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

摘要 这个项目的总体目标是同时对免疫寒冷的肿瘤进行重新编程，并摧毁肿瘤 通过过继巨噬细胞转移靶向输送空化增强纳米颗粒。 基因工程免疫细胞有能力治疗复发或难治性癌症患者。然而， 抗原导向疗法，如CAR T细胞疗法，在一些晚期癌症中显示出有限的疗效，因为 对于实体瘤高度免疫抑制的微环境，免疫检查点的表达，以及缺乏 肿瘤相关抗原。因此，需要一种与肿瘤表达无关的治疗方法- 相关抗原，并使实体肿瘤对已有的抗原导向疗法敏感。为了满足这一点 重要需求，我们将开发一种采用细胞转移技术，以提供一类推进剂 从纳米粒子到实体肿瘤。将纳米颗粒输送到巨噬细胞内将增加它们的蓄积 在肿瘤内，并减少脱靶毒性。一旦局部化，二氧化硅纳米颗粒的高度多孔设计 促进气泡表面的成核和生长，引导气泡快速有效地穿透 通过致密的肿瘤组织对高强度聚焦超声(HIFU)的反应。通过加载 免疫调节药物将刺激巨噬细胞转化为纳米颗粒，我们将同时溶解肿瘤 并使大量邻近的肿瘤相关巨噬细胞(TAM)重新极化为抗肿瘤细胞 表型，提供对肿瘤免疫微环境的放大刺激。独一无二的组合 粒子推进和增强的药物运输将使TAMs的复极化最大化，并最终 其他免疫细胞则由不同的药物所包含。在这个R21项目中，我们的主要目标是验证 纳米粒在小鼠4T1乳腺的生物分布、推进和免疫调节作用 肿瘤模型，这将使我们以后研究这项技术在其他侵袭性肿瘤中的能力 模特们。这项工作的结果将是一种采用细胞转移技术来传递推进纳米颗粒 用于治疗免疫原性弱的实体肿瘤，这种方法可扩展到各种癌症。 这项工作的可行性得到了PI的专业知识的支持：纳米界面工程(Goodwin)和 过继巨噬细胞转移到实体瘤(Shield)多管齐下刺激TAMs和 最终，其他与肿瘤相关的免疫细胞。我们将通过以下具体的方式开发这项技术 目的：1)设计基于空化的巨噬细胞药物释放颗粒。2)了解聚焦的效果 超声对肿瘤球体模型上的声触发纳米颗粒的作用。3)评价治疗效果 超声刺激后巨噬细胞介导的颗粒向肿瘤转移的可能性。

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.