title: Targeted delivery of SiRNA to CD33-positive tumor cells with liposomal carrier systems.
abstract: 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.
authors.affiliation: Institut für Zellbiologie und Immunologie, Universität Stuttgart, Allmandring 31, 70569 Stuttgart, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Rothdiener
authors.forename: Dafne
authors.initials: D
authors.lastname: Müller
authors.forename: Patricia Garrido
authors.initials: PG
authors.lastname: Castro
authors.forename: Anja
authors.initials: A
authors.lastname: Scholz
authors.forename: Michael
authors.initials: M
authors.lastname: Schwemmlein
authors.forename: Georg
authors.initials: G
authors.lastname: Fey
authors.forename: Olaf
authors.initials: O
authors.lastname: Heidenreich
authors.forename: Roland E
authors.initials: RE
authors.lastname: Kontermann
mesh_terms: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008081:Liposomes / Q000008:administration & dosage; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering / Q000235:genetics*; D000075142:RUNX1 Translocation Partner 1 Protein; D063268:Sialic Acid Binding Ig-like Lectin 3; D014157:Transcription Factors; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D008081:Liposomes; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000075142:RUNX1 Translocation Partner 1 Protein; C082222:RUNX1T1 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3; D014157:Transcription Factors