Targeted Liposomal Doxorubicin Delivery to Leukemia

Summary

Principal Investigator: Robert Lee
Abstract: Targeted drug delivery has the potential to improve the efficacy of a therapeutic agent while reducing its side effects. Folate receptor type-beta (FRB) is a cell surface marker selectively expressed by approximately70 percent of acute myeloid leukemias (AMLs). Increased FR-beta expression can be specifically induced by all trans retinoic acid (ATRA) in FR-beta-positive KG-1 and primary AML cells, without inducing cellular differentiation or growth inhibition. Folic acid is a high affinity ligand for FR-beta (Kd approximately 1 nM). Importantly, FR-beta expressed by normal hematopoietic cells has been found to be non-functional, whereas the receptor expressed by KG-1 AML cells and FR-beta-transfected CHO cells mediates selective uptake and cytotoxicity of folate-coated liposomes. Both uptake and cytotoxicity of folate coated liposome doxorubicin (f-L-Dox) in KG-1 cells were further increased by ATRA, which induced FR-beta upregulation. Moreover, f-L-DOX exhibited greater therapeutic efficacy than non-targeted liposomal DOX (LDox) in FR positive murine L1210JF and human KG-1 AML ascitic tumor models. Increased survival due to treatment with f-L-Dox was further enhanced by ATRA in the KG-1 engrafted mice. FR-targeted liposomal Dox delivery has also been shown to bypass the P-glycoprotein-mediated drug efflux in FR positive tumor cells exhibiting resistance to free Dox. The objective of this project is to evaluate f-L-Dox, combined with ATRA-induction of FR-beta upregulation, for the treatment of AML, a concept based on the selective targeting of the FR positive tumor cells. The specific aims are: 1. To evaluate the effect of ATRA on FR-beta expression by AML cells in vivo. 2. To evaluate liposome formulation and FR-beta level as factors in the binding and in vitro cytotoxicity of f-L-Dox to AML cells, as well as the pharmacokinetic properties of the liposomes; the effect of dietary folate will also be studied. 3. To evaluate the selective cytotoxicity of f-L-Dox, alone or combined with ATRA, against AML blast cells, clonogenic progenitor cells (CFUs), and primitive AML stem cells (SL-Ics); and 4. To evaluate the in vivo therapeutic efficacy of f-L-Dox alone or combined with ATRA in murine leukemia models. This project should lead to the development of a novel therapeutic strategy based on the combination of targeted drug delivery to tumor cells and upregulation of the cellular target for the treatment of chemotherapy refractory AMLs.
Funding Period: 2003-07-01 - 2010-04-30
more information: NIH RePORT

Top Publications

  1. ncbi Synthesis and evaluation of a novel lipophilic folate receptor targeting ligand
    Ying Liu
    Department of Pharmacy, Wuhan University, China
    Anticancer Res 31:1521-5. 2011
  2. pmc Receptor-targeted nanocarriers for therapeutic delivery to cancer
    Bo Yu
    Department of Chemical and Biomolecular Engineering, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA
    Mol Membr Biol 27:286-98. 2010
  3. pmc Targeting human clonogenic acute myelogenous leukemia cells via folate conjugated liposomes combined with receptor modulation by all-trans retinoic acid
    Hong Li
    Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
    Int J Pharm 402:57-63. 2010
  4. ncbi Targeted drug delivery via folate receptors
    Xiaobin Zhao
    Abbott Laboratories, Global Pharmaceutics and Life Cycle Technology, Abbott Park, IL 60064, USA
    Expert Opin Drug Deliv 5:309-19. 2008
  5. pmc Synthesis and evaluation of a novel ligand for folate-mediated targeting liposomes
    Guangya Xiang
    Pharmacy School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
    Int J Pharm 356:29-36. 2008
  6. pmc Depletion of peripheral macrophages and brain microglia increases brain tumor titers of oncolytic viruses
    Giulia Fulci
    Molecular Neuro oncology Laboratories, Neurosurgery Service, and Center for Molecular Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, USA
    Cancer Res 67:9398-406. 2007
  7. ncbi Role of formulation composition in folate receptor-targeted liposomal doxorubicin delivery to acute myelogenous leukemia cells
    Yanhui Lu
    Division of Pharmaceutics, College of Pharmacy, Department of Internal Medicine, The Ohio State University, 500 W 12th Avenue, Columbus, OH 43210, USA
    Mol Pharm 4:707-12. 2007
  8. ncbi Cholesterol as a bilayer anchor for PEGylation and targeting ligand in folate-receptor-targeted liposomes
    Xiaobin B Zhao
    Division of Pharmaceutics, NCI OSU Comprehensive Cancer Center, NSF Nanoscales Science and Engineering Center NSEC, College of Pharmacy, The Ohio State University, 542 LM Parks Hall, 500 W 12th Ave, Columbus, Ohio 43210, USA
    J Pharm Sci 96:2424-35. 2007
  9. ncbi Induction of folate receptor type beta in a bone marrow engraftment model of acute myelogenous leukemia
    B W Blaser
    Leukemia 21:2233-5. 2007
  10. ncbi Synergistic induction of folate receptor beta by all-trans retinoic acid and histone deacetylase inhibitors in acute myelogenous leukemia cells: mechanism and utility in enhancing selective growth inhibition by antifolates
    Huiling Qi
    Department of Biochemistry and Cancer Biology, Medical University of Ohio, Toledo, Ohio, USA
    Cancer Res 66:5875-82. 2006

