Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University College Station, Kingsville 78363, Texas, United States.
Department of Life Sciences, College of Science and Engineering, Texas A&M University, Corpus Christi 78412, Texas, United States.
ACS Appl Mater Interfaces. 2020 Nov 25;12(47):52402-52414. doi: 10.1021/acsami.0c15983. Epub 2020 Nov 10.
Tumor-associated macrophages (TAMs), a major player in the tumor microenvironment, were recently recognized as a potential therapeutic target. To date, very few anticancer drugs or drug-delivery systems were designed to target the TAMs. Inspired by the "eat me" signal, phosphatidylserine (PS), mediated phagocytic clearance of apoptotic bodies, in this study, the matrix metalloproteinase 2 (MMP2)-sensitive PS-modified nanoparticles were developed. In the design, the PS is externalized to the nanoparticles' surface only when the nanoparticles reach the MMP2-overexpressing tumor site, allowing for the TAM-specific phagocytosis. The nanoparticles' excellent macrophage/TAM selectivity was observed in various biological models, including various cell lines, coculture cells, coculture cell spheroids, zebrafish, and tumor-bearing mice. The nanoparticles' TAM specificity remarkably enhanced the TAM depletion capability of the loaded model drug, dasatinib, resulting in the improved anticancer activity. The MMP2-sensitive apoptotic body-mimicking nanoparticles might be a promising delivery tool for TAM-centered cancer diagnoses and treatments.
肿瘤相关巨噬细胞（TAMs）是肿瘤微环境中的主要参与者，最近被认为是一个潜在的治疗靶点。迄今为止，很少有抗癌药物或药物输送系统被设计用于靶向 TAMs。受“吃我”信号的启发，磷脂酰丝氨酸（PS）介导凋亡小体的吞噬清除，在本研究中，开发了基质金属蛋白酶 2（MMP2）敏感的 PS 修饰的纳米颗粒。在设计中，只有当纳米颗粒到达 MMP2 过表达的肿瘤部位时，PS 才会外排在纳米颗粒的表面，从而允许 TAM 特异性吞噬。在各种生物模型中观察到了纳米颗粒的优异的巨噬细胞/TAM 选择性，包括各种细胞系、共培养细胞、共培养细胞球、斑马鱼和荷瘤小鼠。纳米颗粒的 TAM 特异性显著增强了负载模型药物达沙替尼的 TAM 耗竭能力，从而提高了抗癌活性。MMP2 敏感的凋亡体模拟纳米颗粒可能是一种有前途的用于以 TAM 为中心的癌症诊断和治疗的递送工具。
