title: Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B-cell cytotoxicity in chronic lymphocytic leukemia.
abstract: Selective cytotoxicity to cancer cells without compromising their normal counterparts pose a huge challenge for traditional drug design. Here we developed a tumor antigen-targeted delivery of immunonanoparticle carrying a novel non-immunosuppressive FTY720 derivative OSU-2S with potent cytotoxicity against leukemic B cells. OSU-2S induces activation of protein phosphatase 2A (PP2A), phosphorylation and nuclear translocation of SHP1(S591) and deregulation of multiple cellular processes in chronic lymphocytic leukemia (CLL) resulting in potent cytotoxicity. To preclude OSU-2S-mediated effects on these ubiquitous phosphatases in unintended cells and avoid potential adverse effects, we developed an OSU-2S-targeted delivery of immunonanoparticles (2A2-OSU-2S-ILP), that mediated selective cytotoxicity of CLL but not normal B cells through targeting receptor tyrosine kinase ROR1 expressed in leukemic but not normal B cells. Developing a novel spontaneous CLL mouse model expressing human ROR1 (hROR1) in all leukemic B cells, we demonstrate the therapeutic benefit of enhanced survival with 2A2-OSU-2S-ILP in vivo. The newly developed non-immunosuppressive OSU-2S, its delivery using human CLL directed immunonanoparticles and the novel transgenic (Tg) mouse model of CLL that expresses hROR1 exclusively in leukemic B cell surface are highly innovative and can be applied to CLL and other ROR1+ malignancies including mantle cell lymphoma and acute lymphoblastic leukemia.
authors.affiliation: 1] Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA [2] Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [3] Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Mani
authors.affiliation: 1] Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [2] Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA [3] Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Mao
authors.affiliation: 1] Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA [2] Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: F W
authors.initials: FW
authors.lastname: Frissora
authors.affiliation: 1] Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA [2] Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: C-L
authors.initials: CL
authors.lastname: Chiang
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.affiliation: 1] Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [2] Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA.
authors.forename: B
authors.initials: B
authors.lastname: Yu
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Yan
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
authors.forename: X
authors.initials: X
authors.lastname: Mo
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Flynn
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Jones
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: L
authors.initials: L
authors.lastname: Andritsos
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Baskar
authors.affiliation: Department of Cancer Biology and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL, USA.
authors.forename: C
authors.initials: C
authors.lastname: Rader
authors.affiliation: 1] Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [2] Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Phelps
authors.affiliation: 1] Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [2] Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA [3] Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: C-S
authors.initials: CS
authors.lastname: Chen
authors.affiliation: 1] Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [2] Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA [3] Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: 1] Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA [2] Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [3] Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA [4] Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: 1] Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA [2] Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Lee
authors.affiliation: 1] Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA [2] Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [3] Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: N
authors.initials: N
authors.lastname: Muthusamy
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D016503:Drug Delivery Systems; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000628:therapy*; D008081:Liposomes / Q000737:chemistry; D020522:Lymphoma, Mantle-Cell / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000737:chemistry; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011409:Propylene Glycols / Q000737:chemistry; D011493:Protein Kinase C / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D008081:Liposomes; D011409:Propylene Glycols; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D011493:Protein Kinase C; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine