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

摘要 该项目的总体目标是同时重编程免疫冷肿瘤和破坏肿瘤 通过过继性巨噬细胞转移靶向递送空化增强纳米颗粒， 工程免疫细胞有能力治疗复发性或难治性癌症患者。然而，在这方面， 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， 实体瘤的高度免疫抑制微环境，免疫检查点的表达， 肿瘤相关抗原。因此，需要对肿瘤表达不可知的疗法。 相关抗原，并使实体瘤对已建立的抗原导向疗法敏感。满足这一 重要的需要，我们将开发一种过继细胞转移技术，以提供一类推进 纳米粒子到实体肿瘤。在巨噬细胞内递送纳米颗粒将增加它们的积累 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 促进气泡在其表面上的成核和生长，以引导它们快速有效地渗透 通过致密的肿瘤组织，以响应高强度聚焦超声（HIFU）。通过加载 免疫调节药物，刺激巨噬细胞进入纳米粒子，我们将同时溶解癌症 细胞和大量邻近的肿瘤相关巨噬细胞（TAM）， 表型，提供肿瘤免疫微环境的放大刺激。的独特组合 粒子推进和增强的药物运输将使TAM的复极化最大化， 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 小鼠4T1乳腺癌中纳米颗粒的生物分布、推进和免疫调节作用 这将使我们能够在以后研究这种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过继细胞转移技术， 用于以可扩展至多种癌症的方式治疗免疫原性弱的实体瘤。 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 过继性巨噬细胞转移到实体瘤（Shields），用于多管齐下的方法来刺激TAM， 最终是其他肿瘤相关的免疫细胞。我们将通过以下具体措施开发这项技术 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)了解聚焦的效果 超声对肿瘤球体模型上的声触发纳米颗粒的影响。（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运的可能性。

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.