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

Fatih M. Uckun; Ilker Dibirdik; Sanjive Qazi; Seang Yiv

doi:10.1055/s-0031-1296275

Arzneimittelforschung, Table of Contents

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

¹Molecular Oncology and Drug Discovery Program, Parker Hughes Institute, St. Paul, MN, USA

²Developmental Therapeutics Program, Institute for Pediatric Clinical Research, Childrens Hospital Los Angeles, CA, USA

³Division of Hematology-Oncology, Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA, USA

,

Ilker Dibirdik

¹Molecular Oncology and Drug Discovery Program, Parker Hughes Institute, St. Paul, MN, USA

,

Sanjive Qazi

¹Molecular Oncology and Drug Discovery Program, Parker Hughes Institute, St. Paul, MN, USA

⁴Gustavus Adolphus College, St. Peter, MN, USA

,

Seang Yiv

¹Molecular Oncology and Drug Discovery Program, Parker Hughes Institute, St. Paul, MN, USA

› Author Affiliations

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

Full Text

References

References
1 Burke WM, Jin X, Lin HJ, Huang M, Liu R, Reynolds K et al Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells. Oncogene. 2001; 20: 7925-34
2 Jeong EG, Jeong EG, Kim MS, Nam HK, Min CK, Lee S et al Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers. Clin Cancer Res. 2008; 14: 3716-21
3 Eum SY, Lee YW, Hennig B, Toborek M. Interplay between epidermal growth factor receptor and Janus kinase 3 regulates polychlorinated biphenyl-induced matrix metalloproteinase-3 expression and transendothelial migration of tumor cells. Mol Cancer Res. 2006; 4: 361-70
4 Kim S, Choi JH, Lim HI, Lee SK, Kim WW, Cho S et al EGF-induced MMP-9 expression is mediated by the JAK3/ERK pathway, but not by the JAK3/STAT3 pathway in a SKBR3 breast cancer cell line. Cell Signal. 2009; 21: 892-8
5 Cance WG, Liu ET. Protein kinases in human breast cancer. Breast Cancer Res Treat. 1995; 35: 105-14
6 Uckun FM, Vassilev A, Dibirdik I, Tibbles H. Targeting JAK3 tyrosine kinase-linked signal transduction pathways with rationally designed inhibitors. Anticancer Agents Med Chem. 2007; 7: 612-23
7 Serewko MM, Popa C, Dahler AL, Smith L, Strutton GM, Coman W et al Alterations in gene expression and activity during squamous cell carcinoma development. Cancer Res. 2002; 62: 3759-65
8 Sudbeck EA, Liu X, Narla RK, Mahajan S, Ghosh S, Mao C et al Structure-based design of specific inhibitors of Janus kinase 3 as apoptosis-inducing antileukemic agents. Clin Cancer Res. 1999; 5: 1569-82
9 Lin Q, Lai R, Chirieac LR, Li C, Thomazy VA, Grammatika-kis I et al Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines. Inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells. Am J Pathol. 2005; 167: 969-80
10 Amin HM, Medeiros LJ, Ma Y, Feretzaki M, Das P, Leven-taki V et al Inhibition of JAK3 induces apoptosis and decreases anaplastic lymphoma kinase activity in anaplastic large cell lymphoma. Oncogene. 2003; 22: 5399-407
11 Hu W, Zhang C, Zhang P, Wei D, Zhao Z, Cai M. Inhibition of constitutively activated JAK3 and induction of apoptosis in NALM-6 cell line. Hua Xi Yi Ke Da Xue Bao. 2002; 33: 25-7
12 Chen WS, Kung HI, Yang WK, Lin W. Comparative tyrosine-kinase profiles in colorectal cancers: enhanced arg expression in carcinoma as compared with adenoma and normal mucosa. Int J Cancer. 1999; 83: 579-84
13 Martinez-Lostao L, Briones J, Forne I, Martinez-Gallo M, Ferrer B, Sierra J et al Role of the STAT1 pathway in apoptosis induced by fludarabine and JAK kinase inhibitors in B-cell chronic lymphocytic leukemia. Leuk Lymphoma. 2005; 46: 435-42
14 Mori D, Nakafusa Y, Miyazaki K, Tokunaga O. Differential expression of Janus kinase 3 (JAK3), matrix metalloproteinase 13 (MMP13), heat shock protein 60 (HSP60), and mouse double minute 2 (MDM2) in human colorectal cancer progression using human cancer cDNA microarrays. Pathol Res Pract. 2005; 201: 777-89
15 Walters DK, Mercher T, Gu TL, O’Hare T, Tyner JW, Lo-riaux M et al Activating alleles of JAK3 in acute mega-karyoblastic leukemia. Cancer Cell. 2006; 10: 65-75
16 Witthuhn BA, Williams MD, Kerawalla H, Uckun FM. Differential substrate recognition capabilities of Janus family protein tyrosine kinases within the interleukin 2 receptor (IL2R) system: Jak3 as a potential molecular target for treatment of leukemias with a hyperactive Jak-Stat signaling machinery. Leuk Lymphoma. 1999; 32: 289-97
17 Spano IP, Milano G, Rixe C, Fagard R. JAK/STAT signalling pathway in colorectal cancer: a new biological target with therapeutic implications. Eur J Cancer. 2006; 42: 2668-70
