CD19-antigen specific nanoscale liposomal formulation of a SYK P-site inhibitor causes apoptotic destruction of human B-precursor leukemia cells

Dorothea E. Myers; Seang Yiv; Sanjive Qazi; Hong Ma; Ingrid Cely; Anoush Shahidzadeh; Martha Arellano; Erin Finestone; Paul S. Gaynon; Amanda Termuhlen; Jianjun Cheng; Fatih M. Uckun

doi:10.1039/C4IB00095A

CD19-antigen specific nanoscale liposomal formulation of a SYK P-site inhibitor causes apoptotic destruction of human B-precursor leukemia cells

Dorothea E. Myers,^a Seang Yiv,^a Sanjive Qazi,^a Hong Ma,^a Ingrid Cely,^a Anoush Shahidzadeh,^a Martha Arellano,^a Erin Finestone,^a Paul S. Gaynon,^ab Amanda Termuhlen,^bc Jianjun Cheng^d and Fatih M. Uckun †*^abe

Author affiliations

* Corresponding authors

^a Developmental Therapeutics Program, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027, USA
E-mail: fmuckun@chla.usc.edu
Tel: +1-323-361-4328

^b Division of Hematology-Oncology, Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA

^c Jonathan Jaques Cancer Center, Miller Children's Hospital, Long Beach, CA 90806, USA

^d Department of Materials Science and Engineering, University of Illinois at Urbana–Champaign (UIUC), Urbana, Illinois 61801, USA

^e Developmental Therapeutics Program, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA 90027, USA

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.

Integrative Biology

CD19-antigen specific nanoscale liposomal formulation of a SYK P-site inhibitor causes apoptotic destruction of human B-precursor leukemia cells

Abstract

Article information

Download Citation

Author version available

Search articles by author

Spotlight

Advertisements