We recently discovered the pentapeptide mimic 1,4-Bis (9-0 dihydroquinidinyl) phthalazine / hydroquinidine 1,4-phathalazinediyl diether (C-61) as a tyrosine kinase inhibitor targeting the substrate-binding P-site of SYK as a novel drug candidate against B-lineage acute lymphoblastic leukemia (ALL), the most common form of childhood cancer. In the proposed translational multidisciplinary research project, we will prepare rationally- designed C-61 nanoparticle constructs for more effective delivery of C-61 to leukemia cells in an attempt to further improve its potency and broaden its therapeutic window. Throughout the project, the anti-leukemic activity of the generated C-61 nanoparticles will be evaluated using in vitro and in vivo assay platforms, including quantitative in vitro apoptosis assays, murine BCL-I leukemia model in immunocompetent mice, and SCID mouse xenograft models of human B-lineage ALL.
Under Specific Aim 1, we will develop potent and stable liposomal 1st generation nanoparticle constructs of C-61 by optimizing the intemal core environment and inner monolayer of the large unilamellar liposomal vesicles for maximized C-61 entrapment.
Under Specific Aim 2, we will develop potent 2nd generation liposomal nanoparticle constructs of C-61 with improved pharmacodynamic features by modifying the outer monolayer of the large unilamellar liposomal vesicles with poly(ethylene glycol)-modified lipids.
Under Specific Aim 3, we will develop CD19- directed 3rd generation nanoparticle constructs of C-61 by incorporating anti-CD19 scFv covalently attached to PEGylated phospholipids in the outer layer of the lead 2nd generation nanoparticles.
Under Specific Aim 4, we will study the anti-leukemic activity of the lead CD19-specific 3rd generation C-61 nanoparticle constructs in side by side comparison to standard chemotherapy drugs.
Under Specific Aim 5, we will study the effects of standard anti-leukemia drugs on toxicity, pharmacokinetics, and efficacy of the lead CD19-specific 3rd generation C-61 nanoparticle constructs. The development of cell-type specific nanoparticles targeting SYK-dependent anti-apoptotic survival mechanism in CD19-f- leukemic cells will be a significant step forward to overcome chemotherapy resistance in childhood B-lineage ALL. The successful completion of this research project may provide the foundation for a more effective and potentially paradigm-shifting treatment strategy for B-lineage ALL, the most common form of childhood cancer. New nanotechnology discoveries that will result from our research are anticipated to significantly contribute to the mission of the NCI Alliance for Nanotechnology in Cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA151837-04
Application #
8520251
Study Section
Special Emphasis Panel (ZCA1-SRLB-X (M1))
Program Officer
Grodzinski, Piotr
Project Start
2010-09-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$416,542
Indirect Cost
$156,203
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Uckun, Fatih M; Qazi, Sanjive; Ma, Hong et al. (2015) CD22ΔE12 as a molecular target for corrective repair using RNA trans-splicing: anti-leukemic activity of a rationally designed RNA trans-splicing molecule. Integr Biol (Camb) 7:237-49
Uckun, Fatih M; Myers, Dorothea E; Cheng, Jianjun et al. (2015) Liposomal Nanoparticles of a Spleen Tyrosine Kinase P-Site Inhibitor Amplify the Potency of Low Dose Total Body Irradiation Against Aggressive B-Precursor Leukemia and Yield Superior Survival Outcomes in Mice. EBioMedicine 2:554-62
Uckun, Fatih M; Myers, Dorothea E; Ma, Hong et al. (2015) Low Dose Total Body Irradiation Combined With Recombinant CD19-Ligand × Soluble TRAIL Fusion Protein is Highly Effective Against Radiation-Resistant B-Precursor Acute Lymphoblastic Leukemia in Mice. EBioMedicine 2:306-316
Uckun, Fatih M; Mitchell, Lloyd G; Qazi, Sanjive et al. (2015) Development of Polypeptide-based Nanoparticles for Non-viral Delivery of CD22 RNA Trans-splicing Molecule as a New Precision Medicine Candidate Against B-lineage ALL. EBioMedicine 2:649-59
Cai, Kaimin; He, Xi; Song, Ziyuan et al. (2015) Dimeric drug polymeric nanoparticles with exceptionally high drug loading and quantitative loading efficiency. J Am Chem Soc 137:3458-61
Uckun, Fatih M; Myers, Dorothea E; Qazi, Sanjive et al. (2015) Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia. J Clin Invest 125:1006-18
Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M et al. (2015) IGF1 Receptor Targeted Theranostic Nanoparticles for Targeted and Image-Guided Therapy of Pancreatic Cancer. ACS Nano 9:7976-91
Uckun, Fatih M; Qazi, Sanjive; Cheng, Jianjun (2015) Targeting leukemic stem cells with multifunctional bioactive polypeptide nanoparticles. Future Oncol 11:1149-52
Zheng, Nan; Song, Ziyuan; Liu, Yang et al. (2015) Redox-responsive, reversibly-crosslinked thiolated cationic helical polypeptides for efficient siRNA encapsulation and delivery. J Control Release 205:231-9
Uckun, Fatih M; Ma, Hong; Cheng, Jianjun et al. (2015) CD22ΔE12 as a molecular target for RNAi therapy. Br J Haematol 169:401-14

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