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Arzneimittelforschung 2010; 60(4): 210-217
DOI: 10.1055/s-0031-1296275
Antibiotics · Antimycotics · Antiparasitics · Antiviral Drugs · Chemotherapeutics · Cytostatics
Editio Cantor Verlag Aulendorf (Germany)

Therapeutic nanoparticle constructs of a JAK3 tyrosine kinase inhibitor against human B-lineage ALL cells

Fatih M. Uckun
1   Molecular Oncology and Drug Discovery Program, Parker Hughes Institute, St. Paul, MN, USA
2   Developmental Therapeutics Program, Institute for Pediatric Clinical Research, Childrens Hospital Los Angeles, CA, USA
3   Division of Hematology-Oncology, Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
,
Ilker Dibirdik
1   Molecular Oncology and Drug Discovery Program, Parker Hughes Institute, St. Paul, MN, USA
,
Sanjive Qazi
1   Molecular Oncology and Drug Discovery Program, Parker Hughes Institute, St. Paul, MN, USA
4   Gustavus Adolphus College, St. Peter, MN, USA
,
Seang Yiv
1   Molecular Oncology and Drug Discovery Program, Parker Hughes Institute, St. Paul, MN, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
02 December 2011 (online)

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Abstract

WHI-P131 (CAS 202475-60-3) is a dual-function inhibitor of JAK3 tyrosine kinase that demonstrated potent in vivo anti-inflammatory and anti-leukemic activity in several preclinical animal models. This is the first report of the development of nanoparticle (NP) constructs of WHI-P131. Fourty-eight distinct NP formulations were prepared and WHI-P131 encapsulation efficiencies > 95% and intraliposomal WHI-P131 concentrations >10 mg/mL were achieved in lead NP formulations. The anti-cancer activity of WHI-P131-NP, a PEGylated lead formulation was tested in vitro and in vivo. Notably, WHI-P131-NP was capable of causing apoptotic death in primary leukemia cells from chemotherapy-resistant acute lymphoblastic leukemia (ALL) as well as chronic lymphocytic leukemia (CLL) patients. WHI-P131-NP was also active in the RS4;11 SCID mouse xenograft model of chemotherapy-resistant B-lineage ALL. The life table analysis showed that WHI-P131-NP was more effective than WHI-P131 (P = 0.01), vincristine (P<0.0001), or vehicle (P<0.0001). These experimental results demonstrate that the nanotechnology-enabled delivery of WHI-P131 shows therapeutic potential against leukemias with constitutive activation of the JAK3-STAT3/STAT5 molecular target.

Key words

Acute lymphoblastic leukemia cells - Anti-leukemia agent - CAS 202475-60-3 - JAK3 tyrosine kinase inhibitor - WHI-P131, nanoparticle constructs
 

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