Therapeutic nanoparticle constructs of a JAK3 tyrosine kinase inhibitor against human B-lineage ALL cells.
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 ofWHI-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.
Uckun
Fatih M
FM
Molecular Oncology and Drug Discovery Program, Parker Hughes Institute, St. Paul, MN, USA. fmuckun@chla.usc.edu
Dibirdik
Ilker
I
Qazi
Sanjive
S
Yiv
Seang
S
D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D002138:Calibration; D019070:Cell Lineage; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D015448:Leukemia, B-Cell / Q000188:drug therapy* / Q000473:pathology; D015456:Leukemia, Biphenotypic, Acute / Q000188:drug therapy* / Q000473:pathology; D008081:Liposomes; D051379:Mice; D016513:Mice, SCID; D053758:Nanoparticles; D009994:Osmolar Concentration; D010316:Particle Size; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D008081:Liposomes; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C116180:WHI P131; D053616:Janus Kinase 3