共培养中癌细胞的消除：不同纳米载体在调节 CD47 和钙网蛋白诱导的吞噬作用中的作用,ACS Applied Materials & Interfaces

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共培养中癌细胞的消除：不同纳米载体在调节 CD47 和钙网蛋白诱导的吞噬作用中的作用
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2023-01-12 , DOI: 10.1021/acsami.2c19311
Eman M Hassan ₁ , Samantha McWhirter ₂ , Gilbert C Walker ₂ , Yadienka Martinez-Rubi ₃ , Shan Zou _{1,

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Affiliation

在健康条件下，促吞噬信号和抗吞噬信号是平衡的。Cluster of Differentiation 47 (CD47) 被认为是一种抗吞噬标记物，在包括急性髓性白血病 (AML) 以及肺癌和肝癌在内的多种类型的人类癌细胞中高度表达，使它们能够逃避巨噬细胞的吞噬作用。下调癌细胞上的 CD47 可向巨噬细胞公开钙网蛋白 (CRT) 并恢复其吞噬活性。在此，我们假设使用修饰的氧化石墨烯 (GO) 载体在体外共培养的 AML、A549 肺癌和 HepG2 肝癌细胞中递送小干扰 RNA (siRNA) CD47 (CD47_siRNA)将使 CD47 沉默并标记癌细胞以进行 CRT 介导的吞噬作用。结果显示，在所有使用的癌细胞系中，通过使用 GO 制剂作为载体，CD47 的高敲低效率和 CRT 水平同时显着增加。CRT 在癌细胞上的存在明显高于 CD47 敲低前的水平，并且需要在与人类巨噬细胞共培养时实现吞噬作用。脂质纳米颗粒（LNPs）和修饰的氮化硼纳米管（BNPs）用于携带CD47_siRNA，并比较了共培养的三种癌细胞中CD47的敲低效率值，使用LNPs作为载体实现了> 95％的敲低效率. 有趣的是，CD47 的高效敲低是通过使用 LNPs 和 BNP 载体获得的；然而，在与人类巨噬细胞共培养时发生吞噬作用不需要癌细胞 CRT 水平的增加，这表明其他途径参与了吞噬作用过程。这些发现突出了 2D（氧化石墨烯）、1D（氮化硼纳米管）和“0D”（脂质纳米颗粒）载体在递送 siRNA 以消除共培养中的癌细胞方面的作用，可能通过多种类型的不同吞噬途径人类癌细胞。此外，这些结果解释了针对 CD47 的免疫疗法以及这些载体在筛选此类疗法药物中的潜在用途和“0D”（脂质纳米颗粒）载体，用于递送 siRNA 以消除共培养中的癌细胞，可能通过多种类型的人类癌细胞中的不同吞噬途径。此外，这些结果解释了针对 CD47 的免疫疗法以及这些载体在筛选此类疗法药物中的潜在用途和“0D”（脂质纳米颗粒）载体，用于递送 siRNA 以消除共培养中的癌细胞，可能通过多种类型的人类癌细胞中的不同吞噬途径。此外，这些结果解释了针对 CD47 的免疫疗法以及这些载体在筛选此类疗法药物中的潜在用途体外。

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Elimination of Cancer Cells in Co-Culture: Role of Different Nanocarriers in Regulation of CD47 and Calreticulin-Induced Phagocytosis

Under healthy conditions, pro- and anti-phagocytic signals are balanced. Cluster of Differentiation 47 (CD47) is believed to act as an anti-phagocytic marker that is highly expressed on multiple types of human cancer cells including acute myeloid leukemia (AML) and lung and liver carcinomas, allowing them to escape phagocytosis by macrophages. Downregulating CD47 on cancer cells discloses calreticulin (CRT) to macrophages and recovers their phagocytic activity. Herein, we postulate that using a modified graphene oxide (GO) carrier to deliver small interfering RNA (siRNA) CD47 (CD47_siRNA) in AML, A549 lung, and HepG2 liver cancer cells in co-culture in vitro will silence CD47 and flag cancer cells for CRT-mediated phagocytosis. Results showed a high knockdown efficiency of CD47 and a significant increase in CRT levels simultaneously by using GO formulation as carriers in all used cancer cell lines. The presence of CRT on cancer cells was significantly higher than levels before knockdown of CD47 and was required to achieve phagocytosis in co-culture with human macrophages. Lipid nanoparticles (LNPs) and modified boron nitride nanotubes (BNPs) were used to carry CD47_siRNA, and the knockdown efficiency values of CD47 were compared in three cancer cells in co-culture, with an achieved knockdown efficiency of >95% using LNPs as carriers. Interestingly, the high efficiency of CD47 knockdown was obtained by using the LNPs and BNP carriers; however, an increase in CRT levels on cancer cells was not required for phagocytosis to happen in co-culture with human macrophages, indicating other pathways’ involvement in the phagocytosis process. These findings highlight the roles of 2D (graphene oxide), 1D (boron nitride nanotube), and “0D” (lipid nanoparticle) carriers for the delivery of siRNA to eliminate cancer cells in co-culture, likely through different phagocytosis pathways in multiple types of human cancer cells. Moreover, these results provide an explanation of immune therapies that target CD47 and the potential use of these carriers in screening drugs for such therapies in vitro.

更新日期：2023-01-12

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