Adoptive Macrophage Transfers for Nanoparticle Delivery

摘要 免疫细胞将成为运送生物活性药物和造影剂等货物的下一代交通工具 发炎的组织。由于大量表达趋化因子受体，像巨噬细胞这样的细胞具有 具有显著特异性的炎症组织渗入能力。研究人员正在利用这种能力来 将含有药物和其他货物的附着纳米颗粒直接运输到病变组织(例如，从 癌症、传染病、自身免疫性疾病和心血管疾病)。然而，巨噬细胞 有生命的实体在加载 纳米粒子。因此，有必要了解巨噬细胞和细胞之间的相互作用。 它们携带的是纳米颗粒。为了解决这一知识差距，我的实验室将调查两个重点领域。第一, 我们将研究纳米粒子的物理性质如何影响巨噬细胞的表型。利用纳米制造技术， 我们将创造大小、形状、硬度和组成各不相同的纳米颗粒；将它们直接附着在或 在巨噬细胞内内化；并使用表观基因组学、转录学和 分子表型工具。这一焦点区域将揭示差异表达的基因，这些基因涉及 巨噬细胞对不同设计的纳米颗粒负载的反应。在第二个重点领域，我们将研究 控制细胞介导的纳米颗粒到炎症组织的运输的主要因素。不同的巨噬细胞- 将制造纳米颗粒复合体，并将其注射到具有不同炎症模型的小鼠体内 招募不同亚群的免疫细胞。我们将研究纳米颗粒放置的作用(即 细胞表面与内部)以及巨噬细胞表型在其运输中的作用 对发炎组织有效。这项工作的结果将是一套预测巨噬细胞的设计规则 介导性纳米颗粒向炎症组织的运输。一旦确立，这些规则将被用来指导 新型纳米颗粒的设计可以与巨噬细胞结合，促进特定的表型 有利于特定的治疗，并便于改善到这些患病部位的运输。这样一种能力 将改善临床使用过继转移的巨噬细胞来输送药物、疫苗和对比剂的努力 治疗一系列炎症性疾病的药物。

ABSTRACT Immune cells will serve as next-generation vehicles to deliver cargo such as bioactive drugs and contrast agents to inflamed tissues. Due to their abundant expression of chemokine receptors, cells like macrophages have the capacity to infiltrate inflamed tissues with remarkable specificity. Researchers are exploiting this capability to direct the transport of attached nanoparticles containing drugs and other cargo to diseased tissues (e.g., from cancer, infectious diseases, autoimmune disorders, and cardiovascular disease). However, macrophages are living entities that can change their function in complex and sometimes unexpected ways when loaded with nanoparticles. Thus, there is a fundamental need to understand the interactions between macrophages and the nanoparticles they carry. To address this gap in knowledge, my laboratory will investigate two focus areas. First, we will study how the physical properties of nanoparticles affect macrophage phenotypes. Using nanofabrication, we will create nanoparticles that vary in size, shape, stiffness, and composition; direct their attachment onto, or internalization within, macrophages; and measure their responses using epigenomic, transcriptomic, and molecular phenotyping tools. This focus area will reveal differentially expressed genes that are involved in the macrophage responses to nanoparticle loadings of various design. In the second focus area, we will study the principal factors that govern cell-mediated transport of nanoparticles to inflamed tissues. Different macrophage- nanoparticle complexes will be made and injected into mice harboring different models of inflammation designed to recruit different subpopulations of immune cells. We will study the role of nanoparticle placement (i.e., onto the surfaces of cells versus within their interiors) as well as the role of macrophage phenotypes on their transport efficiency to inflamed tissues. The outcome of this work will be a set of design rules that predict macrophage- mediated transport of nanoparticles to inflamed tissues. Once established, these rules will be exploited to guide the design of new types of nanoparticles that interface with macrophages, promote specific phenotypes that are advantageous for specific treatments, and facilitate improved transport to those diseased sites. Such a capability will improve clinical efforts to use adoptively transferred macrophages to deliver drugs, vaccines, and contrast agents for a range of inflammatory diseases.