title: Targeting Mantle Cell Lymphoma with Anti-SYK Nanoparticles.
abstract: The pentapeptide mimic 1,4-bis(9-O-dihydroquinidinyl)phthalazine / hydroquinidine 1,4-phathalazinediyl diether ("compound 61") (C-61) is the first reported inhibitor targeting the P-site of SYK. Here we report a nanotechnology platform to target C-61 to mantle cell lymphoma (MCL) cells. Liposomal nanoparticles (NP) loaded with C-61 were prepared using the standard thin film evaporation method. The entrapment of C-61 was obtained using the pH gradient procedure with lactobionic acid (LBA) being used as a low pH buffer inside the NP. Formulation F6A was selected as a lead candidate for further biological testing. The average diameter, zeta potential and C-61 content of the F6A NP was 40 nm, 0.1 mV, and 12.6 mg/ml, respectively. F6A induces apoptosis in SYK+but not SYK-leukemia/lymphoma cells. We also evaluated the cytotoxic activity of F6A in the context of anin vitroartificial bone marrow assay platform based on a 3D scaffold with inverted colloidal crystal geometry mimicking the structural topology of actual bone marrow matrix. The ability of C-61 to induce apoptosis in ALL-1 cells was not adversely affected by the scaffolds. F6A, but not the drug-free NP formulation F6B, caused apoptosis of MCL cell lines MAVER-1 and MINO within 24h. Further development of rationally designed SYK inhibitors and their nanoscale formulations may provide the foundation for therapeutic innovation against a broad spectrum of lymphoid malignancies, including MCL.
authors.affiliation: Developmental Therapeutics Program, Children's Hospital Los Angeles, Children's Center for Cancer and Blood Diseases, Los Angeles, CA 90027 ; Department of Pediatrics and Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA 90027.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Cely
authors.forename: Seang
authors.initials: S
authors.lastname: Yiv
authors.forename: Qian
authors.initials: Q
authors.lastname: Yin
authors.forename: Anoush
authors.initials: A
authors.lastname: Shahidzadeh
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.forename: Jianjun
authors.initials: J
authors.lastname: Cheng
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun