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：
9382014
负责人：
Mansoor M Amiji
金额：
$ 17.07万
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 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9382014
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 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 outcome forecast overexpression pre-clinical stem targeted treatment therapy outcome therapy resistant treatment response treatment strategy tumor tumor microenvironment uptake

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 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 outcome forecast overexpression pre-clinical stem targeted treatment therapy outcome therapy resistant treatment response treatment strategy tumor tumor microenvironment uptake

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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，与肿瘤相关的巨噬细胞（TAM）是主要是支持免疫抑制，细胞侵袭，血管生成，转移和治疗性抗性。该项目的主要目的是评估双重二元交付microRNA（mir）-125b（CD44和 M2PEP）靶向透明质酸（HA）基于自组装的纳米颗粒以影响相关的肿瘤巨噬细胞（TAM）从主要的M2到M1表型，以改善治疗作用在KraslSl-G12D/+中，P53FL/FL遗传工程小鼠（KPC-GEM）胰管模型腺癌（PDAC）。在我们的初步研究中，我们表明功能化的HA块形成模块化自我组装纳米平台，以稳定地包裹核酸构建体，包括小干扰 RNA。这些针对CD44的核心壳纳米颗粒已显示出有效的siRNA递送和下降调节体内抗凋亡基因。 Cieslewicz等。已经表明M2PEP具有优先与其他细胞相比，鼠M2极化TAM的结合，快速内在化和积累。在我们的初步研究，我们观察到M2PEP序列与HA自我的结合组装纳米颗粒显示在M2中的这些纳米颗粒的优先积累巨噬细胞。该项目的具体目的如下：AIM-1研究将侧重于配方和 MiR-125b双链体的表征，该双链体包裹在HA-PEI/ha-peg/ha-peg/ha-m2pep纳米组件中。 AIM-2 研究将针对纳米组件的体外评估，以重新偏离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治疗反应和抑制在Ha-pei/ha-peg/ha-ha-中封装的miR-125b双链体的转移 M2PEP与PDAC KPC-GEM模型中的Gemcitabine Plus NAB-PACLITAXEL结合使用。这项研究在评估巨噬细胞复极化方面非常重要（从主要的M2到 M1）作为治疗PDAC并使用巨噬细胞靶向HA的治疗策略纳米颗粒提供microRNA以实现复极化。创新的模块化HA基于HA 纳米平台非常通用，可以提供有效的核酸封装，有效载荷保护和特定于体内TAM的递送以进行有效的复极化。