Scientific Experts

  • Giulia Fulci
  • Guangya Xiang
  • Robert J Lee
  • Hong Li
  • Jun Wu
  • Guido Marcucci
  • Shih Jiuan Chiu
  • Yanhui Lu
  • Shujun Liu
  • Manohar Ratnam
  • Ying Liu
  • Bo Yu
  • Xiaobin Zhao
  • B W Blaser
  • Xiaobin B Zhao
  • Huiling Qi
  • Jun Liu
  • Xing Q Pan
  • Hong Ding
  • Songlin Xu
  • Jing Zhu
  • Bryant Yung
  • Lesheng Teng
  • Longzhu Piao
  • Weiming Xue
  • Heng Chiat Tai
  • L James Lee
  • H Qi
  • Xiaojuan Yang
  • Natarajan Muthusamy
  • A Shatnawi
  • Jianmei Wu
  • R J Lee
  • M Ratnam
  • Alice Lee
  • M Gonit
  • John C Byrd
  • M Guimond
  • Mefsin Gonit
  • Thomas J Rosol
  • John S Mattoon
  • Danilo Perrotti
  • Mamoru Yamaguchi
  • Xueliang Pan
  • Andrea L Levine
  • Qing Liu

Detail Information

Publications15

  1. ncbi Synthesis and evaluation of a novel lipophilic folate receptor targeting ligand
    Ying Liu
    Department of Pharmacy, Wuhan University, China
    Anticancer Res 31:1521-5. 2011
    ..These liposomes were then evaluated as carriers of the chemotherapy agent vincristine (VIN)...
  2. pmc Receptor-targeted nanocarriers for therapeutic delivery to cancer
    Bo Yu
    Department of Chemical and Biomolecular Engineering, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA
    Mol Membr Biol 27:286-98. 2010
    ..In this review, we mainly focus on recent advances on the development of targeted nanocarriers and will introduce novel concepts such as multi-targeting and multi-functional nanoparticles...
  3. pmc Targeting human clonogenic acute myelogenous leukemia cells via folate conjugated liposomes combined with receptor modulation by all-trans retinoic acid
    Hong Li
    Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
    Int J Pharm 402:57-63. 2010
    ..The results demonstrate that the efficiency of FR-mediated targeting of FT-L-DOX was preferentially enhanced by ATRA induced FR-β upregulation in AML clonogenic cells...
  4. ncbi Targeted drug delivery via folate receptors
    Xiaobin Zhao
    Abbott Laboratories, Global Pharmaceutics and Life Cycle Technology, Abbott Park, IL 60064, USA
    Expert Opin Drug Deliv 5:309-19. 2008
    ..FR-targeted agents have shown promising efficacy in preclinical models and significant potential for future clinical application in a wide range of diseases...
  5. pmc Synthesis and evaluation of a novel ligand for folate-mediated targeting liposomes
    Guangya Xiang
    Pharmacy School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
    Int J Pharm 356:29-36. 2008
    ..34 h) showed more rapid plasma clearance than L-DOX (t(1/2)=17.10h). These results suggest that F-PEG-CHEMS is effective as a novel ligand for the synthesis of FR-targeted liposomes...
  6. pmc Depletion of peripheral macrophages and brain microglia increases brain tumor titers of oncolytic viruses
    Giulia Fulci
    Molecular Neuro oncology Laboratories, Neurosurgery Service, and Center for Molecular Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, USA
    Cancer Res 67:9398-406. 2007
    ..In support of this new therapeutic paradigm, we observed intratumoral up-regulation of CD68+ and CD163+ cells following treatment with OV in a patient with glioblastoma...
  7. ncbi Role of formulation composition in folate receptor-targeted liposomal doxorubicin delivery to acute myelogenous leukemia cells
    Yanhui Lu
    Division of Pharmaceutics, College of Pharmacy, Department of Internal Medicine, The Ohio State University, 500 W 12th Avenue, Columbus, OH 43210, USA
    Mol Pharm 4:707-12. 2007
