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

• 批准号: 10512775
• 负责人: Andrew P Goodwin
• 金额: $ 17.43万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10512775
• 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; Drug Transport; Encapsulated; Engineering; Exposure to; Fibroblasts; Flow Cytometry; Focused Ultrasound; Focused Ultrasound Therapy; Goals; Growth; Histologic; Hydrophobicity; Immune; Immunization; Immunologics; Immunologist; Immunomodulators; Immunotherapy; In Vitro; Infusion procedures; Malignant Neoplasms; Mammary Neoplasms; Mediating; Methods; Modeling; Mus; Outcome; Patients; Penetration; Pharmaceutical Preparations; Phenotype; Phospholipids; Population; 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; base; cancer cell; design; effective therapy; histological stains; immune checkpoint; immunoengineering; immunogenic; immunoregulation; interfacial; macrophage; monolayer; nanoparticle; nanoparticle delivery; nanoscale; neoplastic cell; particle; refractory cancer; resiquimod; response; sugar; targeted delivery; trafficking; tumor; tumor-immune system interactions; ultrasound; uptake

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重新编程免疫学冷肿瘤并破坏肿瘤 通过通过过继的巨噬细胞转移的靶向递送增强空化的纳米颗粒的细胞。 工程的免疫细胞具有治疗复发或难治性癌症患者的能力。然而， 抗原定向的疗法（如汽车T细胞疗法）在某些高级癌症中表现出有限的疗效 高度免疫抑制实体瘤的微环境，免疫检查点的表达和缺乏 肿瘤相关的抗原。因此，需要对肿瘤表达不可知的疗法 相关的抗原，并使实体瘤对建立的抗原定向疗法敏感。满足这个 重要的需求，我们将开发一种收养的蜂窝转移技术来提供一类推进 纳米颗粒至实体瘤。纳米颗粒在巨噬细胞中的递送将增加其积累 在肿瘤内并降低脱靶毒性。一旦定位，二氧化硅纳米颗粒的高度多孔设计 促进气泡在其表面上的成核和生长，以指导其快速有效的穿透 通过致密的肿瘤组织，响应高强度聚焦超声（HIFU）。通过加载 刺激巨噬细胞进入纳米颗粒的免疫调节药物，我们将同时裂解癌症 细胞并重复大量相邻的肿瘤相关巨噬细胞（TAM）朝着抗肿瘤 表型，提供了对肿瘤免疫微环境的扩增刺激。独特的组合 颗粒推进和药物的运输增强将最大化TAM的复极化，最终将 其他免疫细胞通过包含不同的药物。在这个R21项目中，我们的主要目标是验证 鼠4T1乳腺中纳米颗粒的生物分布，推进和免疫调节作用 癌模型，这将使​​我们以后可以在其他侵略性肿瘤中研究该技术的能力 型号。这项工作的结果将是一种收养细胞转移技术，以提供推进纳米颗粒 用于以一种可扩展到各种癌症的方式处理弱免疫原性的实体瘤。 PIS的专业知识支持这项工作的可行性：纳米界界面工程（Goodwin）和 采用巨噬细胞转移到实体瘤（盾牌），以刺激TAM和 最终其他与肿瘤相关的免疫细胞。我们将通过以下特定开发这项技术 目的：1）设计巨噬细胞中基于空化的药物释放的颗粒。 2）了解聚焦的效果 在声学上触发纳米颗粒上的超声检查肿瘤球体模型。 3）评估治疗性 超声刺激后巨噬细胞介导的颗粒向肿瘤的转运的潜力。