title: CD19-antigen specific nanoscale liposomal formulation of a SYK P-site inhibitor causes apoptotic destruction of human B-precursor leukemia cells.
abstract: We report the anti-leukemic potency of a unique biotargeted nanoscale liposomal nanoparticle (LNP) formulation of the spleen tyrosine kinase (SYK) P-site inhibitor C61. C61-loaded LNP were decorated with a murine CD19-specific monoclonal antibody directed against radiation-resistant CD19-receptor positive aggressive B-precursor acute lymphoblastic leukemia (ALL) cells. The biotargeted C61-LNP were more potent than untargeted C61-LNP and consistently caused apoptosis in B-precursor ALL cells. The CD19-directed C61-LNP also destroyed B-precursor ALL xenograft cells and their leukemia-initiating in vivo clonogenic fraction. This unique nanostructural therapeutic modality targeting the SYK-dependent anti-apoptotic blast cell survival machinery shows promise for overcoming the clinical radiochemotherapy resistance of B-precursor ALL cells.
authors.affiliation: Developmental Therapeutics Program, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027, USA. fmuckun@chla.usc.edu.
authors.forename: Dorothea E
authors.initials: DE
authors.lastname: Myers
authors.forename: Seang
authors.initials: S
authors.lastname: Yiv
authors.forename: Sanjive
authors.initials: S
authors.lastname: Qazi
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.forename: Ingrid
authors.initials: I
authors.lastname: Cely
authors.forename: Anoush
authors.initials: A
authors.lastname: Shahidzadeh
authors.forename: Martha
authors.initials: M
authors.lastname: Arellano
authors.forename: Erin
authors.initials: E
authors.lastname: Finestone
authors.forename: Paul S
authors.initials: PS
authors.lastname: Gaynon
authors.forename: Amanda
authors.initials: A
authors.lastname: Termuhlen
authors.forename: Jianjun
authors.initials: J
authors.lastname: Cheng
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D018941:Antigens, CD19 / Q000378:metabolism*; D017209:Apoptosis; D001483:Base Sequence; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000379:methods; D019008:Drug Resistance, Neoplasm; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000737:chemistry; D009368:Neoplasm Transplantation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012689:Sequence Homology, Nucleic Acid; D000072377:Syk Kinase
chemical_list: D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D047908:Intracellular Signaling Peptides and Proteins; D008081:Liposomes; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse