Adoptive Macrophage Transfers for Nanoparticle Delivery

摘要 免疫细胞将作为下一代运载工具，运送生物活性药物和造影剂等货物 到发炎的组织由于其趋化因子受体的丰富表达，像巨噬细胞这样的细胞具有趋化性。 以显著的特异性渗透发炎组织的能力。研究人员正在利用这种能力， 引导含有药物和其它货物的附着的纳米颗粒运输到患病组织（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 生物体，可以改变他们的功能，在复杂的，有时意想不到的方式时，加载 纳米粒子因此，了解巨噬细胞和巨噬细胞之间的相互作用是非常必要的。 它们携带的纳米粒子。为了解决这一知识差距，我的实验室将研究两个重点领域。第一、 我们将研究纳米颗粒的物理性质如何影响巨噬细胞表型。利用纳米制造， 我们将创造出大小、形状、硬度和成分各不相同的纳米颗粒;将它们直接附着在 内化，巨噬细胞内;并使用表观基因组学，转录组学， 分子表型分析工具。这一重点领域将揭示差异表达的基因，参与了 巨噬细胞对各种设计的纳米颗粒负载的响应。在第二个重点领域，我们将研究 控制纳米颗粒向发炎组织的细胞介导运输的主要因素。不同的巨噬细胞- 纳米颗粒复合物将被制成并注射到携带不同炎症模型的小鼠体内， 来募集不同的免疫细胞亚群。我们将研究纳米粒子放置的作用（即，到 细胞表面与其内部）以及巨噬细胞表型在其转运中的作用 对发炎组织的功效。这项工作的成果将是一套设计规则，预测巨噬细胞- 介导的纳米颗粒向发炎组织的转运。一旦建立，这些规则将被用来指导 设计新型的纳米颗粒与巨噬细胞接触，促进特定的表型， 这对于特定治疗是有利的，并且有助于改善向那些患病部位的运输。这种能力 将改善临床工作，使用过继转移的巨噬细胞来递送药物、疫苗和造影剂， 用于一系列炎性疾病的药剂。

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.