    ..In MV4-11 cells, the binding and cytotoxicity of FR-targeted liposomal DOX based on this formulation was also enhanced by ATRA-induced FR-beta upregulation...
  8. ncbi Cholesterol as a bilayer anchor for PEGylation and targeting ligand in folate-receptor-targeted liposomes
    Xiaobin B Zhao
    Division of Pharmaceutics, NCI OSU Comprehensive Cancer Center, NSF Nanoscales Science and Engineering Center NSEC, College of Pharmacy, The Ohio State University, 542 LM Parks Hall, 500 W 12th Ave, Columbus, Ohio 43210, USA
    J Pharm Sci 96:2424-35. 2007
    ..In addition, in vivo circulation of cholesterol-anchored liposomes was prolonged compared to non-PEGylated liposomes. These studies suggest that cholesterol is a viable bilayer anchor for synthesis of PEGylated and FR-targeted liposomes...
  9. ncbi Induction of folate receptor type beta in a bone marrow engraftment model of acute myelogenous leukemia
    B W Blaser
    Leukemia 21:2233-5. 2007
  10. ncbi Synergistic induction of folate receptor beta by all-trans retinoic acid and histone deacetylase inhibitors in acute myelogenous leukemia cells: mechanism and utility in enhancing selective growth inhibition by antifolates
    Huiling Qi
    Department of Biochemistry and Cancer Biology, Medical University of Ohio, Toledo, Ohio, USA
    Cancer Res 66:5875-82. 2006
    ..Therefore, the combination of ATRA and innocuous HDAC inhibitors may be expected to facilitate selective FR-beta-targeted therapies in AML...
  11. ncbi Nanoparticles as image enhancing agents for ultrasonography
    Jun Liu
    Biomedical Engineering Department, The Ohio State University, 270 Bevis Hall, 1080 Carmack Road, Columbus, OH 43210, USA
    Phys Med Biol 51:2179-89. 2006
    ..The mean grey scale of mouse livers also increased following particle administration. These results indicated that it is feasible to use solid nanoparticles as contrast enhancing agents for ultrasonic imaging...
  12. ncbi Efficient delivery of an antisense oligodeoxyribonucleotide formulated in folate receptor-targeted liposomes
    Shih Jiuan Chiu
    Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
    Anticancer Res 26:1049-56. 2006
    ..G3139, a phosphorothioate antisense ODN against human bcl2 mRNA, was evaluated in this study...
  13. ncbi A folate receptor-targeted liposomal formulation for paclitaxel
    Jun Wu
    Division of Pharmaceutics, College of Pharmacy, NCI Comprehensive Cancer Center, NSF Nanoscale Science and Engineering Center, The Ohio State University, 542 LM Parks Hall, 500 W 12th Ave, Columbus, OH 43210, United States
    Int J Pharm 316:148-53. 2006
    ..The FR-targeted paclitaxel formulation is potentially useful for treatment of FR+ tumors and warrants further investigation...
  14. ncbi Efficient delivery of a Bcl-2-specific antisense oligodeoxyribonucleotide (G3139) via transferrin receptor-targeted liposomes
    Shih Jiuan Chiu
    Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
    J Control Release 112:199-207. 2006
    ..8 microM to 0.18 microM. In conclusion, Tf-conjugated liposomes are effective delivery vehicles for G3139 antisense oligos in TfR positive K562 cells and warrant further investigation as an in vivo oligo delivery vehicle...
  15. ncbi In vivo antitumor activity of folate receptor-targeted liposomal daunorubicin in a murine leukemia model
    Xing Q Pan
    Sibyl Pharmaceutical Inc, Columbus, OH 43212, USA
    Anticancer Res 25:343-6. 2005
    ..In this study, FR-targeted liposomal daunorubicin was evaluated in an FR+ L1210JF murine ascites tumor model for therapeutic efficacy in vivo...