Institut für Zellbiologie und Immunologie, Universität Stuttgart, Allmandring 31, 70569 Stuttgart, Germany.
J Control Release. 2010 Jun 1;144(2):251-8. doi: 10.1016/j.jconrel.2010.02.020. Epub 2010 Feb 22.
SiRNA molecules represent promising therapeutic molecules, e.g. for cancer therapy. However, efficient delivery into tumor cells remains a major obstacle for treatment. Here, we describe a liposomal siRNA carrier system for targeted delivery of siRNA to CD33-positive acute myeloid leukemia cells. The siRNA is directed against the t(8;21) translocation resulting in the AML1/MTG8 fusion protein. The siRNA was encapsulated in free or polyethylene imine (PEI)-complexed form into PEGylated liposomes endowed subsequently with an anti-CD33 single-chain Fv fragment (scFv) for targeted delivery. The resulting siRNA-loaded immunoliposomes (IL) and immunolipoplexes (ILP) showed specific binding and internalization by CD33-expressing myeloid leukemia cell lines (SKNO-1, Kasumi-1). Targeted delivery of AML1/MTG8 siRNA, but not of mismatch control siRNA, reduced AML1/MTG8 mRNA and protein levels and decreased leukemic clonogenicity, a hallmark of leukemic self-renewal. Although this study revealed that further modifications are necessary to increase efficacy of siRNA delivery and silencing, we were able to establish a targeted liposomal siRNA delivery system combining recombinant antibody fragments for targeted delivery with tumor cell-specific siRNA molecules as therapeutic agents.
siRNA 分子是很有前途的治疗分子，例如用于癌症治疗。然而，将其有效地递送到肿瘤细胞仍然是治疗的主要障碍。在这里，我们描述了一种用于将 siRNA 靶向递送至 CD33 阳性急性髓系白血病细胞的脂质体 siRNA 载体系统。该 siRNA 针对导致 AML1/MTG8 融合蛋白的 t(8;21)易位。siRNA 以游离形式或聚乙烯亚胺 (PEI) 复合物的形式封装在聚乙二醇化脂质体中，随后用抗 CD33 单链 Fv 片段 (scFv) 赋予靶向递送能力。由此产生的负载 siRNA 的免疫脂质体 (IL) 和免疫脂质体复合物 (ILP) 表现出与表达 CD33 的髓样白血病细胞系 (SKNO-1、Kasumi-1) 的特异性结合和内化。AML1/MTG8 siRNA 的靶向递送，而不是错配对照 siRNA 的靶向递送，降低了 AML1/MTG8 mRNA 和蛋白质水平，并降低了白血病集落形成能力，这是白血病自我更新的标志。尽管这项研究表明需要进一步修饰以提高 siRNA 递送和沉默的效率，但我们能够建立一种靶向脂质体 siRNA 递送系统，该系统将重组抗体片段用于靶向递送与肿瘤细胞特异性 siRNA 分子结合作为治疗剂。
