Reprogramming Tumor-Associated Macrophages in PDAC with MicroRNA Nano-Vectors

用 MicroRNA 纳米载体重编程 PDAC 中的肿瘤相关巨噬细胞

基本信息

批准号：
9517784
负责人：
Mansoor M Amiji
金额：
$ 21.73万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9517784
关键词：
Address Affect Apoptotic Binding CD44 gene Cancer Etiology Cancer Model Cells Cessation of life Characteristics Charge Clinical Complex Disease Progression Down-Regulation Encapsulated Ethylenes Evaluation Flow Cytometry Formulation Genes Genetic Engineering Genetically Engineered Mouse Histopathology Human Hyaluronic Acid Imines Immunocompetence Immunocompetent Immunosuppression In Vitro Inflammatory Investigation Literature Malignant Neoplasms Malignant neoplasm of lung MicroRNAs Modeling Morphology Mus Mutation Neoplasm Metastasis Nucleic Acids Paclitaxel Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Peptides Permeability Phenotype Play Refractory Disease Role Sampling Signal Transduction Small Interfering RNA Solid Solid Neoplasm Surface Survival Rate System Technology Therapeutic Therapeutic Effect Tissues Treatment Efficacy Tumor-associated macrophages United States Up-Regulation Work angiogenesis base chemotherapy clinically translatable cytokine ethylene glycol extracellular gemcitabine human disease improved in vivo innovation intravenous administration macrophage mouse model nano nanoassembly nanocarrier nanoparticle nanovector nucleic acid delivery outcome forecast overexpression pre-clinical stem targeted treatment therapy outcome therapy resistant treatment response treatment strategy tumor tumor microenvironment uptake

项目摘要

Preclinical and clinical evidence suggests that tumor-associated macrophages (TAMs) are predominantly of the M2 phenotype that supports immuno-suppression, cellular invasion, angiogenesis, metastasis, and therapeutic resistance. The main objective of this project is to evaluate microRNA (miR)-125b delivery in a dual (CD44 and M2pep) targeted hyaluronic acid (HA)-based self-assembling nanoparticles to affect tumor associated macrophage (TAM) repolarization from a predominant M2 to M1 phenotype for improved therapeutic effect in in a KrasLSL-G12D/+, p53fl/fl genetically-engineered mouse (KPC-GEM) model of pancreatic ductal adenocarcinoma (PDAC). In our preliminary studies, we have shown that functionalized HA blocks form a modular self- assembling nano-platform for stable encapsulation of nucleic acid constructs, including small interfering RNA. These CD44-targeted core-shell nanoparticles have shown effective siRNA delivery and down- regulation of anti-apoptotic genes in vivo. Cieslewicz, et al. have shown that M2pep has preferential binding, rapid internalization, and accumulation in murine M2-polarized TAM's compared to other cells. In our preliminary investigation, we have observed that conjugation of M2pep sequence to the HA self- assembling nanoparticles shows preferential accumulation of these nanoparticles in vitro in M2 macrophages. The specific aims of the project are as follows: Aim-1 studies will focus on formulation and characterization of miR-125b duplex encapsulated in HA-PEI/HA-PEG/HA-m2pep nano-assemblies. Aim-2 studies will be directed towards in vitro evaluation of the nano-assemblies to re-polarize macrophages and their capacity to regulate pro-inflammatory cytokines. Aim-3 studies will address evaluation of the anti-tumor therapeutic response and inhibition of metastasis of miR-125b duplex encapsulated in HA-PEI/HA-PEG/HA- m2pep in combination with gemcitabine plus nab-Paclitaxel in a KPC-GEM model of PDAC. This study is highly significant in evaluating macrophage repolarization (from predominant M2 to M1) as a therapeutic strategy for the treatment of PDAC and using macrophage targeted HA-based nanoparticles to deliver microRNA for accomplishing repolarization. The innovative modular HA-based nano-platform is extremely versatile to afford efficient nucleic acid encapsulation, payload protection, and specific delivery to TAM in vivo for efficient repolarization.

临床前和临床证据表明肿瘤相关巨噬细胞（TAM）主要是支持免疫抑制、细胞侵袭、血管生成的 M2 表型，转移和治疗耐药。该项目的主要目标是评估双（CD44 和 M2pep）靶向基于透明质酸（HA）的自组装纳米颗粒以影响肿瘤相关巨噬细胞 (TAM) 从主要的 M2 表型复极化至 M1 表型，以改善治疗效果在 KrasLSL-G12D/+、p53fl/fl 基因工程小鼠 (KPC-GEM) 胰腺导管模型中腺癌（PDAC）。在我们的初步研究中，我们已经表明功能化的 HA 块形成了一个模块化的自组装纳米平台，用于稳定封装核酸构建体，包括小干扰核糖核酸。这些靶向 CD44 的核壳纳米粒子已显示出有效的 siRNA 递送和下调体内抗凋亡基因的调控。西斯莱维奇等人。已表明 M2pep 具有优先权与其他细胞相比，小鼠 M2 极化 TAM 的结合、快速内化和积累。在在我们的初步调查中，我们观察到 M2pep 序列与 HA 自结合组装纳米颗粒显示这些纳米颗粒在体外优先积聚在 M2 中巨噬细胞。该项目的具体目标如下： Aim-1研究将侧重于制定和封装在 HA-PEI/HA-PEG/HA-m2pep 纳米组件中的 miR-125b 双链体的表征。目标2 研究将针对纳米组件的体外评估，以重新极化巨噬细胞和它们调节促炎细胞因子的能力。 Aim-3 研究将解决抗肿瘤的评估问题封装在 HA-PEI/HA-PEG/HA- 中的 miR-125b 双链体的治疗反应和转移抑制在 PDAC 的 KPC-GEM 模型中，m2pep 与吉西他滨加白蛋白结合型紫杉醇组合。这项研究对于评估巨噬细胞复极化（从主要的 M2 到 M1)作为治疗PDAC的治疗策略并使用基于巨噬细胞靶向HA的纳米粒子传递 microRNA 以实现复极化。基于HA的创新模块化纳米平台用途极其广泛，可提供高效的核酸封装、有效负载保护和体内特异性递送至TAM以实现有效的复极化。