Metrology Research Centre, National Research Council of Canada, Ottawa K1A 0R6, Canada.
Metrology Research Centre, National Research Council of Canada, Ottawa K1A 0R6, Canada; Department of Chemistry, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada.
Colloids Surf B Biointerfaces. 2022 Sep;217:112609. doi: 10.1016/j.colsurfb.2022.112609. Epub 2022 Jun 1.
Acute myeloid leukemia (AML), a malignant disorder of Hematopoietic stem cells, can escape immunosurveillance by over expression of the cluster of differentiation 47 (CD47) marker, which functions as an inhibitory signal, suppressing phagocytosis by binding to signal regulatory protein α (SIRPα) on macrophages. AML is treated mainly by chemotherapy, which has drastic side effects and poor outcomes for the patients. Most AML patients develop drug resistance, so other methods to treat AML are highly required. Small interfering RNA (siRNA) is considered as an antitumor therapeutic due to its ability to silence genes associated with the overexpressed cancer markers and subsequently re-sensitize cancer cells. However, delivering siRNA into cells faces challenges, and the development of an effective delivery system is desired for successful silencing at the gene level. Herein, we report the usage of different formulations of graphene oxide (GO) as carriers for the delivery of CD47_siRNA (siRNA against CD47) into AML cells in vitro. The polyethylene glycol (PEG) and dendrimers (PAMAM) modified GO with small flake sizes achieved the highest silencing efficiency of the anti-phagocytosis marker CD47 gene, resulted CD47 protein down-regulation in AML cells. Moreover, the concentration at which the GO-based formulations was used has shown no cytotoxicity in AML cells or normal blood cells, which could be used to screen potential drugs for targeted gene therapy in AML.
急性髓系白血病 (AML) 是一种造血干细胞的恶性疾病，它通过过度表达分化簇 47 (CD47) 标志物来逃避免疫监视，CD47 标志物作为一种抑制信号，通过与巨噬细胞上的信号调节蛋白 α (SIRPα) 结合来抑制吞噬作用。AML 主要通过化疗治疗，这种治疗方法对患者有很大的副作用和较差的治疗效果。大多数 AML 患者会产生耐药性，因此需要寻找其他方法来治疗 AML。小干扰 RNA (siRNA) 因其能够沉默与过度表达的癌症标志物相关的基因，从而使癌细胞重新敏感而被认为是一种抗肿瘤治疗方法。然而，将 siRNA 递送到细胞中面临挑战，因此需要开发有效的递送系统以在基因水平上实现成功的沉默。在此，我们报告了使用不同形式的氧化石墨烯 (GO) 作为载体将 CD47_siRNA（针对 CD47 的 siRNA）递送到体外 AML 细胞中的情况。具有小片状尺寸的聚乙二醇 (PEG) 和树枝状聚合物 (PAMAM) 修饰的 GO 实现了抗吞噬标志物 CD47 基因的最高沉默效率，导致 AML 细胞中 CD47 蛋白下调。此外，所用 GO 制剂的浓度在 AML 细胞或正常血细胞中均没有显示出细胞毒性，这可用于筛选针对 AML 的靶向基因治疗的潜在药物。