18 Uckun FM, Tibbles H, Ozer Z, Qazi S, Vassilev A. Anti-inflammatory activity profile of JANEX-1 in preclinical animal models. Bioorg Med Chem. 2008; 16: 1287-98
19 Barata JT, Boussiotis VA, Yunes JA, Ferrando AA, Moreau LA, Veiga JP et al IL-7 dependent human leukemia T-cell line as a valuable tool for drug discovery in T-ALL. Blood. 2004; 103: 1891-900
20 Qazi S, Uckun FM. Gene expression profiles of infant acute lymphoblastic leukemia and its prognostically distinct subsets. Br J Hematol. Forthcoming. 2010;
21 Uckun FM, Erbeck D, Qazi S, Venkatachalam TK, Tibbies HE, Vassilev A. Effect of targeting janus kinase 3 on the development of intestinal tumors in the adenomatous polyposis coli (min) mouse model of familial adenomatous polyposis. Arzneimittelforschung. 2007; 57 (6) 320-9
22 Uckun FM, Dibirdik I, Qazi S. Prevention of UVB-induced skin inflammation, genotoxicity, and photocarcinogenesis in mice by WHI-P131, a dual-function inhibitor of Janus kinase 3 and EGF receptor kinase. Arzneimittelforschung. Forthcoming. 2010;
23 Uckun FM, Ek O, Liu XP, Chen CL. In vivo toxicity and pharmacokinetic features of the janus kinase 3 inhibitor WHI-P131 [4-(4’hydroxyphenyl)-amino-6,7-dimethoxyqui-nazoline. Clin Cancer Res. 1999; 5: 2954-62
24 Uckun FM, Roers BA, Waurzyniak B, Liu XP, Cetkovic-Cvrlje M. Janus kinase 3 inhibitor WHI-P131/JANEX-1 prevents graft-versus-host disease but spares the graft-ver-sus-leukemia function of the bone marrow allografts in a murine bone marrow transplantation model. Blood. 2002; 99: 4192-9
25 Davis ME, Chen Z, Shin DM. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov. 2008; 7: 771-82
26 Cho K, Wang X, Nie S, Chen ZG, Shin DM. Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res. 2008; 14 (5) 1310-6
27 Sinha R, Kim GJ, Nie S, Shin DM. Nanotechnology in cancer therapeutics: bioconjugated nanoparticles for drug delivery. Mol Cancer Ther. 2006; 5 (8) 1909-17
28 Owens DE, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006; 307: 93-102
29 Li WM, Mayer L, Bally MB. Prevention of antibody-mediated elimination of ligand-targeted liposomes by using polyethylene glycol)-modified lipids. J Pharm Exp Ther. 2002; 300: 976-83
30 Papahadjopoulos D, Allen TM, Gabizon A, Mayhew E, Mat-thay K, Huang SK et al Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci USA. 1991; 88: 11460-4
31 Mayer LD, Tai LC, Bally MB, Mitilenes GN, Ginsberg RS, Cullis PR. Characterization of liposomal systems containing doxorubicin entrapped in response to pH gradients. Biochim Biophys Acta. 1990; 1025: 143-51
32 Madden TD, Harrigan PR, Tai LC, Bally MB, Mayer LD, Redelmeier TE et al The accumulation of drugs within large unilamellar vesicles exhibiting a proton gradient: a survey. Chem Phys Lipids. 1990; 53: 37-46
33 Fenske DB, Cullis PR. Liposomal nanomedicines. Expert Opin Drug Deliv. 2008; 5 (1) 25-44
34 Szoka FC, Olson F, Heath T, Vail W, Mayhew E, Papahadjopoulos D. Preparation of unilamellar liposomes of intermediate size (0.1-0.2 mumol) by a combination of reverse phase evaporation and extrusion through polycarbonate membranes. Biochim Biophys Acta. 1990; 601 (3) 559-71
35 Boman NL, Mayer LD, Cullis PR. Optimization of the retention properties of vincristine in liposomal systems. Biochim Biophys Acta. 1993; 1152: 253-8
36 Harrigan PR, Wong KF, Redelmeier TE, Wheeler JJ, Cullis PR. Accumulation of doxorubicin and other lipophilic amines into large unilamellar vesicles in response to transmembrane pH gradients. Biochim Biophys Acta. 1993; 1149: 329-38
37 Uckun FM, Morar S, Qazi S. Vinorelbine-based salvage chemotherapy for therapy-refractory aggressive leukemias. Br J Haematol. 2006; 135 (4) 500-8
38 Uckun FM, Ozer Z, Qazi S, Tuel-Ahlgren L, Mao C. Polo-like kinase 1 (PLK1) as a molecular target to overcome Syk-mediated resistance of B-lineage acute lymphoblastic leukemia cells to oxidative stress. Br J Hematol. 2010; 148: 714-25 Epub 2009 Nov 12
39 Jansen B, Kersey JH, Jaszcz WB, Gunther R, Nguyen DP, Chelstrom LM et al Effective immunochemotherapy of human t(4;11) leukemia in mice with severe combined immunodeficiency (SCID) using B43 (anti-CD19)-pokeweed antiviral protein immunotoxin plus cyclophosphamide. Leukemia. 1993; 7 (2) 290-7
40 Nakayama J, Yamamoto M, Hayashi K, Satoh H, Bundo K, Kubo M et al BLNK suppresses pre-B cell leukemogenesis through inhibition of JAK3. Blood. 2009; 113: 1483-92