Macrophage-Mediated Delivery of Acoustically Propelled Nanoparticles for Sensitizing Immunologically Cold Tumors

巨噬细胞介导的声学推进纳米颗粒的递送用于敏化免疫冷肿瘤

基本信息

批准号：
10646371
负责人：
Andrew P Goodwin
金额：
$ 20.64万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646371
关键词：
4T1 Ablation Acoustics Address Adoptive Cell Transfers Advanced Malignant Neoplasm Aftercare Agonist Antigens Biodistribution Breast Cancer Cell Breast Carcinoma CAR T cell therapy Cell Count Cells Chemotaxis Consultations Cytotoxic T-Lymphocytes Dendritic Cells Dissociation Drug Transport Encapsulated Engineering Exposure to Fibroblasts Flow Cytometry Focused Ultrasound Focused Ultrasound Therapy Goals Growth Histologic Hydrophobicity Immune Immunologic Sensitization Immunologic Stimulation Immunologics Immunologist Immunotherapy In Vitro Infusion procedures Macrophage Malignant Neoplasms Mammary Neoplasms Mediating Methods Modeling Mus Outcome Patients Penetration Pharmaceutical Preparations Phenotype Phospholipids Population Porosity Relapse Signal Transduction Silicon Dioxide Solid Neoplasm Stains Surface Suspensions TLR7 gene Technology Technology Transfer Therapeutic Therapeutic Effect Tissues Toxic effect Tumor Antigens Tumor Burden Tumor-associated macrophages Work cancer cell comparison control design effective therapy histological stains immune checkpoint immune modulating agents immunoengineering immunogenic immunoregulation interfacial migration monolayer nanoparticle nanoparticle delivery nanoscale neoplastic cell particle programs refractory cancer resiquimod response sugar targeted delivery trafficking tumor tumor-immune system interactions ultrasound uptake

项目摘要

ABSTRACT The overall goal of this project is to simultaneously reprogram immunologically cold tumors and destroy tumor cells through the targeted delivery of cavitation-enhancing nanoparticles by adoptive macrophage transfers. Engineered immune cells have the capacity to treat patients with relapsing or refractory cancers. However, antigen-directed therapies like CAR T-cell therapy have shown limited efficacy in some advanced cancers due to the highly immunosuppressive microenvironment of solid tumors, expression of immune checkpoints, and lack of tumor-associated antigens. Thus, there is a need for therapies that are agnostic to the expression of tumor- associated antigens and that sensitize solid tumors to established antigen-directed therapies. To meet this important need, we will develop an adoptive cellular transfer technology to deliver a class of propulsive nanoparticles to solid tumors. Delivery of nanoparticles inside of macrophages will increase their accumulation within tumors and reduce off-target toxicity. Once localized, the highly porous design of the silica nanoparticles promotes the nucleation and growth of bubbles on their surfaces to guide their rapid and efficient penetration through dense tumorous tissue in response to high-intensity focused ultrasound (HIFU). By loading immunomodulatory drugs that stimulate macrophages into the nanoparticles, we will simultaneously lyse cancer cells and repolarize a large volume of neighboring tumor-associated macrophages (TAMs) toward antitumor phenotypes, providing amplified stimulation of the tumor immune microenvironment. The unique combination of particle propulsion and enhanced transport of drugs will maximize the repolarization of TAMs and eventually other immune cells by the inclusion of different drugs. In this R21 project, our primary goals are to validate the biodistribution, propulsion, and immunomodulatory effects of the nanoparticles in murine 4T1 mammary carcinoma models, which will allow us to later study the capabilities of this technology in other aggressive tumor models. The outcome of this work will be an adoptive cell transfer technology to deliver propulsive nanoparticles for treating solid tumors that are weakly immunogenic in a way that is extendable to a variety of cancers. Feasibility for this work is supported by the expertise of the PIs: nanoscale interfacial engineering (Goodwin) and adoptive macrophage transfers to solid tumors (Shields) for a multipronged approach to stimulate TAMs and eventually other tumor-associated immune cells. We will develop this technology through the following Specific Aims: 1) Design particles for cavitation-based drug release in macrophages. 2) Understand effects of focused ultrasound on acoustically triggered nanoparticles on tumor spheroid models. And 3) Evaluate the therapeutic potential of macrophage-mediated transport of particles to tumors after ultrasound stimulation.

抽象的该项目的总体目标是同时对免疫冷肿瘤进行重编程并破坏肿瘤通过过继性巨噬细胞转移有针对性地递送增强空化的纳米粒子。工程免疫细胞有能力治疗复发性或难治性癌症患者。然而， CAR T 细胞疗法等抗原导向疗法在某些晚期癌症中显示出有限的疗效，因为实体瘤的高度免疫抑制微环境、免疫检查点的表达和缺乏肿瘤相关抗原。因此，需要对肿瘤表达不可知的治疗方法。相关抗原并使实体瘤对已建立的抗原导向疗法敏感。为了满足这个重要的需求，我们将开发一种过继性细胞转移技术来提供一类推进力纳米粒子对实体瘤的影响。巨噬细胞内纳米粒子的递送将增加其积累在肿瘤内并减少脱靶毒性。一旦定位，二氧化硅纳米粒子的高度多孔设计促进气泡在其表面成核和生长，引导其快速有效的渗透响应高强度聚焦超声 (HIFU) 穿过致密的肿瘤组织。通过加载刺激巨噬细胞进入纳米粒子的免疫调节药物，我们将同时裂解癌症细胞并使大量邻近的肿瘤相关巨噬细胞（TAM）重新极化以抗肿瘤表型，提供对肿瘤免疫微环境的放大刺激。独特的组合粒子推进和增强的药物运输将最大化 TAM 的复极化，并最终其他免疫细胞通过包含不同的药物来实现。在这个 R21 项目中，我们的主要目标是验证纳米颗粒在小鼠 4T1 乳腺中的生物分布、推进和免疫调节作用癌症模型，这将使我们能够在以后研究该技术在其他侵袭性肿瘤中的能力模型。这项工作的成果将是一种传递推进纳米颗粒的过继细胞转移技术用于以可扩展到多种癌症的方式治疗弱免疫原性的实体瘤。这项工作的可行性得到了 PI 专业知识的支持：纳米级界面工程 (Goodwin) 和巨噬细胞过继转移至实体瘤（Shields），采用多管齐下的方法来刺激 TAM 和最终是其他肿瘤相关的免疫细胞。我们将通过以下具体方式开发这项技术目的：1) 设计用于巨噬细胞中基于空化的药物释放的颗粒。 2）了解集中注意力的效果肿瘤球体模型上的声学触发纳米粒子的超声。 3) 评估治疗效果超声刺激后巨噬细胞介导的颗粒向肿瘤转运的潜力。