title: Targeted therapy with MXD3 siRNA, anti-CD22 antibody and nanoparticles for precursor B-cell acute lymphoblastic leukaemia.
abstract: Conventional chemotherapy for precursor B-cell (preB) acute lymphoblastic leukaemia (ALL) has limitations that could be overcome by targeted therapy. Previously, we discovered a potential therapeutic molecular target, MDX3 (MAX dimerization protein 3), in preB ALL. In this study, we hypothesize that an effective siRNA therapy for preB ALL can be developed using antiCD22 antibody (αCD22 Ab) and nanoparticles. We composed nanocomplexes with super paramagnetic iron oxide nanoparticles (SPIO NPs), αCD22 Abs and MXD3 siRNA molecules based on physical interactions between the molecules. We demonstrated that the MXD3 siRNA-αCD22 Ab-SPIO NP complexes entered leukaemia cells and knocked down MXD3, leading the cells to undergo apoptosis and resulting in decreased live cell counts in the cell line Reh and in primary preB ALL samples in vitro. Furthermore, the cytotoxic effects of the MXD3 siRNA-αCD22 Ab-SPIO NP complexes were significantly enhanced by addition of the chemotherapy drugs vincristine or doxorubicin. We also ruled out potential cytotoxic effects of the MXD3 siRNA-αCD22 Ab-SPIO NP complexes on normal primary haematopoietic cells. Normal B cells were affected while CD34-positive haematopoietic stem cells and non-B cells were not. These data suggest that MXD3 siRNA-αCD22 Ab-SPIO NP complexes have the potential to be a new targeted therapy for preB ALL.
authors.affiliation: Department of Pediatrics, University of California Davis, Sacramento, CA, USA; Stem Cell Program and Institute for Regenerative Cures, University of California Davis, Sacramento, CA, USA.
authors.forename: Noriko
authors.initials: N
authors.lastname: Satake
authors.forename: Connie
authors.initials: C
authors.lastname: Duong
authors.forename: Cathy
authors.initials: C
authors.lastname: Chen
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Barisone
authors.forename: Elva
authors.initials: E
authors.lastname: Diaz
authors.forename: Joseph
authors.initials: J
authors.lastname: Tuscano
authors.forename: David M
authors.initials: DM
authors.lastname: Rocke
authors.forename: Jan
authors.initials: J
authors.lastname: Nolta
authors.forename: Nitin
authors.initials: N
authors.lastname: Nitin
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000737:chemistry / Q000494:pharmacology*; D000912:Antibodies, Neoplasm / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D058185:Magnetite Nanoparticles / Q000737:chemistry*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000737:chemistry / Q000494:pharmacology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm; C497867:CD22 protein, human; C543450:MXD3 protein, human; D058185:Magnetite Nanoparticles; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D051918:Sialic Acid Binding Ig-like Lectin 2
keywords: MXD3 siRNA; RNA inhibition; antiCD22 antibody; precursor B-cell acute lymphoblastic leukaemia; superparamagnetic iron oxide nanoparticle