Acute myeloid leukemia (AML) is the most common type of leukemia in adults and the second most common in children. While progress has been made in the treatment of several types of leukemia, improvement in survival rate for both adult and pediatric AML has not occurred. Development of targeted nanocarriers loaded with molecularly targeted therapeutics represents a novel strategy for improving treatment of AML. GTI-2040, an antisense oligodeoxyribonucleotide (ODN) against the R2 subunit of ribonucleotide reductase (RNR), is a promising agent for overcoming chemoresistance in AML. Enhancement in clinical efficacy of GTI-2040 and reduction in side effects can potentially be achieved through targeted delivery of GTI-2040 using multifunctional nanovehicles consisting of immunoconjugates of lipopolyplexes (ILPs). The objective of this project, therefore, is to design, synthesize, and evaluate anti-CD33 mAb conjugated lipopolyplexes (anti- CD33-ILPs) for down regulation of R2 and for AML therapy. CD33 is a myeloid lineage marker frequently expressed on AML blast cells. ILPs will be synthesized by both conventional bulk-mixing (BM) and novel micro-/nanofluidic (MF/NF) methods, and conjugated to anti-CD33 via a protein a linker. This will be followed by in vitro evaluation for R2 down regulation activity and in vivo evaluation for pharmacokinetic (PK) properties, pharmacodynamic (PD) endpoints and therapeutic activities.
The Specific Aims of this application include to 1) design and optimize anti-CD33-ILP formulation for targeted delivery of GTI-2040 to AML cells;2) develop micro-/nanofluidic (MF/NF) methods for synthesis of anti-CD33-GTI-2040-ILPs;3) evaluate in vitro the biological activities of anti-CD33-GTI- 2040-ILPs using AML cell lines and patients'primary malignant blasts;4) evaluate pharmacokinetic (PK) properties and pharmacodynamic (PD) endpoints and therapeutic activities of anti-CD33-GTI- 2040-ILPs in preclinical murine models of AML. This project will be carried out via an interdisciplinary approach by investigators with expertise in drug delivery (RLee), PK/PD (Chan), nanoengineering (LJLee, Guan), biochemistry and molecular biology (Jin), and experimental therapeutics (Marcucci, Byrd, Muthusamy). Success of this project may lead to not only development of a novel clinical agent for AML, but also technological advances in nanocarrier design and synthesis with broad applications in oligonucleotide therapeutics.

Public Health Relevance

We seek to develop novel nanotechnology to create multifunctional immunonanoparticles for the delivery antisense oligodeoxyribonucleotides to treat acute myeloid leukemia (AML). Success of this project may lead to not only development of a novel clinical agent for AML, but also technological advances in nanocarrier design and synthesis with broad applications in oligonucleotide therapeutics.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-NANO-M (01))
Program Officer
Yovandich, Jason L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Other Health Professions
Schools of Pharmacy
United States
Zip Code
Mao, Yicheng; Wang, Jiang; Zhao, Yuan et al. (2014) A novel liposomal formulation of FTY720 (fingolimod) for promising enhanced targeted delivery. Nanomedicine 10:393-400
Huang, Xiaomeng; Schwind, Sebastian; Yu, Bo et al. (2013) Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles: a novel therapeutic strategy in acute myeloid leukemia. Clin Cancer Res 19:2355-67
Yu, Bo; Mao, Yicheng; Bai, Li-Yuan et al. (2013) Targeted nanoparticle delivery overcomes off-target immunostimulatory effects of oligonucleotides and improves therapeutic efficacy in chronic lymphocytic leukemia. Blood 121:136-47
Xie, Jing; Teng, Lesheng; Yang, Zhaogang et al. (2013) A polyethylenimine-linoleic acid conjugate for antisense oligonucleotide delivery. Biomed Res Int 2013:710502
Zhou, Chenguang; Zhang, Yue; Yu, Bo et al. (2013) Comparative cellular pharmacokinetics and pharmacodynamics of siRNA delivery by SPANosomes and by cationic liposomes. Nanomedicine 9:504-13
Piao, Longzhu; Li, Hong; Teng, Lesheng et al. (2013) Human serum albumin-coated lipid nanoparticles for delivery of siRNA to breast cancer. Nanomedicine 9:122-9
Zhou, Chenguang; Mao, Yicheng; Sugimoto, Yasuro et al. (2012) SPANosomes as delivery vehicles for small interfering RNA (siRNA). Mol Pharm 9:201-10
Zhang, Yue; Zhou, Chenguang; Kwak, Kwang Joo et al. (2012) Efficient siRNA delivery using a polyamidoamine dendrimer with a modified pentaerythritol core. Pharm Res 29:1627-36
Yu, Bo; Zhu, Jing; Xue, Weiming et al. (2011) Microfluidic assembly of lipid-based oligonucleotide nanoparticles. Anticancer Res 31:771-6
Xu, Songlin; Liu, Ying; Tai, Heng-Chiat et al. (2011) Synthesis of transferrin (Tf) conjugated liposomes via Staudinger ligation. Int J Pharm 404:205-10

Showing the most recent 10 out of 20 publications