了解，增强对所涉及的协同机制的理解，并将提供新颖的DDND 未来提供其他治疗剂的设计。