title: Dual functional BAFF receptor aptamers inhibit ligand-induced proliferation and deliver siRNAs to NHL cells.
abstract: The B-cell-activating factor (BAFF)-receptor (BAFF-R) is restrictedly expressed on B-cells and is often overexpressed in B-cell malignancies, such as non-Hodgkin's lymphoma. On binding to its ligand BAFF, proliferation and cell survival are increased, enabling cancer cells to proliferate faster than normal B-cells. Nucleic acid aptamers can bind to target ligands with high specificity and affinity and may offer therapeutic advantages over antibody-based approaches. In this study, we isolated several 2'-F-modified RNA aptamers targeting the B-cell-specific BAFF-R with nanomolar affinity using in vitro SELEX technology. The aptamers efficiently bound to BAFF-R on the surface of B-cells, blocked BAFF-mediated B-cell proliferation and were internalized into B-cells. Furthermore, chimeric molecules between the BAFF-R aptamer and small interfering RNAs (siRNAs) were specifically delivered to BAFF-R expressing cells with a similar efficiency as the aptamer alone. We demonstrate that a signal transducer and activator of transcription 3 (STAT3) siRNA delivered by the BAFF-R aptamer was processed by Dicer and efficiently reduced levels of target mRNA and protein in Jeko-1 and Z138 human B-cell lines. Collectively, our results demonstrate that the dual-functional BAFF-R aptamer-siRNA conjugates are able to deliver siRNAs and block ligand mediated processes, suggesting it might be a promising combinatorial therapeutic agent for B-cell malignancies.
authors.affiliation: Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Jiehua
authors.initials: J
authors.lastname: Zhou
authors.forename: Katrin
authors.initials: K
authors.lastname: Tiemann
authors.forename: Pritsana
authors.initials: P
authors.lastname: Chomchan
authors.forename: Jessica
authors.initials: J
authors.lastname: Alluin
authors.forename: Piotr
authors.initials: P
authors.lastname: Swiderski
authors.forename: John
authors.initials: J
authors.lastname: Burnett
authors.forename: Xizhe
authors.initials: X
authors.lastname: Zhang
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.forename: Robert
authors.initials: R
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Rossi
mesh_terms: D052157:Aptamers, Nucleotide / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors*; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D019041:L-Selectin / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D052157:Aptamers, Nucleotide; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D008024:Ligands; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C435926:TNFRSF13C protein, human; D019041:L-Selectin