CD33
癌症研究
髓系白血病
脂质体
基因沉默
化学
融合蛋白
转染
内化
小干扰RNA
分子生物学
生物
细胞生物学
细胞培养
细胞
重组DNA
干细胞
生物化学
基因
遗传学
川地34
作者
Miriam Rothdiener,Dafne Müller,Patricia Garrido Castro,Anja Scholz,Michael Schwemmlein,Georg H. Fey,Olaf Heidenreich,Roland E. Kontermann
标识
DOI:10.1016/j.jconrel.2010.02.020
摘要
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.
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